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Primary lung adenocarcinomas are rare in pediatric patients, and even rarer in patients without precedent malignancy or congenital malformation. Here we present the first reported case of primary lung cribriform adenocarcinoma with squamoid morules in a previously healthy adolescent female. Molecular testing identified CTNNB1 mutation in the tumor and excluded other common mutations in lung adenocarcinoma. Our case suggests molecular alterations to the same signaling pathway can lead to similar histomorphology regardless of the tissue of origin.

Context.—Recent advances in comprehensive genomic profiling by next-generation sequencing have uncovered the genomic alterations at the molecular level for many types of tumors; as such, numerous small specific molecules that target these alterations have been developed and widely used in the management of these cancers.Objective.—To provide a concise molecular genomic update in solid, bone and soft tissue tumors, hematopoietic as well as lymphoid malignancies; discuss its clinical applications; and familiarize practicing pathologists with the emerging cancer biomarkers and their diagnostic utilities.Data Sources.—This review is based on the National Comprehensive Cancer Network guidelines and peer-reviewed English literature.Conclusions.—Tumor-specific biomarkers and molecular/genomic alterations, including pan-cancer markers, have been significantly expanded in the past decade thanks to large-scale high-throughput technologies and will continue to emerge in the future. These biomarkers can be of great value in diagnosis, prognosis, and/or targeted therapy/treatment. Familiarization with these emerging and ever-changing tumor biomarkers will undoubtedly aid pathologists in making accurate and state-of-the-art diagnoses and enable them to be more actively involved in the care of cancer patients.

Introduction/Objective Beta catenin plays an important role in cancer tumorigenesis and have been found to be associated with metastasis in a variety of tumors. Analyzing TCGA data, we found that 30% of endometrial endometrioid carcinoma cases have beta-catenin mutations. We hypothesize that beta-catenin mutation may be associated with metastasis of endometrial endometrioid carcinoma. ER and PR expression was also compared to determine any changes after metastasis. Methods Retrospective institutional review of all endometrial endometrioid carcinoma (192 cases) between 2011 to 2018 was performed, including 149 cases of FIGO grade I, 38 cases of FIGO grade II and 5 cases of FIGO grade III. 19 cases with paired primary and metastatic specimen were identified. Immunohistochemistry staining (IHC) was carried out for ER, PR and beta-catenin. Results Median patient age was 56 years. The most common metastatic site was vagina, accounting for 68% of metastasis (14/19), followed by bladder (3/19), lung (2/19) and rectum (1/19). The primary and metastatic carcinoma of all 19 cases exhibit very similar morphology. All of those cases were positive and concordant for ER and PR in primary and metastatic endometrioid carcinoma. On the other hand, nuclear beta-catenin staining caused by mutation was positive in 5 metastatic carcinoma but not in primary carcinoma. Conclusion IHC expression of ER and PR remains unchanged between primary and metastatic carcinoma, demonstrating the reliability of ER and PR to confirm the origin of metastatic carcinoma. 26% of the metastatic carcinoma (5/19) exhibit nuclear beta-catenin staining but not in primary carcinoma, suggesting the possible role of beta-catenin in metastasis of endometrial endometrioid carcinoma.

We are presenting an evaluation of Allele Specific Multiplex Sequencing (ASMS) to detect two EGFR somatic mutations (L858R, T790M). Late stage lung cancer samples were tested for both EGFR mutations and were compared to either pyrosequencing or TruSeq. The analytical lower limit of detection (LLOD) for the ASMS-L858R assay was found to be 36 copies, and 72 copies for the ASMS-T790M assay. The forty-one FFPE samples that were tested for T790M showed 100% concordance with the respective comparative method. The forty-five FFPE samples tested previously by Truseq for L858R showed 100% concordance with ASMS. Out of the twenty L858R samples previously tested by pyrosequencing, there was 95% concordance with ASMS. Additionally, twenty-one normal blood samples were tested by ASMS were found to be negative for L858R and T790M. In conclusion, the detection of L858R and T790M by ASMS are in acceptable concordance with both pyrosequencing and TruSeq in detecting EGFR mutations from late stage lung cancer. Further, ASMS was able to detect EGFR (L858R) with 10 picograms (3 copies gDNA) of FFPE extracted DNA, and hence could be used to detect mutations from samples carrying low copy numbers.

The diagnosis and management of urothelial carcinoma is the collaboration efforts of a multidisciplinary team including urologist, oncologist, pathologist, radiologist, and other support teams. Urine cytology and other ancillary tests are important components of these processes. Here, we describe technical aspect of the test and illustrate the clinical significance and limitation of those tests.

Summary: The upper urinary tract includes renal pelvis and ureter which are muscular conduits lined by urothelium. The upper urinary tract may be involved by distinct entities which have different prognosis and diverse treatment options. Here, we focus on noninvasive urothelial carcinoma: low- and high-grade papillary UC, urothelial carcinoma in situ and noninvasive urothelial carcinoma with glandular differentiation; upper urinary tract urothelial carcinoma with intratubular spread; invasive urothelial carcinoma: different differentiation components and different variants; other non-urothelial malignancy: inflammatory myofibroblastic tumor, lymphoma, and rhabdoid tumor; Non-neoplastic tumor-like conditions: ureteropelvic junction (UPJ) obstruction and immunoglobulin G4-related kidney disease

Objectives The most common genetic alterations in prostate cancer are fusions of ERG and other members of the E26 transformation-specific (ETS) family of transcription factors, including ETV1, ETV4, and FLI1. Analyzing TCGA data, we found that similar to ERG fusion, FLI1 fusion-associated FLI1 mRNA level increases. ERG IHC stain has been a surrogate test for ERG fusion. Therefore, we hypothesize that FLI IHC stain could also be used to detect FLI1 fusion in prostate cancer. Methods In total, 111 primary prostate adenocarcinoma (>10% by volume) cases from our institute were selected for tissue microarray (TMA) construction. The regular full section slides and TMA slides were subject to IHC stain of ERG and FLI1 (Santa Cruz, SC-113). The criteria for positive FLI1 are (1) nuclear staining; (2) only in tumor cells, not in nontumor cells; and (3) FLI1-positive cells should be negative for ERG IHC staining. Results For prostate TMA slides, ~50% of cases were positive for ERG; ~30% of cases were weakly positive for FLI1. However, all of the FLI1 weakly positive cases were positive for ERG as well possibly due to cross-reactivity between ERG and FLI1, which was demonstrated in other studies. Conclusion Overall, we conclude that the cross-reactivity between FL1 and ERG precluded the detection of FLI1 fusion in prostatic adenocarcinoma under current conditions. We are in the process of selecting some cases to detect FLI1 fusion by next-generation sequencing (NGS) and FISH.

Summary Micropapillary urothelial carcinoma (MPUC) is an uncommon variant of urothelial carcinoma (UC) with an aggressive clinical course. There have been limited studies on the UC markers GATA-binding protein 3 (GATA3), p63, and p40 in MPUC. Our study investigated the immunoreactivity of these 3 markers in MPUC compared with conventional UC of different grades and stages. Immunohistochemistry was performed on 62 cases of high-grade urothelial carcinoma (HGUC), 16 low-grade urothelial carcinoma (LGUC), and 20 MPUC. p63 expression was strong and diffuse in all LGUC, significantly decreased in high stage and HGUC, and virtually absent in MPUC. p40 expression was decreased in HGUC and markedly decreased in MPUC relative to LGUC. These results suggest that loss of p63 expression in a UC appears to be associated with adverse features—including cases with micropapillary differentiation. Decreased GATA3 expression was seen frequently in high-grade and high–pathologic stage (≥pT2) tumors but was retained in MPUC cases. The findings of retained GATA3 expression in MPUC, which often shows a loss of expression of other urothelial markers such as p63, may be helpful for determining the origin of micropapillary carcinoma of unknown primary. Compared with the traditional markers p63 and p40, GATA3 is the most sensitive marker of conventional UC and MPUC.

Xp11 translocation cancers include Xp11 translocation renal cell carcinoma (RCC), Xp11 translocation perivascular epithelioid cell tumor (PEComa), and melanotic Xp11 translocation renal cancer. In Xp11 translocation cancers, oncogenic activation of TFE3 is driven by the fusion of TFE3 with a number of different gene partners; however, the impact of individual fusion variant on specific clinicopathologic features of Xp11 translocation cancers has not been well defined. In this study, we analyze 60 Xp11 translocation cancers by fluorescence in situ hybridization using custom bacterial artificial chromosome probes to establish their TFE3 fusion gene partner. In 5 cases RNA sequencing was also used to further characterize the fusion transcripts. The 60 Xp11 translocation cancers included 47 Xp11 translocation RCC, 8 Xp11 translocation PEComas, and 5 melanotic Xp11 translocation renal cancers. A fusion partner was identified in 53/60 (88%) cases, including 18 SFPQ (PSF), 16 PRCC, 12 ASPSCR1 (ASPL), 6 NONO, and 1 DVL2. We provide the first morphologic description of the NONO-TFE3 RCC, which frequently demonstrates subnuclear vacuoles leading to distinctive suprabasal nuclear palisading. Similar subnuclear vacuolization was also characteristic of SFPQ-TFE3 RCC, creating overlapping features with clear cell papillary RCC. We also describe the first RCC with a DVL2-TFE3 gene fusion, in addition to an extrarenal pigmented PEComa with a NONO-TFE3 gene fusion. Furthermore, among neoplasms with the SFPQ-TFE3, NONO-TFE3, DVL2-TFE3, and ASPL-TFE3 gene fusions, the RCCs are almost always PAX8 positive, cathepsin K negative by immunohistochemistry, whereas the mesenchymal counterparts (Xp11 translocation PEComas, melanotic Xp11 translocation renal cancers, and alveolar soft part sarcoma) are PAX8 negative, cathepsin K positive. These findings support the concept that despite an identical gene fusion, the RCCs are distinct from the corresponding mesenchymal neoplasms, perhaps due to the cellular context in which the translocation occurs. We corroborate prior data showing that the PRCC-TFE3 RCCs are the only known Xp11 translocation RCC molecular subtype that are consistently cathepsin K positive. In summary, our data expand further the clinicopathologic features of cancers with specific TFE3 gene fusions and should allow for more meaningful clinicopathologic associations to be drawn.

Serous cystic neoplasms of the pancreas are generally considered benign lesions. Malignant counterparts have been occasionally described, and the diagnosis of malignancy is based solely on the presence of synchronous or metachronous metastases to the lymph nodes or liver, direct tumor invasion into adjacent organs, or vascular invasion. However, these malignant serous cystic tumors are lined by benign-appearing glycogen-rich cuboidal cells, which have been morphologically indistinguishable from benign microcystic serous cystadenoma in all the cases reported so far. We report a unique case of microcystic serous cystadenoma giving rise to carcinoma with distinctive histologic features including signet ring-like cells and solid nests. We believe that this case represents the first case of a cytologically malignant neoplasm arising from a benign serous cystadenoma (carcinoma ex microcystic serous cystadenoma).

e23162 Background: Cancer is characterized by a variety of heterogeneous genomic and transcriptomic patterns involving highly complex signaling biological pathways. The problem of identification of the factors driving tumor progression becomes even more challenging due to intricate interaction mechanisms between these pathways. Using novel approaches in machine learning, we demonstrate the ability to quantitatively describe characteristic signaling patterns in cancer based on transcriptomic data Methods: We used RNASeq data from 20531 genes in 174 samples of GBM from The Cancer Genome Atlas including 5 major histological subtypes – Classical, G-CIMP, Mesenchymal, Neural, and Proneural, anddeveloped predictive computational framework for molecular subtype differentiation from normal tissue relying on variance based gene selection and random forest algorithm. Results: We obtained a few key findings – (1) genes from cell signaling pathways alone differentiate each subtype from normal tissue with 100% accuracy; (2) predictive genes are specific to each subtype; (3) inferred pathway interactions are also specific to each subtype; (4) typically most of the predictive genes involved in signaling are down-regulated in tumor compared to normal tissue (MAPT, PRKCG, PDE2A, RYR2, ATP1B1, GRN1, GNAO1), however, in each subtype we observed a smaller subset of predictive genes which are highly up-regulated in tumor (ID3, FN1, JAG1, F2R, COL4A1, EDAR, CDK2, CDK4, MFNG, BIRC5, CCNB2). We detected and quantitatively evaluated characteristic signaling pathway involvement across the GBM subtypes for MAPK, RAP1, RAS, Notch, PI3K-Akt, mTOR, FoxO, Jak-STAT, Wnt, cAMP, and Calcium Signaling, providing a unique approximation for each subtype signaling profile. Conclusions: In this study, we identified gene expression profiles and associated signaling pathways for distinguishing GBM Multiforme subtypes from normal tissue. We observed and described a dense complex picture of interacting signaling pathways. The detected interactions may provide clinical insights and could be used to identify potential therapeutic targets, however, more research is needed to confirm this.

Nested variant of urothelial carcinoma (NVUC) is an uncommon variant with minimally atypical cytology, which may overlap with benign urothelial lesions such as von Brunn nests, cystitis cystica, cystitis glandularis, and nephrogenic adenoma. Because of the tumor's deceptively bland appearance, these cancers can potentially be misdiagnosed as benign lesions, leading in some cases to a significant delay in correct diagnosis and appropriate treatment. Prior studies suggest that Ki67 and p53 are useful markers in distinguishing NVUC from benign lesions. However, the overlap in the rates of immunoreactivity has prevented pathologists from using these markers as reliable adjunct markers in differentiating NVUC from mimickers. In addition, large nested variant urothelial carcinoma (LNVUC), a relatively new entity, shares features of both the NVUC and papillary urothelial carcinomas with an inverted growth pattern. They also mimic benign lesions, such as proliferation of von Brunn nests and inverted urothelial papilloma. With the recent demonstration of a strong association of TERT promoter mutations and urothelial carcinoma, we hypothesized that TERT promoter mutations would be a useful marker to distinguish NVUC and LNVUC from other benign urothelial lesions. We have therefore sequenced the TERT promoter region of 20 cases of NVUC, 10 cases of LNVUC, 5 cases of von Brunn nests, 3 cases of cystitis cystica, 3 cases of cystitis glandularis, and 3 cases of nephrogenic adenoma. We found that 17 of 20 cases of NVUC and 8 of 10 cases of LNVUC had TERT promoter mutation: C228T; no mutation was found in any of the benign mimickers (0/14). This result strongly suggests that TERT promoter mutation is a useful adjunct biomarker to distinguish NVUC and LNVUC from benign mimickers.

Xp11 translocation renal cell carcinomas harbor chromosome translocations involving the Xp11 breakpoint, resulting in gene fusions involving the TFE3 gene. The most common subtypes are the ASPSCR1-TFE3 renal cell carcinomas resulting from t(X;17)(p11;q25) translocation, and the PRCC-TFE3 renal cell carcinomas, resulting from t(X;1)(p11;q21) translocation. A formal clinical comparison of these two subtypes of Xp11 translocation renal cell carcinomas has not been performed. We report one new genetically confirmed Xp11 translocation renal cell carcinoma of each type. We also reviewed the literature for all published cases of ASPSCR1-TFE3 and PRCC-TFE3 renal cell carcinomas and contacted all corresponding authors to obtain or update the published follow-up information. Study of two new, unpublished cases, and review of the literature revealed that 8/8 patients who presented with distant metastasis had ASPSCR1-TFE3 renal cell carcinomas, and all but one of these patients either died of disease or had progressive disease. Regional lymph nodes were involved by metastasis in 24 of the 32 ASPSCR1-TFE3 cases in which nodes were resected, compared with 5 of 14 PRCC-TFE3 cases (P=0.02).; however, 11 of 13 evaluable patients with ASPSCR1-TFE3 renal cell carcinomas who presented with N1M0 disease remained disease free. Two PRCC-TFE3 renal cell carcinomas recurred late (at 20 and 30 years, respectively). In multivariate analysis, only older age or advanced stage at presentation (not fusion subtype) predicted death. In conclusion, ASPSCR1-TFE3 renal cell carcinomas are more likely to present at advanced stage (particularly node-positive disease) than are PRCC-TFE3 renal cell carcinomas. Although systemic metastases portend a grim prognosis, regional lymph node involvement does not, at least in short-term follow-up. The tendency for PRCC-TFE3 renal cell carcinomas to recur late warrants long-term follow-up.

Context.—Glandular lesions of the urinary bladder include a broad spectrum of entities ranging from completely benign glandular lesions to primary and secondary malignancies. Common benign bladder lesions that exhibit glandular differentiation include cystitis cystica, cystitis glandularis, von Brunn nests, nephrogenic adenoma, intestinal metaplasia, urachal remnant, endometriosis, and prostatic-type polyp. The World Health Organization defines primary adenocarcinoma of the bladder as an epithelial malignancy with pure glandular differentiation without evidence of typical urothelial carcinoma. Malignant lesions that should be included in the differential diagnosis of a primary adenocarcinoma of the bladder include noninvasive and invasive urothelial carcinoma with glandular differentiation and secondary malignancies involving the bladder by direct extension or metastasis. The recognition and distinction of these different entities may be a challenge for pathologists, but they are of great clinical importance. Objective.—To review features of primary bladder adenocarcinoma as well as those entities that need to be differentiated from primary bladder adenocarcinoma, with emphasis on clinical findings, pathologic characteristics, and immunoprofiles. Data Sources.—Selected original articles published in the PubMed service of the US National Library of Medicine. Conclusions.—The accurate diagnosis of adenocarcinoma of the urinary bladder is important and challenging. It has to prompt an extensive clinical workup to rule out other glandular lesions in the urinary bladder, especially the possibility of secondary involvement of the bladder by an adenocarcinoma from a different site.

Small cell carcinoma (SmCC) is a distinct clinicopathological entity first described in the lung. It represents approximately 15% of all bronchogenic carcinoma. Extrapulmonary small cell carcinoma (EPSmCC) morphologically indistinguishable from small cell lung cancer (SCLC) was first reported in 1930. Since its first description, EPSmCC has been reported in virtually all anatomical sites, including: gynecologic organs (ovary and cervix); genitourinary organs (urinary bladder and prostate); the gastrointestinal tract (esophagus); skin (Merkel cell carcinoma) and head and neck region. Regardless of the anatomic sites, all SmCCs have similar, if not identical, histo-pathology features and immunohistochemical profile. SmCC is one of the most aggressive malignancies. The molecular mechanisms underlying its development and progression remain poorly understood. Herein, we reviewed the literature in SmCC in respect to its site of occurrence, clinical features, immunohistochemical characteristics. SmCCs have heterogeneous molecular mutations. Dinstinct genetic alterations associated with SmCC from different body sites were reviewed. Some genetic alterations such as RB1, TP53 are commonly seen in different origins of SmCC. Other genes with site specificity were also summarized, such as bladder SmCC with TERT promoter mutations; prostate SmCC with ERG translocations; ovarian SmCC with SMARCA4 mutations; Merkel cell carcinoma (skin) and cervical SmCC with Merkel cell polyomavirus (MCV or MCPyV) and human papillomavirus (HPV). Further studies are needed to employ a genetically oriented approach for the diagnosis and therapy of SmCC.