surgpathcriteria.stanford.edu/...undifferentiated-carcinoma/printable.html Francisco LM, Salinas VH, Brown KE et al. Krukenberg tumors are often (over 80%) found in both ovaries, consistent with its metastatic nature. 4th edn, IARC: Lyon, France, 2010, pp 138. Objective: To investigate the expression of cadherin-17 and SATB-2 and other markers in medullary carcinomas of the large … Tumor B7-H1 and B7-H3 expression in squamous cell carcinoma of the lung. Google Scholar. Poorly differentiated colonic adenocarcinoma, medullary type: clinical, phenotypic, and molecular characteristics. GBP5 promotes NLRP3 inflammasome assembly and immunity in mammals. Rare subtype of colorectal carcinoma. Nature 2014;515:563–567. Microsatellite instability as a marker of prognosis and response to therapy: a meta-analysis of colorectal cancer survival data. Microarray and the Cancer Genome Atlas data analysis identified significant upregulation of several immunoregulatory genes induced by IFNγ including IDO-1, WARS (tRNA(trp)), GBP1, GBP4, GBP5, PDCD1 (PD-1), and CD274 (PD-L1) in medullary carcinoma compared with other microsatellite unstable and microsatellite stable tumors. Zhai L, Spranger S, Binder DC et al. They constitute less than 1% of all colorectal adenocarcinomas. Within medullary carcinomas alone, several markers were positively correlated as well. In brief, RNA was isolated and purified using the RNeasy formalin-fixed paraffin-embedded kit (Qiagen, Valencia, CA, USA). Carcinomas with neuroendocrine differentiation. Eur J Cancer 2010;46:2788–2798. This page was last edited on 24 May 2020, at 20:24. It usually has a favorable prognosis despite its poorly differentiated or undifferentiated histology. Biostatistics 2003;4:249–264. Howitt BE, Shukla SA, Sholl LM et al. Front Oncol 2013;3:326. PubMed  Winn B, Tavares R, Fanion J, Noble L, Gao J, Sabo E, Resnick MB (March 2009). JAMA Oncol 2015;1:1319–1323. J Clin Oncol 2005;23:609–618. It usually has a favorable prognosis despite its poorly differentiated or undifferentiated histology. Inhibition of indoleamine 2,3-dioxygenase 1 expression alters immune response in colon tumor microenvironment in mice. Prognostic significance dependent on study. Medullary carcinoma of the colon is a rare variant of colorectal cancer claimed to have a more favorable prognosis than conventional adenocarcinomas. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Pearson’s correlation coefficient analysis was used to determine the association among lymphocyte counts. Total RNA (containing both mRNA and microRNA) was extracted using the RecoverAll Total Nucleic Acid Extraction Kit for formalin-fixed paraffin-embedded tissues, with DNAse incubation (Life Technologies). PD-L1 (CD274) expression was increased 1.4-fold in medullary carcinoma, although not statistically significant (P=0.08, q=0.1). Robert V Rouse MD rouse@stanford.edu. Tougeron D, Fauquembergue E, Rouquette A et al. Significant differences were observed between PD-1+, PD-L1+, CD8+, and Foxp3+ tumor-infiltrating lymphocytes between medullary carcinoma and poorly differentiated carcinomas. The prognostic significance of tryptophanyl-tRNA synthetase in colorectal cancer. Care was taken to capture areas with similar proportions of cancer cells. all required: (1) lesion has well-circumscribed border, (2) syncytial growth pattern, (3) lymphocytic infiltrate, (4) high nuclear grade (as per Nottingham grading system), (5) no tubule formation. Normalized RNA-seq data for colorectal tumors were downloaded from Firebrowse in September 2015.26 The GAII and HiSeq data sets were kept separate. Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity. Pathologic examination of biopsy, polypectomy and resection specimens is crucial to appropriate patient managemnt, prognosis assessment and family counseling. Clinical data were downloaded from the Cancer Genome Atlas data portal (https://tcga.data.nci.gov/tcga/dataAccessMatrix.htm, download in September 2015). Adv Exp Med Biol 2003;527:183–190. GBP5 overexpression was present in >50% of stromal cells (score 2) in ~48% (50/104) of medullary carcinoma and 36% (8/22) of microsatellite unstable well-differentiated, compared with 15% (7/47) of poorly differentiated colorectal carcinomas and no cases of microsatellite stable well differentiated (P<0.0001). Medullary carcinoma of the colon is a unique histologic subtype of microsatellite unstable colorectal carcinoma but little is known regarding its tumor-immunoregulatory microenvironment. Wick MR, Vitsky JL, Ritter JH, Swanson PE, Mills SE. Br J Cancer 2012;106:141–147. In the United States, it was the second leading cause of death from cancer in 2007 [1]. Foxp3-stained lymphocytic nuclei. Molecular subtypes (microsatellite unstable–high, microsatellite unstable–low, and microsatellite stable) were acquired in the Cancer Genome Atlas clinical data. Liu X, Shin N, Koblish HK et al. . Tumor stromal staining for IDO-1 and GBP5 were similar for medullary carcinoma and microsatellite unstable well differentiated. They are usually positive for CK7, S-100 protein, and P53. Broad Institute TCGA Genome Data Analysis Center (2015): Analysis-ready standardized TCGA data from Broad GDAC Firehose stddata__2015_06_01 run. Characterization of an adaptive immune response in microsatellite-instable colorectal cancer. Regulatory T cells, tumour immunity and immunotherapy. Am J Clin Pathol 2005;123:56–65. There were no appreciable differences in tRNA(trp) staining of stroma across all four categories of tumor. PD-1+ intraepithelial lymphocytes correlated with the presence of PD-L1+ tumor-infiltrating lymphocytes (P=0.0058), Foxp3+ intraepithelial lymphocytes (P=0.0079), and Foxp3+ stromal lymphocytes (P=0.025). Ahmadzadeh M, Johnson LA, Heemskerk B et al. Clin Cancer Res 2015;21:5427–5433. Medullary colorectal carcinoma revisited: a clinical and pathological study of 102 cases. Conclusion We conclude that CDH17 compared with CK20 and CDX2 is a highly sensitive and a specific marker for colon and stomach adenocarcinoma Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Figure 6 Medullary carcinoma showing a pushing border at the tumor edge (original magnification ×40) Carcinogenesis 2013;34:153–162. The greatest differences were seen with IDO-1 epithelial expression (64% of medullary carcinoma vs 19% of poorly differentiated tumors), tRNA(trp) epithelial expression (81% of medullary carcinoma vs 19% of poorly differentiated tumors), CD8+, and PD-L1+ tumor-infiltrating lymphocytes. The blocks were cored at a diameter of 1 mm and transferred to a masterblock using the Beecher Tissue Microarrayer (Beecher Instruments, Silver Spring, MD, USA). Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Statistical significance for genomewide studies. Medullary carcinoma of the colon is a unique histologic subtype of microsatellite unstable colorectal carcinoma but little is known regarding its tumor-immunoregulatory microenvironment. Nayak A, Hao Z, Sadek R et al. Programmed death ligand-1 expression in non-small cell lung cancer. PD-L1 was evaluated within the epithelium and within intratumoral-infiltrating lymphocytes. Blood 2010;115:3520–3530. EMBO J 1992;11:3887–3895. Most medullary carcinomas presented at a lower stage comparable to microsatellite unstable well-differentiated and microsatellite stable well-differentiated with most poorly differentiated colorectal carcinomas presenting at higher stage (P=0.0013). Clinicopathological significance of indoleamine 2,3-dioxygenase 1 expression in colorectal cancer. Subramanian A, Tamayo P, Mootha VK et al. A Phase I study of NLG919 for adult patients with recurrent advanced solid tumors. These pathways are more prevalent in medullary carcinoma compared with other microsatellite unstable colorectal carcinomas. The χ2-analysis was used to assess the immunohistochemical staining scores. The significance of this is not entirely clear as epithelial PD-L1 overexpression is seen in many tumor types.47, 48, 49 In addition, a recent Phase I clinical trial of an anti-PD-L1 antibody (MPDL3280A) showed that PD-L1+ tumor-infiltrating lymphocytes were a better predictor of response to treatment (P=0.007) than PD-L1 expression on tumor cells (P=0.079).50 This association underscores that epithelial expression of PD-L1 may not be entirely predictive of response, and our data support that PD-L1 expression on tumor-infiltrating lymphocytes may be of greater biological importance. Cancer Res 2005;65:1089–1096. LM. Pathological examination showed a medullary carcinoma (MC) of T4aN0M0 Stage IIB. Visual survey of surgical pathology with 11226 high-quality images of benign and malignant neoplasms & related entities. A Krukenberg tumor refers to a malignancy in the ovary that metastasized from a primary site, classically the gastrointestinal tract, although it can arise in other tissues such as the breast. ANOVA and t-test were used for comparing lymphocyte counts among tumor types and between other characteristics. Nishimura H, Nose M, Hiai H et al. J Exp Med 1999;189:1363–1372. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2657293/. Naschberger E, Croner RS, Merkel S et al. At least 90% of the tumor had to contain a solid and syncytial growth pattern (sheets, nests, or trabeculae) consisting of medium-sized cells with vesicular nuclei and prominent nucleoli with a pushing or expansile pattern of growth.19 Poorly differentiated (high grade) carcinomas were defined as having 0–49% gland formation and well-differentiated carcinomas (low grade) were defined as having 50–100% gland formation according to the WHO.20. LM DDx. . PD-1 and its ligands in tolerance and immunity. This study demonstrates overexpression of several immunoregulatory genes in microsatellite unstable colorectal carcinomas and that expression of these genes and proteins is more prevalent in the medullary carcinoma subtype, which may be of use both diagnostically and therapeutically. Most medullary carcinoma patients (82%) were female, whereas 60% of poorly differentiated, 50% of microsatellite unstable well-differentiated and 50% of microsatellite stable well-differentiated patients were female (P=0.0003). A subgroup analysis comparing expression of IDO-1, tRNA(trp), GBP5, and PD-L1 between both microsatellite stable (n=28) and microsatellite unstable (n=19) poorly differentiated carcinomas revealed no statistically significant differences. Am J Pathol 1997;150:1815–1825. American journal of clinical pathology , 123 (1), 56-65. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. Nat Med 2002;8:793–800. Nat Med 2003;9:1269–1274. Systematic review of microsatellite instability and colorectal cancer prognosis. J Dermatol Sci 2005;40:95–103. Since 1990, we prospectively identified 11 patients with a predominantly solid (nonglandular) adenocarcinoma of the colon for which the term medullary adenocarcinoma of the colon (MAC) is proposed. More rare malignancies of the large bowel include signet-ring cell carcinoma, squamous carcinoma, undifferentiated neoplasms and medullary type adenocarcinoma (solid carcinoma with minimal glandular differentiation or slight cellular pleomorphism). Parsa AT, Waldron JS, Panner A et al. Immunohistochemical stains for IDO-1, tRNA(trp), and guanylate-binding proteins (GBP5) were evaluated in epithelium and surrounding stroma. Genome Biol 2015;16:64. We extended this analysis utilizing genomic data from the Cancer Genome Atlas to compare eight cases of medullary carcinoma with other microsatellite unstable and stable carcinomas. Areas of pure invasive carcinoma from each tumor subset were first identified on hematoxylin and eosin-stained slides from each case. Eight tumors morphologically consistent with medullary carcinoma were determined from the Cancer Genome Atlas data and were compared with 47 microsatellite unstable–high, 41 microsatellite unstable–low and 160 microsatellite stable colorectal carcinomas using the HiSeq data set. Nat Immunol 2013;14:1014–1022. Medullary carcinoma of the large intestine: a population based analysis. Asterisk (*) indicates P<0.0001. Herbst RS, Soria JC, Kowanetz M et al. The major role of PD-1 is to reduce activity of T cells during an inflammatory response by inhibiting kinases that are involved in T-cell activation, and its expression is induced when T cells become activated.13, 38, 39 Increased PD-1 expression on tumor-infiltrating lymphocytes is seen in a variety of tumor types,40 including microsatellite unstable colorectal carcinomas.10, 12 Similarly, the PD-1 ligand (PD-L1, CD274) is often upregulated on the tumor cell surface and tumor-infiltrating lymphocytes from many different tumors.15, 41 In our immunohistochemical analysis mean intraepithelial PD-L1+ tumor-infiltrating lymphocytes were higher in medullary carcinoma compared with microsatellite unstable and microsatellite stable colorectal carcinomas. GSEA revealed many biological pathways related to the adaptive inflammatory response, one of the major pathways being that mediated by IFNγ (Table 3). Finally, the presence of CD8+ intraepithelial lymphocytes correlated with PD-L1+ intraepithelial lymphocytes (P=0.0021), Foxp3+ intraepithelial lymphocytes (P=0.0149), and PD-1 intraepithelial lymphocytes (P=0.0007). Ghanipour A, Jirstrom K, Ponten F et al. Epithelial staining was considered negative if there was absent or barely perceptible staining at 10 ×, moderate if easily identifiable at 10 × and intense if easily identifiable at 2 ×. The clinical, histological, histochemical, and immunohistochemical features of these neoplasms were studied. Am J Respir Cell Mol Biol 2005;33:280–289. Stanford University School of Medicine. Epithelial GBP5 was overexpressed in >50% of tumor cells in ~17% (18/104) of medullary carcinoma, 2% (1/47) of poorly differentiated colorectal carcinomas, and no cases of microsatellite unstable well differentiated and microsatellite stable well differentiated (P<0.0089). Percentage of cases by histologic subtype demonstrating epithelial and stromal staining for IDO-1, tRNA(trp) or WARS, GBP5, and PD-L1. MEN IIa syndrome/MEN IIb syndrome. Sci Transl Med 2013;5:200ra116. Velcheti V, Schalper KA, Carvajal DE et al. Two paralogs exist, IDO-1 and IDO-2; however, the function of IDO-2 is less clear because of its very low Trp degradation activity.53 The depletion of Trp in the tumor microenvironment and production of Trp metabolites leads to inhibition of T-cell responses characterized by reduced proliferation, increased apoptosis and differentiation of naive T cells into T regulatory cells.54, 55 IDO-1 overexpression has been described in several tumors, including colorectal carcinomas, and is thought to contribute to their evasion from the host immune system.56, 57, 58 Our analysis of IDO-1 in medullary carcinoma showed a 2.4-fold increase in expression compared with microsatellite unstable-High colorectal carcinomas from the Cancer Genome Atlas data and immunohistochemical analysis showed that tumor cells were positive for IDO-1 in 64% of medullary carcinomas, with ~30% of cases showing a majority of tumor cells with moderate–strong staining. These data are clinically relevant given that clinical trials involving checkpoint blockade agents are being investigated for patients with microsatellite unstable tumors.18. All tests were two-sided with 0.05 as the threshold P-value to be considered statistically significant. 1999 Jul;30(7):843-8. Most of these tumours are adenocarcinomas (96%), that, in some cases, show a mucinous component. Department of Pathology. CDX2, beta-catenin, MLH1 useful for differentiating from poorly differentiated colorectal carcinoma. Murray B Resnick. Gajewski TF, Schreiber H, Fu YX . Google Scholar. Medullary carcinoma of the colon is a unique histologic subtype of microsatellite unstable colorectal carcinoma but little is known regarding its tumor-immunoregulatory microenvironment. We applied strict morphologic criteria to define medullary carcinoma and showed that upregulation of immune-mediated pathways was consistent between the initial gene expression array, the Cancer Genome Atlas data and immunohistochemical analysis. Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. In addition, a previously constructed tissue microarray of colorectal carcinoma was inspected to identify further cases of medullary carcinoma and if a case with potential medullary morphology was detected, whole H&E sections of the case were reviewed by the gastrointestinal pathologist (AJG) for confirmation. Important to identifyin clinical practice. Constitutive and inducible expression of b7 family of ligands by human airway epithelial cells. Medullary carcinoma for both cohorts was defined by applying strict morphologic criteria and demonstration of mismatch-repair protein deficiency by immunohistochemistry. A comparison of genes involved in the interferon-gamma pathway upregulated in medullary carcinoma compared with other microsatellite unstable and microsatellite stable tumors is summarized in Table 4. Medullary thyroid carcinoma. Sporadic medullary carcinoma of the colon: a clinicopathologic comparison with nonhereditary poorly differentiated enteric-type adenocarcinoma and neuroendocrine colorectal carcinoma.

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