High Concordance of Genomic Profiles between Primary and Metastatic Colorectal Cancer.

The comparison of the genetic profiles between primary and metastatic colorectal cancer (CRC) is needed to enable the discovery of useful therapeutic targets against metastatic CRCs. We performed the targeted next generation sequencing assay of 170 cancer-associated genes for 142 metastatic CRCs, including 95 pairs of primary and metastatic CRCs, to reveal their genomic characteristics and to assess the genetic heterogeneity. The most frequently mutated gene in primary and metastatic CRCs was APC (71% vs. 65%), TP53 (54% vs. 57%), KRAS (45% vs. 44%), PIK3CA (16% vs. 19%), SMAD4 (15% vs. 14%) and FBXW7 (11% vs. 11%). The concordance in the top six frequently mutated genes was 85%, on average. The overall mutation frequencies were consistent with two sets of public data (TCGA and MSKCC). To the author's knowledge, this is the first study to compare the genetic profiles of our cohort with that of the metastatic CRCs from MSKCC. Comparative sequencing analysis between primary and metastatic CRCs revealed a high degree of genetic concordance in the current clinically actionable genes. Therefore, the genetic investigation of archived primary tumor samples with the challenges of obtaining an adequate sample from metastatic sites appears to be sufficient for the application of cancer precision medicine in the metastatic setting.

Radiologic-Pathologic Correlation of Hepatobiliary Phase Hypointense Nodules without Arterial Phase Hyperenhancement at Gadoxetic Acid-enhanced MRI: A Multicenter Study.

Background Hepatobiliary phase (HBP) hypointense nodules without arterial phase hyperenhancement (APHE) at gadoxetic acid-enhanced MRI may indicate hepatocellular carcinoma (HCC) or nonmalignant cirrhosis-associated nodules. Purpose To assess the distribution of pathologic diagnoses of HBP hypointense nodules without APHE at gadoxetic acid-enhanced MRI and to evaluate clinical and imaging features in differentiating their histologic grades. Materials and Methods This retrospective multicenter study included pathologic analysis-confirmed HBP hypointense nodules without APHE (≤30 mm) in patients with chronic liver disease or cirrhosis screened between January 2008 and June 2016. Central pathologic review by 10 pathologists determined final histologic grades as progressed HCC, early HCC, high-grade dysplastic nodule (DN), and low-grade DN or regenerative nodule. Gadoxetic acid-enhanced MRI features were analyzed by three radiologists. Multivariable logistic regression analyses with elastic net regularization were performed to identify clinical and imaging features for differentiating histologic grades. Results There were 298 patients (mean age, 59 years ± 10; 226 men) with 334 nodules evaluated, and progressed HCCs were diagnosed in 44.0% (147 of 334), early HCCs in 20.4% (68 of 334), high-grade DNs in 27.5% (92 of 334), and low-grade DNs or regenerative nodules in 8.1% (27 of 334). Serum α-fetoprotein level 100 ng/mL or greater (odds ratio, 2.7; P = .01) and MRI features including well-defined margin (odds ratio, 5.5; P = .003), hypointensity at precontrast T1-weighted imaging (odds ratio, 3.2; P < .001), intermediate hyperintensity at T2-weighted imaging (odds ratio, 3.4; P < .001), and restricted diffusion (odds ratio, 1.9; P = .04) were independent predictors for progressed HCC at multivariable analysis. Conclusion In patients at high risk for hepatocellular carcinoma (HCC), hepatobiliary phase hypointense nodules without arterial phase hyperenhancement at gadoxetic acid-enhanced MRI corresponded mainly to progressed HCCs, early HCCs, and high-grade dysplastic nodules. High α-fetoprotein level and some imaging features at MRI helped to differentiate progressed HCC from lower grade nodules. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Motosugi in this issue.

The histologic detection of Helicobacter pylori in seropositive subjects is affected by pathology and secretory ability of the stomach.

BACKGROUND: Helicobacter pylori is unevenly distributed in hypochlorhydric environments. The study aim was to elucidate the risk factors for a negative Giemsa staining finding in seropositive subjects by measuring the secretory ability of the stomach. METHODS: Subjects aged over 18 years were included consecutively after endoscopic biopsy at gastric lesions with color or structural changes. Blood was sampled for the serum pepsinogen (PG) assay and H. pylori serology test. After excluding the subjects with past H. pylori eradication, the risk factors for a negative Giemsa staining finding in seropositive subjects were analyzed. RESULTS: Among 872 included subjects, a discrepancy between the serum anti-H. pylori IgG and Giemsa staining findings was found in 158 (18.1%) subjects, including 145 Giemsa-negative, seropositive subjects. Gastric adenocarcinoma/adenoma (OR = 11.090, 95% CI = 3.490-35.236) and low serum PG II level (OR = 0.931, 95% CI = 0.899-0.963) were the independent risk factors for a negative Giemsa staining finding in seropositive subjects. The cutoff value of serum PG II level was 7.45 ng/mL (area under curve [AUC] = 0.904, 95% CI = 0.881-0.927). Follow-up studies of Giemsa staining at different sites of the stomach revealed that 75% of the Giemsa-negative seropositive subjects with adenocarcinoma are positive, whereas none of those with low serum PG II level of <7.45 ng/mL revealed positive findings. CONCLUSIONS: The risk of a negative Giemsa staining finding in seropositive subjects is increased in gastric adenocarcinoma/adenoma specimens and in subjects with a diminished gastric secretory ability with low serum PG II level of <7.45 ng/mL. A false-negative Giemsa staining finding is common in subjects with adenocarcinoma, and therefore, additional biopsies at different sites should be performed in these subjects.

Discovery of gastric cancer specific biomarkers by the application of serum proteomics.

Current diagnostic markers for gastric cancer are not sufficiently specific or sensitive for use in clinical practice. The aims of this study are to compare the proteomes of serum samples from patients with gastric cancers and normal controls, and to develop useful tumor markers of gastric cancer by quantitative proteomic analysis. We identified a total of 388 proteins with a ≤1% FDR and with at least two unique peptides from the sera of each group. Among them, 215, 251, and 260 proteins were identified in serum samples of patients in an advanced cancer group, early cancer group, and normal control group, respectively. We selected differentially expressed proteins in cancer patients compared with those of normal controls via semiquantitative analyses comparing the spectral counts of identified proteins. These differentially expressed proteins were successfully verified using an MS-based quantitative assay, multiple reactions monitoring analysis. Four proteins (vitronectin, clusterin isoform 1, thrombospondin 1, and tyrosine-protein kinase SRMS) were shown to have significant changes between the cancer groups and the normal control group. These four serum proteins were able to discriminate gastric cancer patients from normal controls with sufficient specificity and selectivity.

BRAF-Mutated Colorectal Cancer Exhibits Distinct Clinicopathological Features from Wild-Type BRAF-Expressing Cancer Independent of the Microsatellite Instability Status.

In patients with colorectal cancer (CRC), the BRAF V600E mutation has been reported to be associated with several clinicopathological features and poor survival. However, the prognostic implications of BRAF V600E mutation and the associated clinicopathological characteristics in CRCs remain controversial. Therefore, we reviewed various clinicopathological features, including BRAF status, in 349 primary CRCs and analyzed the relationship between BRAF status and various clinicopathological factors, including overall survival. Similar to previous studies conducted in Eastern countries, the incidence of the BRAF V600E mutation in the current study was relatively low (5.7%). BRAF-mutated CRC exhibits distinct clinicopathological features from wild-type BRAF-expressing cancer independent of the microsatellite instability (MSI) status. This mutation was significantly associated with a proximal tumor location (P = 0.002); mucinous, signet ring cell, and serrated tumor components (P < 0.001, P = 0.003, and P = 0.008, respectively); lymphovascular invasion (P = 0.004); a peritumoral lymphoid reaction (P = 0.009); tumor budding (P = 0.046); and peritoneal seeding (P = 0.012). In conclusion, the incidence of the BRAF V600E mutation was relatively low in this study. BRAF-mutated CRCs exhibited some clinicopathological features which were also frequently observed in MSI-H CRCs, such as a proximal location; mucinous, signet ring cell, and serrated components; and marked peritumoral lymphoid reactions.

Diagnostic Limitation of Fine-Needle Aspiration (FNA) on Indeterminate Thyroid Nodules Can Be Partially Overcome by Preoperative Molecular Analysis: Assessment of RET/PTC1 Rearrangement in BRAF and RAS Wild-Type Routine Air-Dried FNA Specimens.

Molecular markers are helpful diagnostic tools, particularly for cytologically indeterminate thyroid nodules. Preoperative RET/PTC1 rearrangement analysis in BRAF and RAS wild-type indeterminate thyroid nodules would permit the formulation of an unambiguous surgical plan. Cycle threshold values according to the cell count for detection of the RET/PTC1 rearrangement by real-time reverse transcription-polymerase chain reaction (RT-PCR) using fresh and routine air-dried TPC1 cells were evaluated. The correlation of RET/PTC1 rearrangement between fine-needle aspiration (FNA) and paired formalin-fixed paraffin-embedded (FFPE) specimens was analyzed. RET/PTC1 rearrangements of 76 resected BRAF and RAS wild-type classical PTCs were also analyzed. Results of RT-PCR and the Nanostring were compared. When 100 fresh and air-dried TPC1 cells were used, expression of RET/PTC1 rearrangement was detectable after 35 and 33 PCR cycles, respectively. The results of RET/PTC1 rearrangement in 10 FNA and paired FFPE papillary thyroid carcinoma (PTC) specimens showed complete correlation. Twenty-nine (38.2%) of 76 BRAF and RAS wild-type classical PTCs had RET/PTC1 rearrangement. Comparison of RET/PTC1 rearrangement analysis between RT-PCR and the Nanostring showed moderate agreement with a κ value of 0.56 (p = 0.002). The RET/PTC1 rearrangement analysis by RT-PCR using routine air-dried FNA specimen was confirmed to be technically applicable. A significant proportion (38.2%) of the BRAF and RAS wild-type PTCs harbored RET/PTC1 rearrangements.

Giant cell hepatitis with autoimmune hemolytic anemia in a Korean infant.

Giant cell hepatitis (GCH) with autoimmune hemolytic anemia (AHA) is a very rare disease characterized by early onset and severe clinical manifestations, including immune hemolytic anemia and hepatitis with cholestasis. The prognosis is poor despite aggressive immunosuppressive therapy. We report here the first case of GCH with AHA in East Asia. A 2-month-old boy was admitted with jaundice. Blood test indicated abnormal liver function and low hemoglobin. Direct Coombs test and several autoantibodies associated with liver disease were positive, and liver biopsy was consistent with GCH. He was treated with prednisolone and ursodeoxycholic acid, and at the time of writing was in clinical and biochemical remission after prednisolone was stopped.

Mixed Carcinoma as an Independent Prognostic Factor in Submucosal Invasive Gastric Carcinoma.

Mixed carcinoma shows a mixture of glandular and signet ring/poorly cohesive cellular histological components and the prognostic significance of each component is not fully understood. This study aimed to investigate the significance of the poorly cohesive cellular histological component as a risk factor for lymph node metastasis and to examine the diagnostic reliability of endoscopic biopsy. Clinicopathologic characteristics of 202 patients who underwent submucosal invasive gastric carcinoma resection with lymph node dissection in 2005-2012 were reviewed. Mixed carcinoma accounted for 27.2% (56/202) of cases. The overall prevalence of lymph node metastasis was 17.3% (35/202). Lymphatic invasion (P < 0.001), family history of carcinoma (P = 0.025), tumor size (P = 0.004), Lauren classification (P = 0.042), and presence of any poorly cohesive cellular histological component (P = 0.021) positively correlated with the lymph node metastasis rate on univariate analysis. Multivariate analyses revealed lymphatic invasion, family history of any carcinoma, and the presence of any poorly cohesive cellular histological component to be significant and independent factors related to lymph node metastasis. Review of preoperative biopsy slides showed that preoperative biopsy demonstrated a sensitivity of 63.6% and a specificity of 100% in detecting the presence of the poorly cohesive cellular histological component, compared with gastrectomy specimens. The presence of any poorly cohesive cellular histological component was an independent risk factor associated with lymph node metastasis in submucosal invasive gastric carcinoma. Endoscopic biopsy had limited value in predicting the presence and proportion of the poorly cohesive cellular histologic component due to the heterogeneity of mixed carcinoma.

Fibrosis Within the Tympanic Membrane.

A primary mass lesion arising from the tympanic membrane is extremely rare. The authors report a patient of extensive fibrosis within the tympanic membrane in a 65-year-old woman who did not have a history of ear infection. The patient complained of slow progressing hearing loss on the left side without otorrhea or otalgia. Otoscopic examination showed a thick tympanic membrane with whitish mass-like bulge, and pure-tone audiometry revealed conductive hearing loss. The lesion was totally resected, and final findings of a histopathologic examination revealed extensive fibrosis with subsiding inflammation within the tympanic membrane. Fibrosis within the tympanic membrane may present with slow progressing conductive hearing loss and should be considered a possible differential diagnosis of mass lesions in the tympanic membrane.

Risk of lymph node metastasis in differentiated type mucosal early gastric cancer mixed with minor undifferentiated type histology.

BACKGROUND: The possibility of lymph node metastasis is critical to the assessment of the indication for endoscopic submucosal dissection. The differentiation of tumors is an important predicting factor for lymph node metastasis. Even though gastric cancers frequently show intratumoral heterogeneity, most studies have not considered the effects of the minor histologic components. The purpose of this study was to investigate the relationship between the presence of undifferentiated type histology (UD-min) within differentiated type tumors and lymph node metastases in early gastric cancer confined to the mucosal layer. METHODS: A retrospective study of 847 patients who underwent surgery for differentiated early gastric cancer, confined to mucosa, was conducted. We analyzed the proportion of the undifferentiated type components of the tumor and their relationship with lymph node metastasis. RESULTS: The overall rate of lymph node metastasis was 1.7 % (14/847 patients) and 215 differentiated tumors (25.4 %) have UD-min. UD-min was associated with female sex, younger age, larger tumor size, and the presence of ulcer. Lymph node metastasis rate with or without UD-min was 5.1 % (11/215) versus 0.5 % (3/632), respectively (p < 0.001). UD-min was found to be associated with lymph node metastasis in the multivariate analyses (odds ratio [OR] = 4.39, CI 1.08-17.89). When three risk factors (tumor size >2 cm, ulcer, and UD-min) were present concurrently, the rate of lymph node metastasis was high (10 %). CONCLUSIONS: The presence of an UD-min component should be considered when assessing curative resection status of endoscopic submucosal dissection for differentiated type mucosal cancer.

Effect of submucosal fibrosis on endoscopic submucosal dissection of colorectal tumors: pathologic review of 173 cases.

BACKGROUND AND AIMS: Endoscopic submucosal dissection (ESD) is now commonly performed as a treatment for colorectal tumors. However, little is known about the relationship between submucosal fibrosis and the outcome of the colonic ESD procedure. The aims of this study were to investigate the relationship between the degree of submucosal fibrosis in colorectal tumors and the outcomes of ESD for these tumors and to evaluate the risk factors for submucosal fibrosis. METHODS: We retrospectively reviewed the records of patients with colorectal adenoma or carcinoma who had undergone an ESD, during a four-year period from January 2010 to December 2013. The resected specimens were histologically examined after Masson's trichrome staining, and the severity of the submucosal fibrosis was classified as no fibrosis (F0), mild fibrosis (F1), or severe fibrosis (F2). RESULTS: Among a total of 173 cases (106 male, mean age 65.0 ± 10.2 years; F0 33, F1 78, F2 62) enrolled, 46 incidences of complications (perforation 19, post-coagulation syndrome 21, bleeding 6) had developed. Multivariate analysis revealed that F2 fibrosis was significantly associated with the development of complications. Submucosal invasion and large tumor size (≥ 30 mm) were identified as independent predictors of F2 fibrosis. CONCLUSION: Severe fibrosis is the most powerful risk factor for complications and can interfere with en bloc resections. The possibility of submucosal fibrosis should be considered, and the procedure should be cautiously performed in cases where the tumor diameter is greater than 30 mm and when submucosal cancer is suspected.

Expression of Peroxisome Proliferator Activated Receptor gamma in Prostatic Adenocarcinoma.

Peroxisome proliferator-activated receptor gamma (PPAR-γ), a ligand-activated transcription factor has been investigated as the target for cancer treatment as well as metabolic disorders. Recent studies have demonstrated that PPAR-γ ligands are anti-tumorigenic in prostate cancer due to anti-proliferative and pro-differentiation effects. The aim of this study was to validate PPAR-γ expression in malignant and benign prostate tissues by immunohistochemistry and quantitative real-time polymerase chain reaction (PCR). A total of 730 prostatic adenocarcinomas (PCAs) including 63 whole sections from radical prostatectomy specimens and tissue microarrays containing 667 PCAs were subject to immunostaining for two PPAR-γ antibodies. Twenty-five benign prostate tissues and PCAs were selected for investigating mRNA expression by quantitative real-time PCR. 10.7% of PCAs (78/730) showed cytoplasmic immunoreactivity of PPAR-γ and no nuclear immunoreactivity was noted in PCAs. Most benign prostatic glands showed negative immunoreactivity of PPAR-γ except for variable weak cytoplasmic staining in some glands. Nuclear immunoreactivity of PPAR-γ was noted some central zone and verumontanum mucosal epithelium. The constitutive PPAR-γ mRNA showed significantly lower level in PCAs compared to that in the benign tissues. There was no difference of PPAR-γ mRNA expression between low (≤7) and high (>7) Gleason score groups. There was no association of PPAR-γ mRNA level or cytoplasmic immunostaining with Gleason grade or pathologic stage. Our study supported the evidence of extra-nuclear localization and nongenomic actions of PPAR-γ. Further studies are needed to assess the functional role of PPAR-γ and to validate its therapeutic implication in prostate cancer.

Low prevalence of microsatellite instability in interval gastric cancers.

BACKGROUND AND AIM: Esophagogastroduodenoscopy (EGD) is recommended at 2-year intervals in countries with a high prevalence of gastric cancer. The aim of this study was to determine whether interval gastric cancers that develop within 2 years of a previous complete screening are associated with microsatellite instability (MSI). METHODS: Newly diagnosed gastric cancer patients who had undergone gastrectomy were included. Of these 459 patients, 177 were classified as interval gastric cancer since they were diagnosed within 2 years of a previous EGD. Noninterval gastric cancer patients were subclassified into 65 patients who underwent previous EGD between the past 2 and 10 years and 217 patients without EGD during the last 10 years. Analysis for MSI was conducted using two mononucleotide and three dinucleotide markers. RESULTS: MSI was found more frequently in noninterval gastric cancers than in interval gastric cancers (p = 0.009). Interval gastric cancers were associated with a higher prevalence of early gastric cancer (p = 0.006), smaller size (p < 0.001), and lower TNM stages (p = 0.006). On logistic regression analysis, noninterval gastric cancers were related to MSI (p = 0.010) and larger size (≥4 cm) (p = 0.009). Subjects with interval gastric cancer showed better survival than those with noninterval gastric cancer (p = 0.006). CONCLUSIONS: During a 2-year screening interval, noninterval gastric cancers tend to be larger, more advanced, and associated with MSI. Biannual EGD screening is effective for detecting small gastric cancers at an early stage, but is not useful in detecting gastric cancers with MSI.

Is Helicobacter Pylori associated with Her2/neu Overexpression in Gastric Cancer Patients who Underwent Curative Resection?

BACKGROUND/AIMS: Human epidermal growth factor receptor 2 (Her2/neu) is an important target for treatment of gastric cancer using trastuzumab and Helicobacter pylori is a well-known risk factor of gastric cancer. We investigated the association of Her2/neu overexpression with Helicobacter pylori and other clinicopathologic factors in gastric cancer patients who underwent curative resection. METHODOLOGY: Her2/neu immunohistochemistry was performed in gastric cancer patients who underwent curative gastrectomy or endoscopic submucosal dissection. Analysis about its associations with clinicopathologic features such as Lauren histologic types, differentiation, Helicobacter pylori infection, location, depth of invasion, lymph node metastasis, and AJCC tumor stage was performed retrospectively. RESULTS: The incidence of Her2/neu 3+, 2+, 1+ and 0 was 8.9%, 22.1%, 4.4% and 64.6% respectively. Intestinal type of gastric cancer showed higher incidence of Her2/neu 3+ than diffuse type. The score 2+ and 3+ was more common in Helicobacter pylori-positive patients than Helicobacter pylori-negative patients (p = 0.024). 7th American joint Cancer Committee Tumor stage, depth of tumor invasion and lymph node metastasis did not show correlation with the level of Her2/neu expression. CONCLUSIONS: Helicobacter pylori-positive gastric cancer showed more Her2/neu overexpression. Helicobacter pylori eradication may be necessary to avoid Her2/neu overexpression.

Primary ductal adenocarcinoma of the lacrimal gland, associated with abundant intracytoplasmic lumens containing some eosinophilic hyaline globules: cytological, histological and ultrastructural findings.

A primary ductal adenocarcinoma (PDA) of the lacrimal gland is a rare distinct subtype of an epithelial tumor arising in the lacrimal gland. PDA is the counterpart of salivary duct carcinoma (SDC) resembling an invasive ductal carcinoma (IDC) of the breast. In our case, PDA revealed histopathological and immunohistochemical results corresponding to SDC. Interestingly, the tumor cells showed intracytoplasmic vacuoles containing dense eosinophilic hyaline globules at light microscopy. Ultrastructurally, the tumor cells exhibited microvilli-lined intracytoplasmic lumen containing homogenous electron-dense secretory products. A previous study demonstrated that numerous intracytoplasmic lumens of tumor cells are favored breast malignant tumor, similar to the histopathology of PDA, rather than benign lesion. This characteristic finding may be meaningful to diagnose high grade epithelial tumors including PDA.

Gastric cancers with microsatellite instability exhibit high fluorodeoxyglucose uptake on positron emission tomography.

BACKGROUND: Gastric cancers exhibit various degrees of (18)F-fluorodeoxyglucose (FDG) uptakes on positron emission tomography/computed tomography (PET/CT) imaging. The aim of this study was to evaluate whether FDG uptake in gastric cancer varies according to the microsatellite instability (MSI) status. METHODS: Consecutive gastric cancer patients who underwent PET/CT imaging and MSI analysis were included in the study. The maximum standardized uptake value (SUVmax) of gastric cancer was assessed using PET/CT imaging. RESULTS: Of 131 gastric cancers, 16 exhibited a high incidence of MSI (MSI-H) and 3 exhibited a low incidence of MSI (MSI-L). In 29 subjects who showed no uptake on PET/CT imaging the gastric cancers were all microsatellite stable (MSS). Gastric cancers with MSI were related to age older than 60 years (p = 0.002), cancer volume larger than 10 cm(3) (p = 0.015), and the presence of FDG uptake on PET/CT imaging (p = 0.001). A higher SUVmax of gastric cancer was linked to the presence of MSI (p < 0.001). CONCLUSION: The presence of MSI is related to FDG uptake in gastric cancer. Care should be taken with MSS gastric cancers, because they show lower SUVmax on PET/CT imaging than MSI gastric cancers.

Clinical outcomes for patients with perforations during endoscopic submucosal dissection of laterally spreading tumors of the colorectum.

BACKGROUND: Endoscopic submucosal dissection (ESD) for colorectal neoplasms is not widely performed because of the high risk of perforation. Perforations are divided into macroperforations and microperforations. Currently, there is a limited amount of clinical data on the outcome of patients with these types of perforations during colonic ESD. The aim of this study was to investigate the clinical outcome of patients who sustained colon perforations during ESD. We also compared the clinical outcome of patients with microperforations and those with macroperforations. METHODS: This study enrolled 101 patients with colorectal laterally spreading tumors (LST) who underwent ESD. We retrospectively reviewed their medical records, including patient demographic data and the clinical, endoscopic, and pathologic features. In the cases where perforation had occurred, the course of hospital treatment was analyzed. All ESD-related perforations were divided into macroperforations and microperforations. A macroperforation was defined as a gross perforation that occurred during an ESD procedure and a microperforation was defined by free air visible on X-rays after the procedure. RESULTS: Of the 101 enrolled patients, 9 (8.9 %) developed perforations. The most common tumor morphology was nongranular-type LST (5 of 9 cases, 55.6 %) based on endoscopic examination. Five patients had microperforations and four had macroperforations. All macroperforations were closed primarily by endoclips during ESD. The endoscopic characteristics did not differ between the groups. However, the length of hospital stay and the mean duration of NPO and antibiotic treatments were longer for microperforation patients. All patients had conservative nonsurgical management such as fasting, intravenous antibiotics, and nasogastric tube drainage. CONCLUSIONS: The clinical complications for microperforation patients were worse than those for macroperforation patients. However, the clinical prognoses of patients with perforations that occur during colonic ESD are favorable.

Genetic alteration and immunohistochemical staining patterns of ovarian high-grade serous adenocarcinoma with special emphasis on p53 immnnostaining pattern.

We evaluated p53, KRAS, BRAF and CTNNB1 mutation and p53, WT1, p16 and beta-catenin expression in 31 ovarian high-grade serous adenocarcinoma. Twenty-five (80.6%) tumors contained functional mutations of p53; three frameshift, four nonsense and 19 missense mutations. None of the tumors showed KRAS, BRAF or CTNNB1 mutation. In all 18 tumors with missense mutations, ≥60% of tumor cells were strongly positive for p53 immunostaining whereas all tumors with frameshift or nonsense mutations were completely negative. Missense mutation was correlated with diffuse and strong imunoreaction and frameshift/nonsense mutation was correlated with completely negative immunoreaction (P = 0.000). Tumors with wild-type p53 revealed a wide range of immunostaining patterns. In 27 (87.1%) and 18 (58.1%) tumors, ≥50% of tumor cells were moderate to strongly positive for WT1 and p16, respectively. A considerable intratumoral heterogeneity for p16 expression was present. None of the tumors demonstrated nuclear beta-catenin expression. p53 mutations appear to be a powerful molecular marker for ovarian high-grade serous adenocarcinoma. Using p53 with an appropriate interpretation criteria together with WT1, p16 and beta-catenin, most of the high-grade serous adenocarcinoma could be distinguished from other ovarian tumors.

Microsatellite instability, EMAST, and morphology associations with T cell infiltration in colorectal neoplasia.

BACKGROUND AND OBJECTIVES: Colorectal tumors are often observed with tumor infiltrating lymphocytes, presumably as a host-immune response, and patterns may segregate by types of genomic instability. Microsatellite unstable (MSI) colorectal cancers contain a pronounced lymphocyte reaction that can pathologically identify these tumors. Colorectal tumors with elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) have not been examined for lymphocyte patterns. METHODS: We evaluated a 108-person cohort with 24 adenomas and 84 colorectal cancers for MSI and EMAST. Immunohistochemical detection of CD4+ and CD8+ T cell infiltration were performed. Prognostic relevance was assessed by survival analysis. RESULTS: CD8+ T cell infiltration in the tumor cell nest (p = 0.013) and tumor stroma (p = 0.004) were more prominent in moderately and poorly differentiated adenocarcinoma than in adenoma and well-differentiated adenocarcinoma. CD8+ T cells in the tumor cell nest (p = 0.002) and tumor stroma (p = 0.009) were at higher density in tumors with ulcerating features compared to tumors with a sessile or polypoid appearance. MSI-H tumors showed a higher density of CD8+ T cell infiltrations in tumor cell nests (p = 0.003) and tumor stroma (p = 0.001). EMAST-positive tumors showed a higher density of CD8+ T cell infiltrations than EMAST-negative tumors both in tumor cell nest (p = 0.027) and in tumor stroma (p = 0.003). These changes were not observed with CD4+ T lymphocytes. There was no difference in cancer patient survival based on density of CD8+ cells. CONCLUSIONS: CD8+ T lymphocytes, but not CD4+ cells, were increased in tumor cell nests and the tumor stroma in both MSI and EMAST tumors, and showed higher infiltration in ulcerated tumors. CD8+ T lymphocyte infiltration is associated with both EMAST and MSI patterns, and increases with histological advancement.

Primary pure squamous cell carcinoma of the thyroid: report and histogenic consideration of a case involving a BRAF mutation.

Primary squamous cell carcinoma of the thyroid (SCC-T) is extremely rare. Its clinical presentation is similar to that of anaplastic carcinoma. Metastasis or extension from the head and neck area should be ruled out, as patients with SCC-T have a poorer prognosis than patients who have a thyroid extension from an adjacent tumor. An 87-year-old man presented with a longstanding painless mass in the right thyroid and had experienced 2 months of pain upon swallowing. A right lobectomy was performed with resection of thyroid cartilage, cricoid cartilage, a portion of the first to third tracheal ring and the right neck lymph node. A histological examination revealed pure SCC. The tumor cells showed diffuse immunoreactivity to CK5/6, CK19 and p63. Immunoreactivity to EMA and p53 was focally positive. TTF-1, galectin 3 and thyroglobulin immunoreactivity was restricted to the non-neoplastic thyroid tissue. Both tumor cells and non-neoplastic follicular cells were negative for CD5. The MIB-1 index was 36%. DNA extracted from the tumor identified a BRAF V600E mutation in exon 15 and a BRAF G468A mutation in exon 11, whereas DNA from non-tumorous cells did not contain a mutation. These molecular findings may suggest a direct transformation from papillary carcinoma to SCC-T.