Giant cell tumor of paralaryngeal soft tissues, extending to the laryngeal cartilage.

Paralaryngeal mass with secondary extension to the thyroid cartilage involving confluent cysts, subjected to conservative surgical treatment with a diagnosis of giant cell tumor of soft tissues, a neoplasm morphologically similar but genetically unrelated to osseous giant cell tumors.

Biological and therapeutic implications of RKIP in Gastrointestinal Stromal Tumor (GIST): an integrated transcriptomic and proteomic analysis.

BACKGROUND: Gastrointestinal stromal tumors (GIST) represent a significant clinical challenge due to their metastatic potential and limited treatment options. Raf kinase inhibitor protein (RKIP), a suppressor of the MAPK signaling pathway, is downregulated in various cancers and acts as a metastasis suppressor. Our previous studies demonstrated low RKIP expression in GIST and its association with poor outcomes. This study aimed to expand on the previous findings and investigate the biological and therapeutic implications of RKIP loss on GIST. METHODS: To validate the RKIP prognostic significance, its expression was evaluated by immunohistochemistry in 142 bona fide GIST cases. The functional role of RKIP was evaluated in vitro, using the GIST-T1 cell line, which was knocked out for RKIP. The biological and therapeutic implications of RKIP were evaluated by invasion, migration, apoptosis, and 2D / 3D viability assays. Additionally, the transcriptome and proteome of RKIP knockout cells were determined by NanoString and mass spectrometry, respectively. RESULTS: Immunohistochemical analysis revealed the absence of RKIP in 25.3% of GIST cases, correlating with a tendency toward poor prognosis. Functional assays demonstrated that RKIP knockout increased GIST cells' invasion and migration potential by nearly 60%. Moreover, we found that RKIP knockout cells exhibited reduced responsiveness to Imatinib treatment and higher cellular viability in 2D and 3D in vitro models, as assessed by apoptosis-related protein expression. Through comprehensive genetic and proteomic profiling of RKIP knockout cells, we identified several putative RKIP-regulated proteins in GIST, such as COL3A1. CONCLUSIONS: Using a multidimensional integrative analysis, we identified, for the first time in GIST, molecules and pathways modulated by RKIP that may potentially drive metastasis and, consequently, poor prognosis in this disease.

Analysis of RPL37A, MTSS1, and HTRA1 expression as potential markers for pathologic complete response and survival.

BACKGROUND: Non-metastatic locally advanced breast carcinoma (LABC) treatment involves neoadjuvant chemotherapy (NCT). We evaluated the association of clinical-pathological data and immunoexpression of hormone receptors, HER2 and Ki67, and new biomarkers, RPL37A, MTSS1 and HTRA1, with pathological complete response (PCR) or tumour resistance (stable disease or disease progression), disease-free survival (DFS) and cancer-specific survival (CSS). METHODS: This is a retrospective study of 333 patients with LABC who underwent NCT. Expression of MTSS1, RPL37A and HTRA1/PRSS11 was evaluated by immunohistochemistry in TMA slides. Cutoff values were established for low and high tumour expression. ROC plotter evaluated response to NCT. Chi-square test for factors related to PCR, and Kaplan-Meier test and Cox model for factors related to DFS and CSS were prformed. RESULTS: The mean follow-up was 70.0 months and PCR rate was 15.6%. At 120 months, DFS rate was 32.5% and CSS rate was 67.1%. In multivariate analysis, there was an association between: (1) necrosis presence, intense inflammatory infiltrate, ER absence, HER2 molecular subtype and high RPL3A expression with increased odds of PCR; (2) lymph node involvement (LNI), high Ki67, low RPL37A and high HTRA1 expression with increased risk for NCT non-response; (3) LNI, high proliferation, necrosis absence, low RPL37A and high HTRA1 expression with increased recurrence risk; (4) advanced LNI, ER negative tumours, high HTRA1, low RPL37A expression and desmoplasia presence with higher risk of cancer death. CONCLUSION: RPL37A is a potential biomarker for response to NCT and for prognosis. Additional studies evaluating HTRA1 and MTSS1 prognostic value are needed.

miRNA expression profiling of hereditary breast tumors from BRCA1- and BRCA2-germline mutation carriers in Brazil.

BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene expression regulation and have been described as key regulators of carcinogenesis. Aberrant miRNA expression has been frequently reported in sporadic breast cancers, but few studies have focused on profiling hereditary breast cancers. In this study, we aimed to identify specific miRNA signatures in hereditary breast tumors and to compare with sporadic breast cancer and normal breast tissues. METHODS: Global miRNA expression profiling using NanoString technology was performed on 43 hereditary breast tumors (15 BRCA1, 14 BRCA2, and 14 BRCAX), 23 sporadic breast tumors and 8 normal breast tissues. These normal breast tissues derived from BRCA1- and BRCA2- mutation carriers (n = 5) and non-mutation carriers (n = 3). Subsequently, we performed receiver operating characteristic (ROC) curve analyses to evaluate the diagnostic performance of differentially expressed miRNAs. Putative target genes of each miRNAs considered as potential biomarkers were identified using miRDIP platform and used for pathway enrichment analysis. RESULTS: miRNA expression analyses identified several profiles that were specific to hereditary breast cancers. A total of 25 miRNAs were found to be differentially expressed (fold change: > 2.0 and p < 0.05) and considered as potential biomarkers (area under the curve > 0.75) in hereditary breast tumors compared to normal breast tissues, with an expressive upregulation among BRCAX cases. Furthermore, bioinformatic analysis revealed that these miRNAs shared target genes involved in ErbB, FoxO, and PI3K-Akt signaling pathways. CONCLUSIONS: Our results showed that miRNA expression profiling can differentiate hereditary from sporadic breast tumors and normal breast tissues. These miRNAs were remarkably deregulated in BRCAX hereditary breast cancers. Therefore, miRNA signatures can be used as potential novel diagnostic biomarkers for the prediction of BRCA1/2- germline mutations and may be useful for future clinical management.

The Brazilian TP53 mutation (R337H) and sarcomas.

Sarcomas represent less than 1% of all solid neoplasms in adults and over 20% in children. Their etiology is unclear, but genetic susceptibility plays an important role in this scenario. Sarcoma is central in Li-Fraumeni Syndrome (LFS), a familial predisposition cancer syndrome. In Brazil, the high prevalence of p.Arg337His mutations in the TP53 gene brings about a unique condition: a cluster of LFS. In the present work, we studied 502 sarcoma patients not selected by age or family history in an attempt to assess the impact of the so-called "Brazilian germline TP53 mutation" (p.Arg337His) on this tumor type. We found that 8% of patients are carriers, with leiomyosarcoma being the main histologic type of sarcoma, corresponding to 52.5% of the patients with the mutated TP53 gene. These findings emphasize the importance of genetic counseling and can better guide the management of sarcoma patients.

Effectiveness and Safety of Implant-Based Breast Reconstruction in Locally Advanced Breast Carcinoma: A Matched Case-Control Study.

BACKGROUND: Immediate implant-based breast reconstruction (IBBR) is rarely performed in patients with locally advanced breast carcinoma (LABC). It has not been considered the best indication, and the literature is scarce about this subject. PATIENTS AND METHODS: A retrospective matched case-control study was performed in patients with LABC submitted to neoadjuvant chemotherapy (NCT). Forty-eight patients undergoing immediate IBBR were matched with 96 patients undergoing conventional mastectomy. Patients were matched according to 2 models based on prognostic characteristics prior to NCT and response to NCT. Local recurrence and disease-free survival were compared between the groups. In the IBBR group, local complications were evaluated. RESULTS: In all, 196 patients were evaluated. The mean tumour size of IBBR patients was 5.8 cm. 83.3% (180/196) of the patients had clinical stage III. At a mean follow-up of 74.7 months, the local recurrence rate was 6.2% (3/48), 15.6% (15/96) and 13.7% (13/95) in the IBBR, model 1 and model 2 groups, respectively (p > 0.05). Disease-free survival was higher in the IBBR group than in the model 1 group (mean 88.8 vs. 73.7 months; p = 0.05). In the group submitted to IBBR, 14.6% (7/48) of patients presented loss of prosthesis and 48.8% (20/41) developed capsular contracture. CONCLUSION: Immediate IBBR may be a safe and effective surgical procedure in selected patients with LABC.

Presence of microsatellite instability in esophageal squamous cell carcinoma associated with chagasic megaesophagus.

AIM: The molecular pathogenesis of esophageal squamous cell carcinoma (ESCC) has been increasingly studied, but there is no report on the role of MSI in ESCC development associated with chagasic megaesophagus (CM).Results/methodology: In four ESCC/CM (4/19) we found microsatellite instability (MSI) alterations (21.1%), being three MSI-L (15.8%) and one MSI-H (5.3%). Four out of 35 ESCC cases showed MSI-L (11.4%) and only one out of 26 CM cases presented MSI-L (3.9%). The MSI-H was observed in an ESCC/CM patient that presents lack of MSH6 immunostaining corroborating deficiency in MMR pathway. Interestingly, the MSI-H ESCC/CM case also presented a deletion the HSP110 poly(T)17 gene. DISCUSSION/CONCLUSION: Taking together, we concluded that MSI is a rare event in esophageal squamous cell carcinoma, but can be associated with CM.

Loss of MTAP expression is a negative prognostic marker in Ewing sarcoma family of tumors.

AIM: The Ewing sarcoma family of tumors (ESFT) is a group of malignant small round cell neoplasms of bones and soft tissues closely histogenetically related. Methylthioadenosine phosphorylase (MTAP) deficiency has been recently associated with increased tumor aggressiveness and poor outcomes in different types of neoplasms. However, the expression of this biomarker and its biological role in ESFT remain largely unknown. METHODS: Immunohistochemical expression of MTAP was accessed in 112 patients with ESFT in a tissue microarray platform and associated with clinicopathological parameters and overall survival (OS). RESULTS: Loss of MTAP expression was significantly associated with lower OS in both univariate and multivariate analyses. CONCLUSION: Loss of MTAP expression is an independent negative prognostic biomarker in ESFT.

Lack of microsatellite instability in gastrointestinal stromal tumors.

The microsatellite instability (MSI) phenotype may constitute an important biomarker for patient response to immunotherapy, particularly to anti-programmed death-1 inhibitors. MSI is a type of genomic instability caused by a defect in DNA mismatch repair (MMR) proteins, which is present mainly in colorectal cancer and its hereditary form, hereditary nonpolyposis colorectal cancer. Gastrointestinal stromal tumor (GIST) development is associated with activating mutations of KIT proto-oncogene receptor tyrosine kinase (KIT) or platelet-derived growth factor receptor α (PDGFRA), which are oncogenes that predict the response to imatinib mesylate. In addition to KIT/PDGFRA mutations, other molecular alterations are important in GIST development. In GISTs, the characterization of the MSI phenotype is scarce and the results are not consensual. The present study aimed to assess MSI in a series of 79 GISTs. The evaluation of MSI was performed by pentaplex polymerase chain reaction comprising five markers, followed by capillary electrophoresis. The expression of MMR proteins was evaluated by immunohistochemistry. Regarding the KIT/PDGFRA/B-Raf proto-oncogene, serine/threonine kinase molecular profile of the 79 GISTs, 83.6% of the tumors possessed KIT mutations, 10.1% had PDGFRA mutations and 6.3% were triple wild-type. The mutated-PDGFRA cases were associated with gastric location and a lower mitotic index compared with KIT-mutated and wild-types, and these patients were more likely to be alive and without cancer. MSI analysis identified 4 cases with instability in one marker, however, additional evaluation of normal tissue and immunohistochemical staining of MMR proteins confirmed their microsatellite-stable nature. The results of the present study indicated that MSI is not involved in GIST tumorigenesis and, therefore, cannot serve as a biomarker to immunotherapy response in GIST.

Breast-conserving surgery in locally advanced breast cancer submitted to neoadjuvant chemotherapy. Safety and effectiveness based on ipsilateral breast tumor recurrence and long-term follow-up.

OBJECTIVE:: To evaluate ipsilateral breast tumor recurrence after breast-conserving surgery for locally advanced breast cancer. METHODS:: A retrospective observational cohort study was performed in patients with locally advanced breast cancer submitted to breast-conserving surgery after neoadjuvant chemotherapy based on an adriamycin-cyclophosphamide-paclitaxel regimen. We evaluated the clinical, pathologic, immunohistochemistry, and surgical factors that contribute to ipsilateral breast tumor recurrence and locoregional recurrence. A Kaplan-Meier analysis and Cox model were used to evaluate the main factors related to disease-free survival. RESULTS:: Of the 449 patients who received neoadjuvant chemotherapy, 98 underwent breast-conserving surgery. The average diameter of the tumors was 5.3 cm, and 87.2% reached a size of up to 3 cm. Moreover, 86.7% were classified as clinical stage III, 74.5% had T3-T4 tumors, 80.5% had N1-N2 axilla, and 89.8% had invasive ductal carcinoma. A pathologic complete response was observed in 27.6% of the tumors, and 100.0% of samples had free margins. The 5-year actuarial overall survival rate was 81.2%, and the mean follow-up was 72.8 months. The rates of ipsilateral breast tumor recurrence and locoregional recurrence were 11.2% and 15.3%, respectively. Multifocal morphology response was the only factor related to ipsilateral breast tumor recurrence disease-free survival (p=0.04). A multivariate analysis showed that the pathologic response evaluation criteria in solid tumors (RECIST)-breast cutoff was the only factor related to locoregional recurrence disease-free survival (p=0.01). CONCLUSIONS:: Breast-conserving surgery is a safe and effective therapy for selected locally advanced breast tumors.

Breast-conserving surgery in locally advanced breast cancer submitted to neoadjuvant chemotherapy. Safety and effectiveness based on ipsilateral breast tumor recurrence and long-term follow-up

OBJECTIVE: To evaluate ipsilateral breast tumor recurrence after breast-conserving surgery for locally advanced breast cancer. METHODS: A retrospective observational cohort study was performed in patients with locally advanced breast cancer submitted to breast-conserving surgery after neoadjuvant chemotherapy based on an adriamycin-cyclophosphamide-paclitaxel regimen. We evaluated the clinical, pathologic, immunohistochemistry, and surgical factors that contribute to ipsilateral breast tumor recurrence and locoregional recurrence. A Kaplan-Meier analysis and Cox model were used to evaluate the main factors related to disease-free survival. RESULTS: Of the 449 patients who received neoadjuvant chemotherapy, 98 underwent breast-conserving surgery. The average diameter of the tumors was 5.3 cm, and 87.2% reached a size of up to 3 cm. Moreover, 86.7% were classified as clinical stage III, 74.5% had T3-T4 tumors, 80.5% had N1-N2 axilla, and 89.8% had invasive ductal carcinoma. A pathologic complete response was observed in 27.6% of the tumors, and 100.0% of samples had free margins. The 5-year actuarial overall survival rate was 81.2%, and the mean follow-up was 72.8 months. The rates of ipsilateral breast tumor recurrence and locoregional recurrence were 11.2% and 15.3%, respectively. Multifocal morphology response was the only factor related to ipsilateral breast tumor recurrence disease-free survival (p=0.04). A multivariate analysis showed that the pathologic response evaluation criteria in solid tumors (RECIST)-breast cutoff was the only factor related to locoregional recurrence disease-free survival (p=0.01). CONCLUSIONS: Breast-conserving surgery is a safe and effective therapy for selected locally advanced breast tumors.

HER2 testing in gastric cancer: An update.

Human epidermal growth factor receptor 2 (HER2) overexpression is increasingly recognized as a frequent molecular abnormality in gastric and gastroesophageal cancer. With the recent introduction of HER2 molecular targeted therapy for patients with advanced gastric cancer, determination of HER2 status is crucial in order to select patients who may benefit from this treatment. This paper provides an update on our knowledge of HER2 in gastric and gastroesophageal cancer, including the prognostic relevance of HER2, the key differences between HER2 protein expression interpretation in breast and gastric cancer, the detection methods and the immunohistochemistry scoring system.

Absence of Microsatellite Instability In Soft Tissue Sarcomas.

OBJECTIVE: Here, we analyze a series of soft tissue sarcomas (STS), which are a heterogeneous group of mesenchymal neoplasms, for the presence and frequency of microsatellite instability (MSI). MSI has been proposed to be clinically relevant for colorectal cancer, yet on STS its role is not consensual, partly due to the limited number of cases analyzed and methodology issues. METHODS: The detailed evaluation of MSI in tumor samples from 71 STS patients was performed by pentaplex PCR of the MSI markers NR-27, NR-21, NR-24, BAT-25, and BAT-26, followed by capillary electrophoresis. The expression of DNA mismatch repair (MMR) proteins (MLH1, MSH2, MSH6, and PMS2) was also evaluated in suspected MSI-positive cases by immunohistochemistry. RESULTS: The MSI analysis showed instability of one MSI marker in a total of 3 cases (4.2%). However, MMR protein expression was not affected, demonstrating that all cases were microsatellite stable. CONCLUSION: Our results suggest that MSI does not play a role in STS tumorigenesis. © 2015 S. Karger AG, Basel.

HER2 in gastric cancer: comparative analysis of three different antibodies using whole-tissue sections and tissue microarrays.

AIM: To compare the performance of three commercially available anti-human epidermal growth factor receptor 2 (HER2) antibodies in whole-tissue sections and tissue microarrays (TMAs) of a series of gastric tumors. METHODS: We present a comparative analysis of three anti-HER2 antibodies (HercepTest, 4B5 and SP3) using TMA and whole-tissue sections prepared from the same paraffin blocks of 199 gastric adenocarcinomas operated upon between January 2004 and December 2008 at a Brazilian cancer hospital. The data on the patients' age, sex, the anatomical location of the tumor and the Lauren's histological classification were collected from clinical and pathological records. The immunohistochemical (IHC) results were examined by two pathologists and the cases were classified as positive (3+), equivocal (2+) and negative (0 or 1+), according to the criteria of the IHC scoring system of gastric cancer. TMAs and whole-tissue sections were evaluated separately and independently. All cases yielding discordant IHC results and/or scored as 2+ were subjected to dual-color in situ hybridization in order to determine the final HER2 status. Besides determining the sensitivity and predictive value for HER2-positive status, we measured the accuracy of each antibody by calculating the area under the receiver operating characteristic (ROC) curve. The agreement between the results obtained using the TMAs and those obtained using the whole-tissue sections was assessed by means of Kappa coefficient. RESULTS: Intratumoral heterogeneity of HER2 expression was observed with all antibodies. HER2-positive expression (3+) in the whole-tissue sections was observed in 23 cases (11.6%) using the 4B5 antibody, in 18 cases (9.1%) using the SP3 antibody and in 10 cases (5.1%) using the HercepTest antibody. In the TMAs, 11 positive cases (5.6%) were identified using SP3 antibody, 9 (4.6%) using the 4B5 antibody and 6 (3%) using the HercepTest antibody. The sensitivity using whole-tissue sections and TMA, respectively, was 95.2% and 42.9% with 4B5, 90.5% and 66.7% with SP3 and 47.6% and 42.9% with HercepTest. The accuracy, calculated from the area under the ROC curve, using whole-tissue sections and TMA, respectively, was 0.91 and 0.79 by 4B5, 0.86 and 0.80 by SP3 and 0.73 and 0.71 by HercepTest. The concordance of the results obtained using whole-tissue sections and TMA was 97.4% (Kappa 0.75) using HercepTest, 85.6% (Kappa 0.56) using SP3 and 84.1% (Kappa 0.38) using 4B5. CONCLUSION: The use of the 4B5 antibody on whole-tissue sections was the most accurate IHC method for evaluating HER2 expression in gastric adenocarcinoma.

Malignant fat-forming solitary fibrous tumor (lipomatous hemangiopericytoma) in the neck: Imaging and histopathological findings of a case.

Fat-forming solitary fibrous tumor (SFT) is a rare variant of solitary fibrous tumor, a mesenchymal fibroblastic neoplasia with a particular branching hypervascular pattern. This tumor is usually classified as benign and only very few fat-forming SFTs with malignant histologic features have been reported. We report a histologically malignant fat-forming solitary fibrous tumor in a 61-year-old man, located in his neck. Ultrasonography examination was first performed showing a heterogeneous lesion, predominantly hyperechoic, with sound beam attenuation, containing two hypoechoic solid nodules. Magnetic resonance imaging and computed tomography examinations demonstrated a heterogeneous and predominantly adipose mass, containing post contrast enhancing solid nodules and thin septations. Treatment consisted of total removal of the lesion. Histologically, the tumor showed hypercellularity, numerous mitoses and cytological atypia, fulfilling the criteria for malignancy. The patient had no metastasis. This rare tumor may be confused with other fat-containing lesions on imaging examinations, mainly liposarcoma.