BRCA-mutated gastric adenocarcinomas are associated with chromosomal instability and responsiveness to platinum-based chemotherapy

Background@#Homologous recombination defect is an important biomarker of chemotherapy in certain tumor types, and the presence of pathogenic or likely pathogenic mutations involving BRCA1 or BRCA2 (p-BRCA) mutations is the most well-established marker for the homologous recombination defect. Gastric cancer, one of the most prevalent tumor types in Asia, also harbors p-BRCA mutations. @*Methods@#To investigate the clinical significance of p-BRCA mutations, we analyzed 366 gastric cancer cases through next-generation sequencing. We determined the zygosity of p-BRCA mutations based on the calculated tumor purity through variant allelic fraction patterns and investigated whether the presence of p-BRCA mutations is associated with platinum-based chemotherapy and a certain molecular subtype. @*Results@#Biallelic p-BRCA mutation was associated with better response to platinum-based chemotherapy than heterozygous p-BRCA mutation or wild type BRCA genes. The biallelic p-BRCA mutations was observed only in the chromosomal instability subtype, while all p-BRCA mutations were heterozygous in microsatellite instability subtype. @*Conclusions@#In conclusion, patients with gastric cancer harboring biallelic p-BRCA mutations were associated with a good initial response to platinum-based chemotherapy and those tumors were exclusively chromosomal instability subtype. Further investigation for potential association with homologous recombination defect is warranted.

Uterine Malignant Mixed Müllerian Tumors Following Treatment with Selective Estrogen Receptor Modulators in Patients with Breast Cancer: A Report of 13 Cases and Their Clinicopathologic Characteristics

BACKGROUND: Breast cancer treatment with selective estrogen receptor modulators (SERMs) increases the incidence of uterine malignant mixed Müllerian tumors (uMMMTs). We examine clinicopathologic characteristics and prognosis of SERM-associated uMMMTs (S-uMMMTs) and discuss possible pathogenetic mechanisms. METHODS: Among 28,104 patients with breast cancer, clinicopathologic features and incidence of uMMMT were compared between patients who underwent SERM treatment and those who did not. Of 92 uMMMT cases that occurred during the same period, incidence, dose, and duration of SERM treatment, as well as overall survival rate, were compared for patients with breast cancer who underwent SERM treatment and those who did not (S-uMMMT vs NS-uMMMT) and for patients without breast cancer (de novo-uMMMT). Histopathological findings and immunophenotypes for myogenin, desmin, p53, WT-1, estrogen receptor (ER) α, ERβ, progesterone receptor, and GATA-3 were compared between S-uMMMT and de novo-uMMMT. RESULTS: The incidence of S-uMMMT was significantly higher than that of NS-uMMMT (6.35-fold). All patients with SERM were postmenopausal and received daily 20–40 mg SERM. Cumulative SERM dose ranged from 21.9 to 73.0 g (mean, 46.0) over 39–192 months (mean, 107). Clinicopathologic features, such as International Federation of Gynecology and Obstetrics stage and overall survival, were not significantly different between patients with S-uMMMT and NS-uMMMT or between patients with S-uMMMT and de novo-uMMMT. All 11 S-uMMMT cases available for immunostaining exhibited strong overexpression/null expression of p53 protein and significantly increased ERβ expression in carcinomatous and sarcomatous components. CONCLUSIONS: SERM therapy seemingly increases risk of S-uMMMT development; however, clinicopathologic features were similar in all uMMMTs from different backgrounds. p53 mutation and increased ERβ expression might be involved in the etiology of S-uMMMT.

Clinical Utility of a Fully Automated Microsatellite Instability Test with Minimal Hands-on Time

BACKGROUND: Microsatellite instability (MSI) analysis is becoming increasingly important in many types of tumor including colorectal cancer (CRC). The commonly used MSI tests are either time-consuming or labor-intensive. A fully automated MSI test, the Idylla MSI assay, has recently been introduced. However, its diagnostic performance has not been extensively validated in clinical CRC samples.METHODS: We evaluated 133 samples whose MSI status had been rigorously validated by standard polymerase chain reaction (PCR), clinical next-generation sequencing (NGS) cancer panel test, or both. We evaluated the diagnostic performance of the Idylla MSI assay in terms of sensitivity, specificity, and positive and negative predictive values, as well as various sample requirements, such as minimum tumor purity and the quality of paraffin blocks.RESULTS: Compared with the gold standard results confirmed through both PCR MSI test and NGS, the Idylla MSI assay showed 99.05% accuracy (104/105), 100% sensitivity (11/11), 98.94% specificity (93/94), 91.67% positive predictive value (11/12), and 100% negative predictive value (93/93). In addition, the Idylla MSI assay did not require macro-dissection in most samples and reliably detected MSI-high in samples with approximately 10% tumor purity. The total turnaround time was about 150 minutes and the hands-on time was less than 2 minutes.CONCLUSIONS: The Idylla MSI assay shows good diagnostic performance that is sufficient for its implementation in the clinic to determine the MSI status of at least the CRC samples. In addition, the fully automated procedure requires only a few slices of formalin-fixed paraffin-embedded tissue and might greatly save time and labor.

High prevalence of TP53 mutations is associated with poor survival and an EMT signature in gliosarcoma patients

Gliosarcoma (GS) is a rare variant (2%) of glioblastoma (GBM) that poses clinical genomic challenges because of its poor prognosis and limited genomic information. To gain a comprehensive view of the genomic alterations in GS and to understand the molecular etiology of GS, we applied whole-exome sequencing analyses for 28 GS cases (6 blood-matched fresh-frozen tissues for the discovery set, 22 formalin-fixed paraffin-embedded tissues for the validation set) and copy-number variation microarrays for 5 blood-matched fresh-frozen tissues. TP53 mutations were more prevalent in the GS cases (20/28, 70%) compared to the GBM cases (29/90, 32%), and the GS patients with TP53 mutations showed a significantly shorter survival (multivariate Cox analysis, hazard ratio=23.9, 95% confidence interval, 2.87–199.63, P=0.003). A pathway analysis showed recurrent alterations in MAPK signaling (EGFR, RASGRF2 and TP53), phosphatidylinositol/calcium signaling (CACNA1s, PLCs and ITPRs) and focal adhesion/tight junction (PTEN and PAK3) pathways. Genomic profiling of the matched recurrent GS cases detected the occurrence of TP53 mutations in two recurrent GS cases, which suggests that TP53 mutations play a role in treatment resistance. Functionally, we found that TP53 mutations are associated with the epithelial–mesenchymal transition (EMT) process of sarcomatous components of GS. We provide the first comprehensive genome-wide genetic alternation profiling of GS, which suggests novel prognostic subgroups in GS patients based on their TP53 mutation status and provides new insight in the pathogenesis and targeted treatment of GS.

Good Laboratory Standards for Clinical Next-Generation Sequencing Cancer Panel Tests

Next-generation sequencing (NGS) has recently emerged as an essential component of personalized cancer medicine due to its high throughput and low per-base cost. However, no sufficient guidelines for implementing NGS as a clinical molecular pathology test are established in Korea. To ensure clinical grade quality without inhibiting adoption of NGS, a taskforce team assembled by the Korean Society of Pathologists developed laboratory guidelines for NGS cancer panel testing procedures and requirements for clinical implementation of NGS. This consensus standard proposal consists of two parts: laboratory guidelines and requirements for clinical NGS laboratories. The laboratory guidelines part addressed several important issues across multistep NGS cancer panel tests including choice of gene panel and platform, sample handling, nucleic acid management, sample identity tracking, library preparation, sequencing, analysis and reporting. Requirements for clinical NGS tests were summarized in terms of documentation, validation, quality management, and other required written policies. Together with appropriate pathologist training and international laboratory standards, these laboratory standards would help molecular pathology laboratories to successfully implement NGS cancer panel tests in clinic. In this way, the oncology community would be able to help patients to benefit more from personalized cancer medicine.

Mixed Carcinoid-Mucinous Adenocarcinoma Arising in Mature Teratoma of Mesentery

No abstract available.

Overexpression of C-reactive Protein as a Poor Prognostic Marker of Resectable Hepatocellular Carcinomas

BACKGROUND: C-reactive protein (CRP) is an acute phase reactant synthesized in the liver. CRP immunoreactivity is a feature of inflammatory hepatocellular adenomas with a higher risk of malignant transformation. A high serum CRP level denotes poor prognosis in hepatocellular carcinoma (HCC) patients. This study was conducted to determine whether CRP is produced in HCC and to assess the clinicopathologic significance of CRP expression in cancer cells. METHODS: CRP immunoreactivity was examined in treatment-naive HCCs (n=224) using tissue microarrays and was correlated with clinicopathologic parameters. The expression of CRP mRNA and protein was also assessed in 12 HCC cases by quantitative real-time polymerase chain reaction and immunoblotting. Hep3B and SNU-449 HCC cell lines were used for the analysis of CRP mRNA regulation by interleukin 6 (IL-6). RESULTS: CRP was expressed in 133 of 224 HCCs (59.4%) with a variable degree of immunoreactivity (grade 1 in 25.9%; grade 2 in 20.1%; grade 3 in 13.4%). There was an inverse relationship between grade 3 CRP immunoreactivity and cancer-specific survival (p=.0047), while no associations were found with other parameters, including recurrence-free survival. The CRP mRNA expression level was significantly higher in CRP immunopositive cases than in immunonegative cases (p<.05). CRP mRNA expression was increased in Hep3B cells, but was not detected in SNU-449 cells even after IL-6 treatment. CONCLUSIONS: We report the expression of CRP in HCC for the first time. CRP expression was associated with poor cancer-specific survival in patients with resectable HCC.

Accuracy of Core Needle Biopsy Versus Fine Needle Aspiration Cytology for Diagnosing Salivary Gland Tumors

BACKGROUND: Core needle biopsy is a relatively new technique used to diagnose salivary gland lesions, and its role in comparison with fine needle aspiration cytology needs to be refined. METHODS: We compared the results of 228 ultrasound-guided core needle biopsy and 371 fine needle aspiration procedures performed on major salivary gland tumors with their postoperative histological diagnoses. RESULTS: Core needle biopsy resulted in significantly higher sensitivity and more accurate tumor subtyping, especially for malignant tumors, than fine needle aspiration. No patient developed major complications after core needle biopsy. CONCLUSIONS: We recommend ultrasoundguided core needle biopsy as the primary diagnostic tool for the preoperative evaluation of patients with salivary gland lesions, especially when malignancy is suspected.

Peritoneal Carcinosarcoma and Ovarian Papillary Serous Carcinoma Are the Same Origin: Analysis of TP53 Mutation and Microsatellite Suggests a Monoclonal Origin

No abstract available.

Clinicopathological Analysis of 21 Thymic Neuroendocrine Tumors

BACKGROUND: Thymic neuroendocrine carcinomas (NECs) are uncommon, for which there is no established information available because of a limited number of epidemiological study in Asia. METHODS: We reviewed 21 cases of surgically resected thymic NECs, and evaluated their pathological and clinical features. RESULTS: It showed male predominance (male/female ratio, 15/6) with wide age range from 20 to 72 years (mean age, 49 years). All 21 cases were divided into two types according to the World Health Organization criteria: atypical carcinoid (n=18) and large cell NEC (n=3). Three cases of atypical carcinoid (AC) were associated with ectopic Cushing's syndrome. All the patients (3/3) with large cell NEC (3/3) and 16.7% (3/18) of those with AC died of tumor progression. Common sites of metastasis included lung, lymph node, brain, lumbar spine, mediastinum, bone, and liver. CONCLUSIONS: In conclusion, thymic neuroendocrine tumors carry a poor prognosis. Regarding the tumor classification, our results showed that a vast majority of carcinoids in the thymus correspond to ACs. In addition, our results also indicate that typical carcinoid is a very rare entity. Some cases of AC exhibited a large size, solid pattern and they showed aggressive clinical behavior, which highlights the spectrum of histologic appearances of thymic NECs.

Clinicopathological Analysis of 21 Thymic Neuroendocrine Tumors

BACKGROUND: Thymic neuroendocrine carcinomas (NECs) are uncommon, for which there is no established information available because of a limited number of epidemiological study in Asia. METHODS: We reviewed 21 cases of surgically resected thymic NECs, and evaluated their pathological and clinical features. RESULTS: It showed male predominance (male/female ratio, 15/6) with wide age range from 20 to 72 years (mean age, 49 years). All 21 cases were divided into two types according to the World Health Organization criteria: atypical carcinoid (n=18) and large cell NEC (n=3). Three cases of atypical carcinoid (AC) were associated with ectopic Cushing's syndrome. All the patients (3/3) with large cell NEC (3/3) and 16.7% (3/18) of those with AC died of tumor progression. Common sites of metastasis included lung, lymph node, brain, lumbar spine, mediastinum, bone, and liver. CONCLUSIONS: In conclusion, thymic neuroendocrine tumors carry a poor prognosis. Regarding the tumor classification, our results showed that a vast majority of carcinoids in the thymus correspond to ACs. In addition, our results also indicate that typical carcinoid is a very rare entity. Some cases of AC exhibited a large size, solid pattern and they showed aggressive clinical behavior, which highlights the spectrum of histologic appearances of thymic NECs.

Benign Metastasizing Leiomyoma with Multiple Lymph Node Metastasis: A Case Report / Journal of the Korean Cancer Association, 대한암학회지

This is a case report about benign metastasizing leiomyoma with multiple lymph node metastasis. A 34-year-old woman received an abdominal myomectomy for a suspicious leiomyoma. On the pathology report, atypical leiomyoma was suspected. Due to the suspicion of multiple lymph node metastasis on pelvis computed tomography (CT) 1 year after the operation, she was transferred to the Samsung Medical Center on October, 2009 for further work up. According to original slide review, it was determined to be a benign leiomyoma with a mitotic count <5/10 high-power fields, little cytological atypia and no tumor cell necrosis. Additional immunostaining was done. Multiple lymph node metastasis and a small lung nodule were identified on positron emission tomogarphy-CT and chest CT. Extensive debulking surgery and diagnostic video-assisted thoracoscopic surgery (VATS) wedge resection were subsequently done. Metastatic lesions were reported to have a histology similar to that of the original mass. VATS right upper lobectomy with mediastinal lymph node dissection was performed because of the pathology result of VATS (adenocarcinoma). She started taking an aromatase inhibitor (Letrozole(R)) and there was no evidence of recurrence of disease on an imaging study and no post-operative complications until recently.

Clinical significance of HIF-2alpha immunostaining area in radioresistant cervical cancer / 부인종양

OBJECTIVE: Hypoxia has been established as a key factor influencing the pathophysiology of malignant growth. Hypoxia-induced changes in gene expression are coordinated primarily by hypoxia inducible factor-1 alpha (HIF-1alpha) and HIF-2alpha. The purpose of this study was to determine whether or not HIF-2alpha expression is associated with survival and response to radiation in patients with cervical cancer. METHODS: After reviewing the medical records of 119 patients treated in our institution by primary therapy for stage IIB-IVA cervical cancer, we performed a case-control study. Cases (n=12) were selected from patients with local recurrence or radiation failure after primary radiation therapy with or without concurrent chemoradiation. For each case, we selected two controls from patients who had no evidence of local recurrence. Using pre-treatment paraffin-embedded tissues, we evaluated the expression of HIF-2alpha by immunohistochemistry. Staining was scored based on intensity (intensity score [IS], 0-3) and proportion (proportion score [PS], 0-100). The results were analyzed by the Student t-test, Mann-Whitney U test, Fisher's exact test, and Cox proportional hazards regression model. RESULTS: Cytoplasmic expression of HIF-2alpha, representing the degree of hypoxia, had a relationship with poor response to radiotherapy. The hazard ratio of recurrence was 1.71 for the HIF-2alpha IS (p=0.110) and 1.04 for the HIF-2alpha PS (p<0.001), indicating that the HIF-2alpha staining area correlates weakly with the risk for recurrence. CONCLUSION: The HIF-2alpha expression area may have an important role in radioresistance in patients with locally advanced cervical cancer. We conclude that a wider area of hypoxia predicts an increased probability of radioresistance.

Pulmonary Carcinoma with beta-Human Chorionic Gonadotropin Expression: Further Understanding and Suggestions for This Entity from Six Cases Experience in a Single Institution

PURPOSE: beta-human chorionic gonadotropin (beta-hCG) expressing pulmonary carcinoma is very rare, and little is known about this entity. The aim of this study was to find the characteristic clinicopathologic features of beta-hCG expressing pulmonary carcinoma. MATERIALS AND METHODS: Of all 2790 lobectomy specimens of lung excised between January 2006 and December 2010, only six cases of beta-hCG expressing pulmonary carcinoma were identified retrospectively. The cases were classified according to the WHO classification, and clinicopathologic features were investigated. RESULTS: The patients consisted of 4 males and 2 females, and the median age was 64 years. Half of the patients presented with blood tinged sputum or hemoptysis. The median tumor diameter was 4.2 cm. All but one case showed prominent area of hemorrhage and necrosis. All six cases were pleomorphic carcinoma, composed of various types of non-small cell carcinomatous component and giant cell component. All cases showed significant area of beta-hCG positivity, and beta-hCG was usually expressed in the pleomorphic giant cells. CONCLUSION: In pulmonary carcinoma with pleomorphic giant cells, is necessary to check immunohistochemical stain for beta-hCG and to follow up the serum beta-hCG levels, to further establish the concept of beta-hCG expressing pulmonary carcinoma.

A Case of Gastric Adenocarcinoma in a Patient with X-linked Agammaglobulinemia / 대한소화기내시경학회지

X-linked agammaglobulinemia is a common type of primary immunodeficiency disorder that's caused by mutation of the BTK gene. The absence of B lymphocytes and plasma cells causes recurrent infections. Patients with X-linked agammaglobulinemia also have a high risk for developing hematological malignancies and, to a lesser degree, carcinoma. We report here on a 26-years-old male patient who suffered with X-linked agammaglobulinemia that was caused by BTK gene mutation, and he developed a gastric cancer in the antrum. He was noted to have chronic atrophic gastritis and diffuse intestinal metaplasia on the endoscopic examination that was done 7 years previously. We recommend regular esophagogastroduodenoscopic evaluation for a patient with X-linked agammaglobulinemia in order to make an early diagnosis of stomach carcinoma.

Papillary Thyroid Carcinoma of a Diffuse Sclerosing Variant: Ultrasonographic Monitoring from a Normal Thyroid Gland to Mass Formation

A diffuse sclerosing variant of papillary thyroid carcinoma is uncommon and has a tendency for rapid growth and a higher incidence of cervical lymph node metastases. We experienced a case of a diffuse sclerosing variant of papillary thyroid carcinoma in a 48-year-old man. This case showed benign features on initial ultrasonography and positron emission tomography (PET) scan. A new nodule was detected on follow-up ultrasonography that showed rapid enlargement. This case was confirmed by surgical excision. We herein describe the initial and follow-up ultrasonographic findings of a diffuse sclerosing variant of papillary thyroid carcinoma.

Mucinous Bronchioloalveolar Carcinoma Associated with Bronchiectatic Cyst: A Brief Case Report

Herein we report a rare case of mucinous bronchioloalveolar carcinoma (BAC) associated with a solitary bronchiectatic cyst in a 29-year-old man. The patient presented with hemoptysis and had a history of pulmonary tuberculosis. Chest radiographs and computed tomography revealed a well-circumscribed, thin-walled cavitary lesion in the right upper pulmonary lobe. Gross examination of a lobectomy specimen showed a bronchiectatic cavity and a fungus ball within it. There were also several ill-defined small gray-white nodules around the cyst, nodules that were mucinous BAC. On microscopy, they were composed of columnar tumor cells along the intact alveolar walls in a single layer.

Mucinous Bronchioloalveolar Carcinoma Associated with Bronchiectatic Cyst: A Brief Case Report

Herein we report a rare case of mucinous bronchioloalveolar carcinoma (BAC) associated with a solitary bronchiectatic cyst in a 29-year-old man. The patient presented with hemoptysis and had a history of pulmonary tuberculosis. Chest radiographs and computed tomography revealed a well-circumscribed, thin-walled cavitary lesion in the right upper pulmonary lobe. Gross examination of a lobectomy specimen showed a bronchiectatic cavity and a fungus ball within it. There were also several ill-defined small gray-white nodules around the cyst, nodules that were mucinous BAC. On microscopy, they were composed of columnar tumor cells along the intact alveolar walls in a single layer.

A Case of Degos' Disease Presenting with Abdominal Angina and Widespread Skin Lesions

Malignant atrophic papulosis (MAP), also known as Degos' disease, is a rare and often fatal occlusive thrombotic vasculopathy, with fewer than seven cases reported in Korea. MAP is characterized by porcelain-white, atrophic, papular skin lesions and multi-organ system involvement, especially the gastrointestinal (GI) tract and nervous system. Involvement of the GI tract is usually associated with a poor prognosis. To date, no treatment has been shown to be effective in the treatment of MAP. We describe a 52-year-old man who presented with a 5-month history of abdominal angina and a 2-year history of multiple skin lesions on the trunk and extremities. The skin lesions were papules, 4-6 mm in diameter, with a porcelain-white center and a slightly raised erythematous telangiectatic rim. A biopsy of a skin lesion showed a wedge-shaped degeneration of collagen in the dermis and atrophic epidermis. An explorative laparoscopy revealed multiple, yellow-white plaques scattered throughout the small bowel. A biopsy of the small bowel showed sclerotic vascular alterations containing intravascular fibrin thrombi. He was started on aspirin (100 mg daily) and has survived for 24 months since the onset of gastrointestinal symptoms.

A Case of Degos' Disease Presenting with Abdominal Angina and Widespread Skin Lesions

Malignant atrophic papulosis (MAP), also known as Degos' disease, is a rare and often fatal occlusive thrombotic vasculopathy, with fewer than seven cases reported in Korea. MAP is characterized by porcelain-white, atrophic, papular skin lesions and multi-organ system involvement, especially the gastrointestinal (GI) tract and nervous system. Involvement of the GI tract is usually associated with a poor prognosis. To date, no treatment has been shown to be effective in the treatment of MAP. We describe a 52-year-old man who presented with a 5-month history of abdominal angina and a 2-year history of multiple skin lesions on the trunk and extremities. The skin lesions were papules, 4-6 mm in diameter, with a porcelain-white center and a slightly raised erythematous telangiectatic rim. A biopsy of a skin lesion showed a wedge-shaped degeneration of collagen in the dermis and atrophic epidermis. An explorative laparoscopy revealed multiple, yellow-white plaques scattered throughout the small bowel. A biopsy of the small bowel showed sclerotic vascular alterations containing intravascular fibrin thrombi. He was started on aspirin (100 mg daily) and has survived for 24 months since the onset of gastrointestinal symptoms.