Interpretation of PD-L1 expression in gastric cancer: summary of a consensus meeting of Korean gastrointestinal pathologists

Nivolumab plus chemotherapy in the first-line setting has demonstrated clinical efficacy in patients with human epidermal growth factor receptor 2–negative advanced or metastatic gastric cancer, and is currently indicated as a standard treatment. Programmed death-ligand 1 (PD-L1) expression is an important biomarker for predicting response to anti–programmed death 1/PD-L1 agents in several solid tumors, including gastric cancer. In the CheckMate-649 trial, significant clinical improvements were observed in patients with PD-L1 combined positive score (CPS) ≥ 5, determined using the 28-8 pharmDx assay. Accordingly, an accurate interpretation of PD-L1 CPS, especially at a cutoff of 5, is important. The CPS method evaluates both immune and tumor cells and provides a comprehensive assessment of PD-L1 expression in the tumor microenvironment of gastric cancer. However, CPS evaluation has several limitations, one of which is poor interobserver concordance among pathologists. Despite these limitations, clinical indications relying on PD-L1 CPS are increasing. In response, Korean gastrointestinal pathologists held a consensus meeting for the interpretation of PD-L1 CPS in gastric cancer. Eleven pathologists reviewed 20 PD-L1 slides with a CPS cutoff close to 5, stained with the 28-8 pharmDx assay, and determined the consensus scores. The issues observed in discrepant cases were discussed. In this review, we present cases of gastric cancer with consensus PD-L1 CPS. In addition, we briefly touch upon current practices and clinical issues associated with assays used for the assessment of PD-L1 expression in gastric cancer.

A Case of Acute Myocarditis as the Initial Presentation of Crohn's Disease

We experienced a case of acute myocarditis as the initial presentation of Crohn's disease. A 19-year-old woman was admitted with impaired consciousness, shock, and respiratory failure. She had suffered from frequent diarrhea and abdominal pain for several years. Cardiac troponin I and creatine kinase-MB fraction levels were elevated to 5.32 and 16.66 ng/mL, respectively. A 12-lead electrocardiogram showed sinus tachycardia, and a chest radiograph revealed interstitial pulmonary edema. An echocardiogram showed dilated ventricles with akinesia of the basal to apical inferoseptal, anteroseptal, anterior, and inferior left ventricular walls and severely impaired systolic function. Intensive care with inotropic support was effective, and her clinical condition gradually improved. Two weeks later, a colonoscopy revealed ulceration with stenosis in the terminal ileum and multiple aphthous ulcers in the rectum. A biopsy of the rectum revealed non-caseating granulomatous inflammation. She was diagnosed with Crohn's disease presenting with acute myocarditis.

Carcinoma ex Pleomorphic Adenoma of the Salivary Glands: Distinct Clinicopathologic Features and Immunoprofiles Between Subgroups According to Cellular Differentiation

In carcinoma ex pleomorphic adenoma (CXPA), pleomorphic adenoma (PA) and diverse carcinoma components showing luminal (ductal) or non-luminal (myoepithelial) differentiation coexist. To elucidate the clinicopathological implications of cellular differentiation in CXPA and the potential role of p53, vascular endothelial growth factor (VEGF), c-erbB-2, c-kit, and glucose transporter 1 (Glut-1) in carcinogenesis, we analyzed 11 CXPAs with luminal differentiation (CXPAs-LD) and 6 CXPAs with non-luminal differentiation (CXPAs-NLD) and compared protein expressions in residual PAs and carcinomas by immunohistochemistry. Among the CXPAs-LD, 5 were invasive and 8 were histologically high-grade tumors. The 5-year survival rate was 72.7%. P53, c-erbB-2, VEGF, and Glut-1 were more immunoreactive in carcinoma components than in PAs (P = 0.008, 0.004, 0.002, and 0.024, respectively); c-erbB-2 overexpression was associated with high histological grade (P = 0.024). Carcinoma components frequently lacked c-kit expression (P = 0.009). CXPAs-NLD were all low-grade and invasive with a larger mean tumor size (5.2 cm) than CXPAs-LD (3.3 cm) (P = 0.040). The patients remained disease-free without significant immunohistochemical expression. The immunoprofiles and clinical course of CXPA differed according to cellular differentiation. Therefore, it is important to report the histological subtype and to assess potential biomarkers in diagnostic and therapeutic trials.

A Metastatic Granulocyte Colony-Stimulating Factor Producing Sarcomatoid Carcinoma of the Lung Causing Jejunal Intussusception: Report of a Case

A 75-year-old man was referred to our hospital with intestinal obstruction caused by intussusception. Abdominal computed tomography (CT) revealed seven polypoid masses in the small intestine, while chest CT revealed a mass in the right lower lobe. Preoperative laboratory tests showed white blood cell (WBC) and neutrophil differential counts of 63,630/mm3 and 95%, respectively. The serum granulocyte colony-stimulating factor (G-CSF) was 114 pg/mL, which was elevated (normal range, <18.1 pg/mL). After resection of the small bowel, the WBC count decreased to 20,510/mm3. The pathology showed a poorly differentiated carcinoma with sarcomatous components confirmed by positive immunostaining of cytokeratin (AE1/AE3) and vimentin in the small intestine. Furthermore, immunohistochemistry with specific monoclonal antibodies against G-CSF was positive. A lung biopsy revealed the same histological findings as the small intestine lesion. Therefore, the patient was diagnosed as having a G-CSF producing sarcomatoid carcinoma of the lung with metastasis to the small intestine.

Sarcomatoid carcinoma of the mandible: report of a case

Sarcomatoid carcinoma is a rare and occurs mainly in the upper aerodigestive tract such as the oral cavity, esophagus and vocal cords. It is a unique variant of squamous cell carcinoma. We report the case of a patient with spindle cell squamous cell carcinoma involving the mandible. At initial examination, overlying mucosa of that lesion was normal appearance. One week later, that lesion showed ulcerative and bloody change and rapid growth in size. This case showed unpredictable rapid growth although rapid growth in size was suspected of undergoing malignancy.

A Case of Isolated Invasive Aspergillus Colitis Presenting with Hematochezia in a Nonneutropenic Patient with Colon Cancer

Gastrointestinal invasive aspergillosis is often reported as part of a disseminated infection, and rarely as an isolated organ infection. Isolated invasive Aspergillus colitis is very rare, being observed only in patients with hematological malignancy and neutropenia. We encountered an unusual case of isolated invasive Aspergillus colitis presenting with hematochezia in a nonneutropenic patient with colon cancer. Fungal hyphae with surrounding inflammatory cells and mucosal necrosis were observed during the histological examination of a biopsy sample obtained at endoscopy. This case indicates that isolated invasive Aspergillus colitis may develop in a variable context of immunosuppression.

Primary Splenic Vascular Lesions: A Clinicopathologic, Immunophenotypic and Radiopathologic Correlation Study of 40 Cases

BACKGROUND: Primary splenic vascular lesions include the tumor and the inflammatory condition. A primary splenic vascular tumor is rare but is the most common tumor of the benign primary splenic tumors. METHODS: We describe the clinicopathological, radiological, and immunophenotypical findings of 40 cases of primary vascular lesions identified at our hospital from 1996 to 2009. RESULTS: The patients included 18 men and 22 women, aged 12 to 74 years, with a mean of 43.3-years and median of 40-years. They comprised 14 hemangiomas (35%), 13 lymphangiomas (32.5%), three hamartomas (7.5%), three littoral cell angiomas (7.5%), three sclerosing angiomatoid nodular transformations (SANT, 7.5%) and four angiosarcomas (10%). The majority of the patients (65%) were asymptomatic. Some of the patients (32.5%) complained of abdominal pain, and 2.5% of the patients presented with fever. Metastases were identified in 75% of the patients with an angiosarcoma at the initial work-up. One angiosarcoma patient died of the disease despite adjuvant chemoradiotherapy. The radiological findings for hamartoma, littoral cell angioma, and SANT were nonspecific. Microscopically, six types of vascular lesions showed classic morphological and immunophenotypical features of their type. CONCLUSIONS: One should be aware of rare splenic vascular lesions when radiological findings are nonspecific. Histomorphological and immunophenotypical features are helpful for the differential diagnosis.

Double Intussusception in a Preterm Infant / 대한주산의학회잡지

Intussusception is a common surgical disorder in infancy. Intussusception in preterm infant is very rare and about 40 cases have been reported. Furthermore, double intussusception is extremely rare in children and there seems to be no such a case reported in preterm infant. We report a case of idiopathic double intussusception in the preterm infant, who was born at 25 weeks' gestation, underwent an explolaparotomy for bowel perforation on 39 days of life, and during the operation, an ileo-ileo-colic intussusception was found without a leading point.

Solitary Necrotic Nodule of the Liver Mimicking Metastasis in Patient with Early Gastric Cancer: 3T MRI and PET/CT Findings

Solitary necrotic nodule (SNN) of the liver is a very uncommon benign lesion, and it is detected incidentally as a rule. It is important to differentiate SNN radiologically from various single hepatic nodules because SNN mimics hepatic metastasis, especially in staging work up of known primary malignancy. The reported imaging findings of SNN are well-defined nodule without enhancement or with subtle peripheral enhancement. There has been no report about the target-like SNN of the liver and about the imaging finding of 3T magnetic resonance imaging and positron emission tomography. We report a case of targetlike SNN of the liver, mimicking hepatic metastasis, with findings of various imaging modalities and try to find a cause of this nodule according to the pathologic and literature review.

Comparison of Silver-Enhanced in situ Hybridization and Fluorescence in situ Hybridization for HER2 Gene Status in Breast Carcinomas / 한국유방암학회지

PURPOSE: Silver-enhanced in situ hybridization (SISH) is a newly developed method to evaluate HER2 gene amplification in invasive breast carcinomas. Most laboratories widely use fluorescence in situ hybridization (FISH) to evaluate the HER2 gene amplification status because FISH is a very sensitive and accurate technique. However, this technique is not the best because it requires specialized equipment and interpretation skills. We compared a new technique of SISH with FISH for assessing HER2 gene amplification in invasive breast carcinomas. METHODS: HER2 gene amplification was assessed in 165 cases of invasive breast carcinoma by FISH and SISH with constructing a tissue microarray. The tumors were assessed by the guidelines of the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP). Positivity was defined as a HER2/Chromosome 17 ratio greater than 2.2. Negativity was defined if the ratio was less than 1.8. The tumor was considered as equivocal for HER2 gene amplification if the ratio was between 1.8 and 2.2. The HER2 protein status was assessed. Immunostaining for HER2 protein was performed in a Benchmark automatic immunostaining device with using whole tissue sections. RESULTS: There was agreement of the HER2 gene amplification status by SISH and FISH in 162 of 165 cases, which is a concordance rate of 98.2% (kappa=0.94). There were three discrepant cases, with two of them being FISH positive and SISH negative (one case was IHC negative and one case was IHC positive) and one case was FISH negative and SISH equivocal. CONCLUSION: The 98.2% concordance between FISH and SISH meets the ASCO/CAP requirements for test validation of >95% concordance. These results indicate that SISH can be used as an alternative to FISH for assessing the HER2 gene amplification status in breast carcinomas.

Intravascular Leiomyosarcoma of the Femoral Vein: A Case Report

Intravascular leiomyosarcomas of the femoral vein are extremely rare. Our patient was initially diagnosed with a deep vein thrombosis based on ultrasonography and venography. The thrombectomy specimen consisted of typical spindle cells with variable anaplasia arranged in a fasciculating and interlacing pattern. The final diagnosis was proved to be an intravascular leiomyosarcoma confirmed by immunohistochemical studies for smooth muscle actin, desmin, vimentin, CD34 and CD68.

Correlation of Expression of galectin-3, skp2, p27 and cyclin D1 in Benign and Malignant Thyroid Lesions

BACKGROUND: The overexpression of cyclin D1 and galectin-3 and the loss of p27 in thyroid cancers have recently been reported by many studies. The S-phase kinase associated protein 2 (skp2) plays an important role in the degradation of p27. We compared the correlation of the expressions of galectin-3, p27, cyclin D1 and skp2 in thyroid lesions. METHODS: Sixty five cases were included in this study and immunohistochemical staining for galectin-3, skp2, p27 and cyclin D1 was performed. RESULTS: The expression of galectin-3 increased in the order of nodular hyperplasia, follicular adenoma, follicular carcinoma and papillary carcinoma (p<0.01). The expression rate of skp2 was 0% for nodular hyperplasia, 16.7% for follicular adenoma, 33.3% for follicular carcinoma and 16.7% for papillary carcinoma. The loss of the expression of p27 was more frequently detected in papillary carcinoma as compared with nodular hyperplasia (p<0.01). The increased expression of cyclin D1 was noted in follicular adenoma and carcinoma as compared with nodular hyperplasia (p=0.043). The expression of galectin-3 was related with the loss of a p27 expression (p<0.01), and the expression of skp2 was related with the expression of the cyclin D1 (p=0.022). CONCLUSIONS: Galectin-3 appears to be the most useful marker for making the diagnosis of thyroid lesions. The loss of a p27 expression can help differentiate nodular hyperplasia and papillary carcinoma, and the determining the expression of cyclin D1 may be helpful for the differential diagnosis of nodular hyperplasia and follicular neoplasm.

A Case of Plasma Cell Granuloma of Skull in a Patient with Systemic Lupus Erythematosus / 대한류마티스학회지

Plasma cell granuloma, a form of inflammatory pseudotumor, is a rare nonneoplastic lesion that is characterized by cellular proliferation composed predominantly of polyclonal plasma cells with other inflammatory cells in fibrovascular background. We have experienced an unusual case of plasma cell granuloma of skull that developed in a patient with systemic lupus erythematosus (SLE). A 42-year-old female diagnosed with SLE 13 years ago has complained of palpable scalp mass and headache beginning ten days previously. A brain magnetic resonance imaging showed intensely enhanced soft tissue mass with focal bone defect in right parietal bone and whole body positron emission tomography suggested high possibility of malignancy. Surgical tumor removal was performed. Biopsy specimen revealed inflammatory proliferation predominantly with mature plasma cells which were determined to be polyclonal in immunostaining. Currently, 4 months after surgery, the patient are on regular follow-up with oral medications (prednisolone, hydroxychloroquine) for SLE without evidence of recurrence.

Ruptured Epidermal Inclusion Cyst in the Axilla: A Case Report

Epidermal inclusion cysts, the most common type of simple epithelial cyst, are typically well-encapsulated, subepidermal and mobile nodules. They may occur anywhere, but are mostly found on the scalp, face, neck, trunk, and back. Less than 10% of epidermal inclusion cysts occur on the extremities, and even fewer are found on the palms, soles, and breasts. If epidermal inclusion cysts rupture, foreign body reaction, granulomatous reaction or abscess formation could follow. We described here the sonographic findings of ruptured epidermal inclusion cyst of the right axilla in a 33-year-old woman who presented with a palpable axillary mass forming an inflammatory abscess. Address for reprints : Hak Hee Kim, M.D., Department of Radiology, Asan Medial Center, University of Ulsan, College of Medicine 388-1 Pungnap-2dong, Songpa-gu, Seoul 138-736, Korea.

Expression of Survivin, HSP90, Bcl-2 and Bax Proteins in N-butyl-N-(4-hydroxybutyl)nitrosamine-induced Rat Bladder Carcinogenesis

BACKGROUND: Survivin belongs to the inhibitor of apoptosis family, and it has recently been found to be expressed in most solid tumors. Therefore, its expression is suggested to have prognostic significance. However, no data are available concerning the significance of survivin for the carcinogenesis of bladder cancer. METHODS: In order to induce urothelial tumor in the rat urinary bladder, 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) was administered to male Sprague-Dawley rats for 30 weeks. We used immunohistochemistry to investigate the expressions of survivin, HSP90, Bcl-2 and Bax in rat bladder carcinogenesis. RESULTS: Urothelial cell hyperplasia, papilloma, non-invasive urothelial carcinoma and invasive urothelial carcinoma appeared at 5, 10, 20 and 30 weeks, respectively. The expressions of survivin and HSP90 increased sequentially from normal mucosa, hyperplasia, papilloma, non-invasive urothelial carcinoma to invasive urothelial carcinoma. The expressions of Bcl-2 and Bax did not increase, however the number of cases with more than 1 of Bcl-2/Bax expression ratio increased sequentially during the progression of urothelial lesion. The expression of survivin showed a statistically significant correlation with the expression of HSP90 and the Bcl-2/Bax expression ratio. CONCLUSIONS: Our findings suggest that survivin may be involved in the carcinogenesis of rat bladder and its expression is correlated with the expression of HSP90 and the Bcl-2/Bax expression ratio.

Mast Cell and Macrophage Counts and Microvessel Density in Invasive Breast Carcinoma-Comparison Analysis with Clinicopathological Parameters / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The purpose of this study was to evaluate the clinicopathological significance of the microvessel density and macrophage and mast cell counts in invasive breast carcinomas. MATERIALS AND METHODS: 45 invasive breast carcinomas were immunohistochemically stained with the endothelial antigen, CD34, and macrophage marker, CD68. 0.1% toluidine blue was used to highlight mast cells. The microvessel and mast cell counts were performed at x200 magnification and the macrophages at x400 magnification. RESULTS: With the 45 invasive breast carcinomas, there were no statistically significant associations between the mast cell, macrophage and microvessel counts and the tumor size and lymph node status. ER and PR negative mast cells infiltrated more than in cases of positive stati, with statistical significance (p-value=0.010 and 0.005, respectively). The macrophage counts were negatively correlated with the PR status (p-value=0.030). With respect to the c-erbB-2 status, there was no significance correlation with the mast cell, macrophage and microvessel counts. The mast cell counts showed significantly positive correlation with the microvessel counts in the invasive breast carcinomas (p-value=0.015). In a comparison of the macrophage counts with the microvessel counts, a positive tendency for both parameters, but without statistical significance (p-value=0.310). CONCLUSION: Increasing numbers of mast cells and macrophages were recruited in invasive breast carcinomas, which contribute to angiogenesis. The microvessel density in invasive breast carcinomas had no statistically significant association with the tumor size, lymph node status, and histological grade, presence of DCIS component, estrogen/progesterone receptor status and cerbB-2 status. The evaluation of angiogenesis using these methods is not thought to provide an independent clinicopathological factor in invasive breast carcinomas.

Expression of Cyclins (D1, A, E, and B1) in N-butyl-N-(4-hydroxybutyl)nitrosamine-induced Rat Bladder Carcinogenesis

BACKGROUND: Cell cycle deregulation plays a major role in chemical multistage carcinogenesis.Therefore, the evaluation of cell cycle proteins is important. METHODS: In order to induce carcinogenesis in the rat urinary bladder, 0.05% N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)was administered to male Sprague-Dawley rats for 30 weeks. Expressions of cyclin D1, A, E, and B1 were examined by immunohistochemical stainings. RESULTS: Urothelial cell hyperplasia appeared at 5 weeks, followed by papilloma at 10 weeks. Superficial carcinoma was observed at 20 weeks, and invasive carcinoma developed in 40% (4/10) of the rats at 30 weeks. Expressions of cyclin D1 and A increased sequentially from normal mucosa throughhyperplasia, papilloma, and carcinoma (p<0.01). Expressions of cyclin D1, B1 and cyclin Ewere higher in invasive carcinomas than in superficial carcinomas (p<0.01). In contrast, therewas no significant difference in the expression of cyclin B1 between hyperplasia, papillomaand superficial carcinoma. CONCLUSIONS: The present results indicate the important roles of cyclin D1 and A in the development of BBN-induced urothelial carcinoma of rats. Aberrantexpression of cyclin B1 and E may contribute to the progression from superficial to invasivebladder cancer rather than tumorigenesis.

HER-2/neu Oncogene Amplification by Chromogenic in situ Hybridization and Immunohistochemical Expression of Topoisomerase II-alpha in the Breast Cancer

BACKGROUND: Amplifications of the HER-2/neu oncogene and the Topoisomerase II-alpha gene are important determiners of the response to chemotherapy in the breast cancer. For detecting HER-2/neu amplification, fluorescent in situ hybridization and immunohistochemistry are currently regarded as standard methods. Chromogenic in situ hybridization (CISH) is investigated as a new modification of in situ hybridization. The purpose of this study is to compare the efficacy of CISH and immunohistochemistry (IHC) in detecting HER-2/neu oncogene amplification and to investigate the prognostic significance of the HER-2/neu oncogene and the Topoisomerase II-alpha gene in breast cancer. METHODS: Using CISH and IHC the amplifications and protein expressions of the HER-2/neu oncogene were studied on paraffin sections of 43 infiltrating duct carcinomas. The expression of the Topoisomerase II-alpha gene was studied immunohistochemically. RESULTS: Of the 43 infiltrating duct carcinomas, amplifications of the HER-2/neu oncogene by CISH were observed in 8 cases (18.6%), and the HER-2/neu protein was deemed overexpressed by IHC in 9 cases (20.9%). The amplifications of the HER-2/neu oncogene showed a statistically significant correlation with tumor size, histological grade, and the Topoisomerase II-alpha index. The Topoisomerase II-alpha index showed a statistically significant correlation with tumor size, lymph node status, stage, histologic grade, and estrogen receptor status. CONCLUSIONS: CISH is a useful alternative for determining HER-2/neu amplification, especially for confirming the immunohistochemical staining results. HER-2/neu amplification and the Topoisomerase II-alpha gene index may be prognostic factors of breast cancer.