Min-Shu Hsieh

Clinical and the Prognostic Characteristics of Lung Adenocarcinoma Patients with ROS1 Fusion in Comparison with Other Driver Mutations in East Asian Populations

Introduction: The prevalence, demographic features, and clinical outcomes of lung adenocarcinoma patients with novel ROS1 oncogenic rearrangement in East Asian populations are not clear. This study aimed to investigate the clinical and prognostic characteristics of lung adenocarcinoma in patients with ROS1 fusion compared with other driver mutations. Methods: Multiplex reverse transcription-polymerase chain reaction was used to detect the ROS1 fusion gene in lung adenocarcinoma cases. Immunohistochemistry was used to confirm the expression of ROS1. The demographic data and clinical outcomes of patients with the ROS1 fusion gene were compared with those of patients without the ROS1 fusion gene, including those with the EGFR mutation, EML4-ALK fusion, KRAS mutation, and quadruple-negative patients. Results: Of 492 patients with lung adenocarcinoma, 12 (2.4%) had the ROS1 fusion gene. Their median age was 45.0 years, significantly younger than that of the ROS1 fusion-negative cohorts (p < 0.001). Acinar (including cribriform) and solid patterns were the two most common histologic subtypes in the ROS1 fusion tumors (7 of 12, 58.3%) and were predominantly seen in CD74-ROS1 fusion tumors (66.7%). There was no significant survival difference between the ROS1 fusion-positive and ROS1 fusion-negative cohorts in surgical group, but ROS1 fusion-positive patients might have worse outcomes than EGFR-mutant patients in the stage IV group. Conclusions: The ROS1 fusion gene can be successfully detected in East Asian patients with lung adenocarcinoma using multiplex reverse transcription-polymerase chain reaction. These patients tend to be younger and have characteristic histologic subtypes. Due to the small number of ROS1 fusion patients, the prognostic value of ROS1 fusion need further studies to confirm.

SOX10-positive salivary gland tumors: a growing list, including mammary analogue secretory carcinoma of the salivary gland, sialoblastoma, low-grade salivary duct carcinoma, basal cell adenoma/adenocarcinoma, and a subgroup of mucoepidermoid carcinoma

Transcription factor SRY-related HMG-box 10 (SOX10) is an important marker for melanocytic, schwannian, myoepithelial, and some salivary gland tumors. The aim of this study was to investigate SOX10 expression more thoroughly in the salivary gland neoplasms, including mammary analogue secretory carcinoma and hyalinizing clear cell carcinoma harboring specific genetic rearrangements. A new rabbit monoclonal anti-SOX10 antibody (clone EP268) was used to examine SOX10 expression in 14 different types of salivary gland tumors. We found that acinic cell carcinoma (AciCC), adenoid cystic carcinoma, mammary analogue secretory carcinoma (MASC), epithelial-myoepithelial carcinoma, low-grade salivary duct carcinoma, sialoblastoma, basal cell adenocarcinoma, basal cell adenoma, and pleomorphic adenoma were SOX10 positive. Salivary duct carcinoma, lymphoepithelial carcinoma, hyalinizing clear cell carcinoma, and oncocytoma were SOX10 negative. Earlier, mucoepidermoid carcinoma (MEC) was considered a SOX10-negative tumor. This study identified a subgroup of SOX10-positive MEC cases with characteristic polygonal epithelial cells, pale-to-eosinophilic cytoplasm, and colloid-like dense eosinophilic material. Our data show SOX10 expression can be observed in salivary gland tumors with either one of the 4 cell types: acinic cells, cuboidal ductal cells with low-grade cytologic features, basaloid cells, and myoepithelial cells. In this article we thoroughly evaluated SOX10 expression in salivary gland tumors. SOX10 is useful in the differential diagnosis between myoepithelial carcinoma with clear cell features and hyalinizing clear cell carcinoma. It can also be used to discriminate low-grade salivary duct carcinoma from high-grade ones. Pathologists should be cautious with the interpretation of SOX10 positivity in salivary gland tumors, and correlation with histologic feature is mandatory.

Papillary-cystic pattern is characteristic in mammary analogue secretory carcinomas but is rarely observed in acinic cell carcinomas of the salivary gland

Mammary analogue secretory carcinoma (MASC) has a specific ETV6-NTRK3 translocation and morphologically overlaps with acinic cell carcinoma (AciCC). Before the recognition of MASC, in AciCC, four histologic patterns were identified including microcystic, solid, papillary-cystic, and follicular. The aim of this study was to evaluate histologic patterns in these two neoplasms through comprehensive histologic subtyping. Using fluorescence in situ hybridization (FISH), we identified 14 cases of MASC and 21 cases of AciCC. We used comprehensive histologic subtyping to provide a semiquantitive assessment of histologic patterns in each tumor and performed immunohistochemical analyses including S100/vimentin/mammaglobin/DOG1. MASC often presented papillary-cystic patterns without a solid component, previously considered to be one of the four major patterns associated with AciCC. However, in our study, this histologic feature was rarely seen in AciCC and more characteristic of MASC. In aspiration cytology samples, MASC was associated with more cellular atypia. An immunohistochemical panel of S100/mammaglobin/DOG1 was found useful for differential diagnosis. Comprehensive subtyping of histologic patterns is a useful screening method prior to initiation of molecular testing.

Clinical and prognostic implications of RET rearrangements in metastatic lung adenocarcinoma patients with malignant pleural effusion

OBJECTIVES RET rearrangements represent one of the newest molecular targets in non-small cell lung cancer (NSCLC). However, the prevalence, clinical characteristics, and outcome of patients with RET-rearranged lung adenocarcinoma in metastatic disease remain uncertain. MATERIALS AND METHODS Multiplex reverse transcription-polymerase chain reaction (RT-PCR) was used to detect KIF5B-RET and CCDC6-RET fusions from specimens of malignant pleural effusion (MPE) in patients with metastatic lung adenocarcinoma. The demographic data and outcome of patients with RET-rearranged tumors were compared with those with EGFR-mutant, KRAS-mutant, EML4-ALK-rearranged, and quadri-negative tumors. RESULTS Of the 722 patients with MPE of lung adenocarcinoma screened, 17 (2.4%) had RET-rearranged tumors. The detected RET rearrangements comprised 11 (65%) KIF5B-RET and 6 (35%) CCDC6-RET fusions, including 2 novel fusion variants identified. The presence of RET rearrangements was not associated with age at diagnosis, gender or smoking history, but predominantly seen in solid histological subtype. None of patients with RET-rearranged tumors had received kinase inhibitors with activity against RET kinase. The median overall survival was 22.4 months (95% CI, 8.8-36.0) for the 17 patients with RET-rearranged tumors, compared with 21.3 months (95% CI, 18.7-23.9; P=0.57) for the 451 patients with EGFR-mutant tumors, 5.4 months (95% CI, 2.7-8.1; P=0.002) for the 13 patients with KRAS-mutant tumors, 18.9 months (95% CI, 10.7-27.1; P=0.82) for the 51 patients with EML4-ALK-rearranged tumors, and 12.0 months (95% CI, 9.0-15.0; P=0.07) for the 190 patients with quadri-negative tumors. CONCLUSION Multiplex RT-PCR from specimens of MPE is feasible for the screening of RET rearrangements in NSCLC. Metastatic RET-rearranged lung adenocarcinoma patients with MPE might have favorable survival comparable to those with metastatic EGFR-mutant tumors.

NUT Midline Carcinoma Case Report and Review of the Literature

NUT midline carcinoma (NMC) is a recently described, undifferentiated carcinoma with specific NUT gene rearrangement, which often involves midline organs such as the nasal cavity, paranasal sinuses, mediastinum, or intrathoracic organs. It was previously considered a disease of children or young adults, but middle-aged or elderly patients have subsequently been seen. Here, the authors report the case of a 54-year-old woman who presented with a left-nasal-cavity mass and diplopia. The tumor enlarged rapidly and extended to the left orbital cavity and brain base despite chemotherapy and radiotherapy. Pathological examination of the resected tumor showed an undifferentiated carcinoma with occasional abrupt keratinizing squamous differentiation. Immunohistochemical analysis with an antibody to NUT revealed that most of the tumor cells were positive. BRD4-NUT gene fusion was demonstrated by fluorescence in situ hybridization, confirming the diagnosis of NMC. This case emphasizes the importance of considering NMC in the differential diagnosis in older adults.

Efficacy of Pemetrexed-Based Chemotherapy in Patients with ROS1 Fusion–Positive Lung Adenocarcinoma Compared with in Patients Harboring Other Driver Mutations in East Asian Populations

Introduction: The efficacy of pemetrexed‐based chemotherapy in patients with advanced lung adenocarcinoma with novel ROS proto‐oncogene 1, receptor tyrosine kinase gene (ROS1) oncogenic rearrangement is unclear. This study aimed to compare the efficacy of pemetrexed‐based chemotherapy in patients with advanced ROS1‐fusion lung adenocarcinoma with its efficacy in those having different driver mutations. Methods: We retrospectively identified patients with advanced lung adenocarcinoma who were screened for epidermal growth factor receptor gene (EGFR) mutations, echinoderm microtubule associated protein like 4 gene (EML4)–anaplastic lymphoma receptor tyrosine kinase gene (ALK) translocation, Kirsten rat sarcoma viral oncogene homolog gene (KRAS) mutations, and ROS1 fusion by using multiplex reverse‐transcriptase polymerase chain reaction. Patients who received pemetrexed‐based therapy were enrolled for further analysis. The demographic data, clinical outcomes, and thymidylate synthase immunostaining (H‐score) of patients with ROS1 fusion–positive lung adenocarcinomas were compared with those of patients harboring EGFR mutations, EML4‐ALK fusion, KRAS mutations, and quadruple negativity. Results: A total of 253 patients with advanced lung adenocarcinoma received a pemetrexed‐based regimen and were classified on the basis of molecular findings as follows: 102 patients (40.3%) with EGFR mutations, 32 patients (12.6%) with EML4‐ALK translocation, three patients (1.2%) with KRAS mutations, 19 patients (7.5%) with ROS1 fusion, and 97 patients (38.3%) with quadruple‐negative status. Patients with ROS1 fusion had a better overall response rate (57.9%, p = 0.026), disease control rate (89.5%, p = 0.033), and longer progression‐free survival (7.5 months, p = 0.003) compared with patients harboring other driver mutations. However, the H‐score of thymidylate synthase was not associated with the response to pemetrexed therapy in patients with different molecular subtypes of lung adenocarcinoma. Conclusions: ROS1 fusion positivity is probably a favorable factor of pemetrexed‐based therapy for patients with lung adenocarcinoma.

Myxoid Adrenal Cortical Carcinoma Presenting as Primary Hyperaldosteronism Case Report and Review of the Literature

The authors report a case of myxoid adrenal cortical carcinoma (ACC) clinically manifesting as primary hyperaldosteronism. The 82-year-old female patient had a history of hypertension and was sent to the emergency room because of change in consciousness. Ventricular fibrillation occurred, and severe hypokalemia was found. Increased renal loss of potassium, high serum aldosterone level, low renin activity, and a huge tumor in the left suprarenal area were revealed when tests were conducted to determine the cause of her hypokalemia. Left adrenalectomy was performed. The tumor measured 13 cm in diameter and showed a heterogeneous cut surface with gelatinous material. Microscopically, the lesion was composed of polygonal cells with eosinophilic cytoplasm and arranged in arborizing cords in a myxoid background. Capsular and vascular invasion were observed. The tumor stained positive for synaptophysin, melan-A, vimentin, and α-inhibin but negative for cytokeratin. A primary myxoid ACC was diagnosed, which is a rare histological variant. The authors review 13 other reported cases. Most of these were functional tumors causing Cushing syndrome, and only 2 cases presented as primary hyperaldosteronism. All cases had similar microscopic and immunohistochemical features. Distal metastases and local recurrence were not uncommon. Close clinical follow-up is imperative.

Genetic variants of EGF and VEGF predict prognosis of patients with advanced esophageal squamous cell carcinoma.

Purpose To investigate the association between genetic polymorphisms of growth factor-related genes and prognosis in patients with advanced esophageal squamous cell carcinoma (ESCC). Patients and Methods A total of 334 ESCC patients with advanced tumor stages (stages IIB, III and IV) were enrolled in the study. The genotypes of 14 candidate single nucleotide polymorphisms (SNPs) involved in growth factor-related functions were analyzed using iPLEX Gold technology from the genomic DNA of peripheral leukocytes, and were correlated with the clinical outcome of patients. Serum levels of growth factors were examined by enzyme-linked immunosorbent assay (ELISA). Results The genetic polymorphisms of EGF:rs4444903, EGF:rs2237051 and VEGF:rs2010963 showed significant associations with overall survival (OS) of advanced ESCC patients (A/A+ A/G vs. GG, [HR = 0.77, 95% CI = 0.60–0.99, P = 0.039 for rs4444903; A/G+ G/G vs. A/A, [HR = 0.74, 95% CI = 0.58–0.95, P = 0.019 for rs2237051; G/G+G/C vs. C/C, [HR] inves = 0.69, 95% CI = 0.50–0.95, P = 0.023 for rs2010963). EGFR:rs2227983 and 3 SNPs of PIK3CA also showed borderline significant correlation with OS of advanced ESCC patients (P = 0.058 for rs2227983; P = 0.069, 0.091 and 0.067 for rs6443624, rs7651265 and rs7621329 of PIK3CA respectively). According to cumulative effect analysis of multiple SNPs, patients carrying 4 unfavorable genotypes exhibited more than a 3-fold increased risk of mortality. Finally, both EGF and VEGF expression levels significantly associated with patient mortality. Conclusion The genetic variants and expression levels of EGF and VEGF can serve as prognostic predictors in patients with advanced ESCC, and thus provide more information for optimizing personalized therapies for patients with ESCC.

Colonic necrosis in a young patient receiving oral kayexalate in sorbitol: Case report and literature review

Kayexalate (sodium polystyrene sulfonate) is a cation‐exchange resin used to treat patients with hyperkalemia. Concomitant administration of kayexalate and sorbitol may induce gastrointestinal injury, which is potentially lethal. However, this well‐documented complication is often underrecognized both clinically and pathologically. We propose a typical case along with colonoscopic photos and microscopic pictures. Additionally, we also present a review of the literature on this rare drug‐induced side effect.

Hepatic Epithelioid Hemangioendothelioma in Taiwan: A Clinicopathologic Study of Six Cases in a Single Institution Over a 15-Year Period

BACKGROUND/PURPOSE Hepatic epithelioid hemangioendothelioma (HEH) is a rare vascular tumor of the liver typically with a slow but progressive course. We report the clinical and immunohistochemical characteristics of six cases from our institution between 1993 and 2008. METHODS We searched the files of the Department of Pathology in National Taiwan University Hospital from January 1993 to December 2008 and found six cases of primary HEH. The clinical data were reviewed. The microscopic findings of each case were listed and analyzed. Confirmational immunoperoxidase stains were performed with antibodies against two endothelial markers (CD31 and CD34) and one epithelial marker (AE1/AE3 or cytokeratin). RESULTS There were five female patients and one male patient with HEH, and the mean age was 45.3 years (range, 25-86 years). Most patients were asymptomatic and one third of cases presented as right costal or abdominal pain. Anemia was the most common laboratory abnormality. Liver failure developed at the advanced diffuse stage. Imaging studies revealed three different patterns as single nodular, multiple nodular, or diffuse types, reflecting different stages of disease and clinical symptoms. Microscopic findings included intracytoplasmic vascular lumen formation (100%), sinusoidal spreading (100%), vessel obliteration (66.7%), necrosis (66.7%), and cellular pleomorphism (16.7%). All cases expressed endothelial markers of CD31 and CD34, reflecting their vascular nature. Two patients received surgical treatment including partial liver resection and liver transplantation. Tumor recurrence developed 8 and 17 months later, respectively. CONCLUSION HEH showed insidious growth and frequent multicentricity, making early diagnosis and tumor resection difficult. Definite diagnosis totally relies on pathologic study. Tumor progression to hepatic failure is slow. Liver transplantation is currently the most prevalent treatment modality for HEH, but experience in Taiwan is limited due to the rarity of this disease.