Invasive lobular carcinoma enclosed by a benign phyllodes tumor: A case report.

INTRODUCTION AND IMPORTANCE: Phyllodes tumors (PT) account for approximately 1% of all breast tumors. The coexistence of phyllodes tumor and invasive lobular carcinoma in the ipsilateral breast is extremely rare with fewer than six cases reported worldwide in the last 20 years. We hereby present the first in Taiwan. CASE PRESENTATION: A 43-year-old female was presented with a protruding tumor with bleeding tendency over left breast in 2016. Breast sonography revealed highly suspected malignancy (ACR BI-RADS category 5). Computed tomography scan disclosed a protruding mass occupying the left breast. Core needle biopsy showed a fibroepithelial lesion favoring fibroadenoma. Considering clinicopathological discrepancy, a nipple-sparing mastectomy was conducted. Pathology report revealed a benign PT with an incidental finding of invasive lobular carcinoma (pT1cN0) within the tumor. Due to tumor recurrence, the patient received re-operation of total mastectomy in 2017, and is under regular adjuvant hormonal therapy without cancer recurrence to date. CLINICAL DISCUSSION: Physicians could easily overlook carcinomas enclosed by PTs due to its occult property. However, when carcinomatous changes arise from within or along with the PT, the proposed therapeutical course may be altered. Moreover, invasive carcinoma components in PTs possess potential for lymph node metastasis. Multidisciplinary cooperation is key in detecting and managing PT with synchronous carcinomatosis. CONCLUSION: Thorough examination of the excised tumor specimen and ensuring an adequate surgical margin is necessary. Sentinel lymph node biopsy (SLNB) should be considered whenever suspicious clinical features occur in PT patients. This may aid in the detection of microscopic invasive carcinomatous change.

Discordance of Mutation Statuses of Epidermal Growth Factor Receptor and K-ras between Primary Adenocarcinoma of Lung and Brain Metastasis.

Mutations on epidermal growth factor receptor (EGFR) of adenocarcinomas of lung have been found to be associated with increased sensitivity to EGFR tyrosine kinase inhibitors and K-ras mutations may correlate with primary resistance. We aimed to explore the discordant mutation statuses of EGFR and K-ras between primary tumors and matched brain metastases in adenocarcinomas of lung. We used a sensitive Scorpion ARMS method to analyze EGFR mutation, and Sanger sequencing followed by allele-specific real-time polymerase chain reaction to analyze K-ras mutation. Forty-nine paired tissues with both primary adenocarcinoma of lung and matched brain metastasis were collected. Thirteen patients (26.5%) were discordant for the status of EGFR between primary and metastatic sites. K-ras gene could be checked in paired specimens from 33 patients, thirteen patients (39.6%) were discordant for the status of K-ras. In primary lung adenocarcinoma, there were 14 patients of mutant EGFR had mutant K-ras synchronously. This study revealed that the status of EGFR mutation in lung adenocarcinomas is relatively consistent between primary and metastatic sites compared to K-ras mutation. However, there are still a few cases of adenocarcinoma of lung showing discordance for the status of EGFR mutation. Repeated analysis of EGFR mutation is highly recommended if tissue from metastatic or recurrent site is available for the evaluation of target therapy.

The 58-kda microspherule protein (MSP58) represses human telomerase reverse transcriptase (hTERT) gene expression and cell proliferation by interacting with telomerase transcriptional element-interacting factor (TEIF).

58-kDa microspherule protein (MSP58) plays an important role in a variety of cellular processes including transcriptional regulation, cell proliferation and oncogenic transformation. Currently, the mechanisms underlying the oncogenic effect of MSP58 are not fully understood. The human telomerase reverse transcriptase (hTERT) gene, which encodes an essential component for telomerase activity that is involved in cellular immortalization and transformation, is strictly regulated at the gene transcription level. Our previous study revealed a novel function of MSP58 in cellular senescence. Here we identify telomerase transcriptional element-interacting factor (TEIF) as a novel MSP58-interacting protein and determine the effect of MSP58 on hTERT transcription. This study thus provides evidence showing MSP58 to be a negative regulator of hTERT expression and telomerase activity. Luciferase reporter assays indicated that MSP58 could suppress the transcription ofhTERTpromoter. Additionally, stable overexpression of MSP58 protein in HT1080 and 293T cells decreased both endogenous hTERT expression and telomerase activity. Conversely, their upregulation was induced by MSP58 silencing. Chromatin immunoprecipitation assays showed that MSP58 binds to the hTERT proximal promoter. Furthermore, overexpression of MSP58 inhibited TEIF-mediated hTERT transactivation, telomerase activation, and cell proliferation promotion. The inhibitory effect of MSP58 occurred through inhibition of TEIF binding to DNA. Ultimately, the HT1080-implanted xenograft mouse model confirmed these cellular effects. Together, our findings provide new insights into both the biological function of MSP58 and the regulation of telomerase/hTERT expression.

Clinical significance of erythropoietin receptor expression in oral squamous cell carcinoma.

BACKGROUND: Hypoxic tumors are refractory to radiation and chemotherapy. High expression of biomarkers related to hypoxia in head and neck cancer is associated with a poorer prognosis. The present study aimed to evaluate the clinicopathological significance of erythropoietin receptor (EPOR) expression in oral squamous cell carcinoma (OSCC). METHODS: The study included 256 patients who underwent primary surgical resection between October 1996 and August 2005 for treatment of OSCC without previous radiotherapy and/or chemotherapy. Clinicopathological information including gender, age, T classification, N classification, and TNM stage was obtained from clinical records and pathology reports. The mRNA and protein expression levels of EPOR in OSCC specimens were evaluated by Q-RT-PCR, Western blotting and immunohistochemistry assays. RESULTS: We found that EPOR were overexpressed in OSCC tissues. The study included 17 women and 239 men with an average age of 50.9 years (range, 26-87 years). The mean follow-up period was 67 months (range, 2-171 months). High EPOR expression was significantly correlated with advanced T classification (p < 0.001), advanced TNM stage (p < 0.001), and positive N classification (p = 0.001). Furthermore, the univariate analysis revealed that patients with high tumor EPOR expression had a lower 5-year overall survival rate (p = 0.0011) and 5-year disease-specific survival rate (p = 0.0017) than patients who had low tumor levels of EPOR. However, the multivariate analysis using Cox's regression model revealed that only the T and N classifications were independent prognostic factors for the 5-year overall survival and 5-year disease-specific survival rates. CONCLUSIONS: High EPOR expression in OSCC is associated with an aggressive tumor behavior and poorer prognosis in the univariate analysis among patients with OSCC. Thus, EPOR expression may serve as a treatment target for OSCC in the future.

58-kDa microspherule protein (MSP58) is novel Brahma-related gene 1 (BRG1)-associated protein that modulates p53/p21 senescence pathway.

The nucleolar 58-kDa microspherule protein (MSP58) protein is a candidate oncogene implicated in modulating cellular proliferation and malignant transformation. In this study, we show that knocking down MSP58 expression caused aneuploidy and led to apoptosis, whereas ectopic expression of MSP58 regulated cell proliferation in a context-dependent manner. Specifically, ectopic expression of MSP58 in normal human IMR90 and Hs68 diploid fibroblasts, the H184B5F5/M10 mammary epithelial cell line, HT1080 fibrosarcoma cells, primary mouse embryonic fibroblasts, and immortalized NIH3T3 fibroblasts resulted in induction of premature senescence, an enlarged and flattened cellular morphology, and increased senescence-associated ß-galactosidase activity. MSP58-driven senescence was strictly dependent on the presence of functional p53 as revealed by the fact that normal cells with p53 knockdown by specific shRNA or cells with a mutated or functionally impaired p53 pathway were effective in bypassing MSP58-induced senescence. At least two senescence mechanisms are induced by MSP58. First, MSP58 activates the DNA damage response and p53/p21 signaling pathways. Second, MSP58, p53, and the SWI/SNF chromatin-remodeling subunit Brahma-related gene 1 (BRG1) form a ternary complex on the p21 promoter and collaborate to activate p21. Additionally, MSP58 protein levels increased in cells undergoing replicative senescence and stress-induced senescence. Notably, the results of analyzing expression levels of MSP58 between tumors and matched normal tissues showed significant changes (both up- and down-regulation) in its expression in various types of tumors. Our findings highlight new aspects of MSP58 in modulating cellular senescence and suggest that MSP58 has both oncogenic and tumor-suppressive properties.

Anaplastic large cell lymphoma with paraneoplastic leukocytosis: a clinicopathological analysis of five cases.

Anaplastic large cell lymphoma (ALCL) is a type of T-cell lymphoma with a relatively favorable prognosis. However, a certain group of ALCLs is highly aggressive, featuring paraneoplastic leukocytosis (PL) in clinical presentation. The present study evaluated five cases of ALCL presenting with PL, including four men and one woman, with a median age of 58 years. All cases revealed leukocytosis with a range from 15.3 to 112.9 × 10(3) /µL. Five (100%) and 4 (80%) cases demonstrated immunoreactivity for granulocyte-colony-stimulating factor (G-CSF) and tumor necrosis factor-alpha (TNF-α), respectively. There were significant differences in the expression of G-CSF and TNF-α between ALCL cases with or without PL (p < 0.05 for both). The prognosis of ALCL patients with PL was poor. Four of five patients (80%) died of the disease within a median survival time of 3.5 weeks. The release of G-CSF and TNF-α from lymphoma cells may associate with ALCL presenting with PL, leading to cytokine crisis and even poorer prognosis.

Clinical and pathological determinants in tonsillar cancer.

BACKGROUND: The purpose of this study was to present the impact of clinicopathological factors on patient survival in tonsillar squamous cell carcinoma (SCC) that needs to be evaluated. METHOD: This study enrolled 86 patients with tonsillar SCC undergoing surgical resection. RESULTS: The cumulative 5-year disease-specific survival (DSS) rate for stages I, II, III, and IVa/b tumors was 100%, 91.7%, 100%, and 61.8%, respectively. Unfavorable cumulative 5-year DSS rates were significantly correlated with advanced T classification (p = .029), tumor thickness over 1 cm (p = .007), 3 or more positive neck lymph nodes (p < .001), and extracapsular spread (ECS; p = .002). Cox regression analysis revealed that the presence of 3 or more positive neck lymph nodes (p = .035) and the stage IVa/b (p = .022) were the independent predictors of the 5-year DSS. CONCLUSION: Patients with tonsillar SCC with stage IVa/b and metastasis to 3 or more lymph nodes have poorer clinical outcomes. Novel therapeutic strategies are necessary for these patients.

Clear cell meningioma with frequent chordoid features and aggressive behavior: a clinicopathologic study of ten cases at a single institution.

Clear cell meningioma is an uncommon variant of meningiomas that often occurs in young patients, shows a proclivity for spinal intradural extramedullary and cerebellopontine angle, and follows an aggressive clinical course. We render clinicopathologic features of ten cases of this rare tumor to further elucidate its behavior. Fifteen specimens of clear cell meningioma belonging to ten patients were obtained at a single institution from 2001 to 2009. Correlations of histologic parameters, immunohistochemical study, and clinical features were assessed. This series included eight men and two women with a mean age of 62.1 years at the first surgery. The mean post-operative follow-up period was 3.9 years. Four patients (40%) had single or multiple local tumor recurrences. The mean time to recurrence was 2.3 years. Seven tumors (46.7%) were combined with chordoid features. There was a wide range of MIB-1 labeling indices (4.4-33.5%, mean 15.8%), which were higher in recurrent tumors, tumors with chordoid features, and tumors with necrosis. There was no correlation between MIB-1 labeling indices and brain invasion. The study illustrates aggressive behavior of clear cell meningioma and frequently combined chordoid features in our cases.

Primary orbital meningioma: a study of six cases at a single institution.

Primary orbital meningioma is a rare tumor of the anterior visual pathway and constitutes approximately 2% of all orbital tumors and 1-2% of all meningiomas. The differentiation from secondary orbital meningioma of intracranial origin is sometimes difficult on image. As the tumor often leads to visual loss if left untreated and surgical intervention inevitably causes morbidity, the timing and modality of treatment are very important. We carried out the study involving six cases (mean age: 42.7 years, male to female ratio: 1:5) of primary orbital meningioma to further elucidate its behavior. The clinical signs and symptoms, diagnosis, treatment strategies, and follow-up information are recorded for all cases. The most frequent initial symptoms were visual complaints (100%) and proptosis (67%). In five cases, the diagnosis was based on pathologic findings and the tumors were all grade I meningiomas. In one case, however, the diagnosis was based on radiographic and clinical findings, lacking histologic confirmation. Five patients were operated on, four underwent tumor removal, and one received eyeball exenteration. One patient was treated with Novalis radiotherapy. The mean follow-up period was 8.8 years (range from 9 months to 15 years). All patients experienced loss of vision during the course without exception. No recurrent tumor was found in five cases during follow-up. In case 5, whose eyeball was exenterated, developed recurrent meningioma 7 years later. She received radiotherapy but the tumor was out of control. She expired 8 years after eyeball exenteration. The primary orbital meningioma is aggressive in behavior despite its benign histopathologic features. Loss of vision is frequently seen even after treatment. The tumor could be fatal if surgery and radiotherapy fail to control its intracranial extension.

Synchronous presentation of uterine leiomyosarcoma and retroperitoneal liposarcoma: analysis by comparative genomic hybridization and review of the literature.

Multiple primary malignant neoplasms are not uncommon, whereas 2 different types of primary sarcomas simultaneously presenting in 1 individual is quite unusual. We encountered a patient presenting with a uterine sarcoma and another retroperitoneal mass at the same time. These 2 tumors showed distinct pathologic and immunohistochemical features. The diagnosis of a synchronous presentation of a uterine leiomyosarcoma and a retroperitoneal sclerosing well-differentiated liposarcoma was rendered. Further study by comparative genomic hybridization showed unrelated genomic alterations of these 2 tumors. Nevertheless, other common genetic alterations such as balanced translocations, point mutations, or epigenetic modifications could still exist because of the limitation of findings by comparative genomic hybridization. In conclusion, both metastasis and multiple primary tumors should always be taken into consideration in differential diagnosis while encountering synchronous sarcomas.

Most primary adrenal lymphomas are diffuse large B-cell lymphomas with non-germinal center B-cell phenotype, BCL6 gene rearrangement and poor prognosis.

Primary adrenal lymphoma is extremely rare, accounting for <1% of non-Hodgkin lymphomas, and lymphoma-associated chromosomal translocations have yet to be reported in this entity. We performed a retrospective study of 10 cases in immunocompetent patients including 4 males and 6 females with a median age of 68 years. The most common presenting symptoms were abdominal pain and fever; unexpectedly, clinically evident adrenal insufficiency was detected only in one patient. The mean tumor size at diagnosis was 8.5 cm. Half of the patients had bilateral involvement. All cases presented with stage IE disease without regional nodal involvement. Histologically, eight cases were diffuse large B-cell lymphoma, all of which carried a non-germinal center B-cell phenotype. Fluorescence in situ hybridization revealed BCL6 gene rearrangement in 5 (83%) of 6 diffuse large B-cell lymphomas investigated. The remaining cases were one case each of plasmablastic lymphoma and extranodal NK/T-cell lymphoma, nasal type, the first and third case of primary adrenal lymphoma of these particular lymphoma subtypes in the English literature, respectively. At a median follow-up of 4.5 months, 7 patients died of lymphoma, 1 died of an unrelated disease, 1 was alive with disease, and 1 was alive without disease. The prognosis of these patients was poor as compared with those with nodal diffuse large B-cell lymphoma. We speculate that the poor outcome of primary adrenal lymphoma might be related to the bulky tumor size at presentation, non-germinal center B-cell phenotype, and frequent BCL-6 gene rearrangement.

Ossifying thymoma clinically presenting with peripheral T-cell lymphocytosis.

We believe there has been only one ossifying thymoma reported in the English literature. We herein reported another such case with additional peculiar presentation of peripheral T-cell lymphocytosis. A 62-year-old woman was incidentally found to have an anterior mediastinal tumor during a medical check-up, which was surgically resected 42 months later and histopathologically confirmed to be a type B1 thymoma with stromal ossification. Fifty months after tumor removal, this patient remains alive and well without relapsed disease.