Aggressive multifocal form of epithelioid hemangioendothelioma--case report

Epithelioid hemangioendothelioma (EHE) is a rare tumor of the vascular origin. It was first described in its pulmonary form by Dail and Leibow in 1975 and named "intravascular bronchioalveolar tumor" (IVBAT). Since then, reports of occurrences of the tumor have been made for number of locations, but most often tumor can be found in soft tissues, liver, lungs, bone and skin. It is considered to be a low or borderline malignant tumor with, usually, slow progression, but aggressive forms have been described. We here report a case of a 46-year old female patient with multifocal malignant tumor spreading to lungs, liver, spleen and with synchronous involvement of lumbal vertebrae, illiac bones and central nervous system dissemination. To the best of the authors knowledge, no case of malignant EHE with multiorgan involvement of this proportions and synchronous central nervous system and bone involvement in one patient has been reported to this date in English-speaking literature.     

Training stem cells for treatment of malignant brain tumors

The treatment of malignant brain tumors remains a challenge. Stem cell technology has been applied in the treatment of brain tumors largely because of the ability of some stem cells to infiltrate into regions within the brain where tumor cells migrate as shown in preclinical studies. However, not all of these efforts can translate in the effective treatment that improves the quality of life for pa-tients. Here, we perform a literature review to identify the problems in the field. Given the lack of efficacy of most stem cell-based agents used in the treatment of malignant brain tumors, we found that stem cell distribution(i.e., only a fraction of stem cells applied capable of targeting tumors) are among the limiting factors. We provide guidelines for potential improvements in stem cell distribution. Specifically, we use an engineered tissue graft platform that replicates the in vivo microenvironment, and provide our data to validate that this culture platform is viable for producing stem cells that have better stem cell distribution than with the Petri dish culture system.     

Long-term follow-up of patients treated with radical surgery for rectal cancer

In developed societies colorectal cancer (CRC) is the second most frequent malignant tumor which causes more than 5000 deaths yearly in Hungary. We have attempted to answer the question how to improve the above mentioned data by the long-term follow-up of patients operated upon for rectal cancer at our department. Of the patients operated on for rectal cancer at our department between March 1990 and April 2006, we have conducted regular follow-up of 297 patients according to a protocol developed by us. We have examined the length of time between the rectum operation and the diagnosis and the number of local recurrences, distant metastases, tumor progression in more than one organ as well as second tumors (independent of the rectal cancer). During this period we found 24 local recurrences, 32 distant metastases, 43 tumor progressions in more than one organ, and 21 second tumors. In two patients, in addition to distant metastases, we found a second CRC independent of the original rectal cancer, and in one patient with tumor progression in more than one organ we also detected breast cancer. In one patient we found 3 second tumors (CR, lung and urinary bladder) independent of the original rectal cancer. Altogether we found tumors in 117 out of 297 patients. During the same period, we performed 69/117 operations and 31/117 patients were alive at the end of our study with a median survival of 60.4 (3-184) months. In summary, we can state that this work is beneficial for curing the recurrence of rectal cancer, making the patients' life longer or making the quality of life better for the patients operated on for rectal cancer.     

Molecular parameters associated with insulinoma progression: chromosomal instability versus p53 and CK19 status

Insulinomas represent the predominant syndromic subtype of endocrine pancreatic tumors (EPTs). Their metastatic potential cannot be predicted reliably using histopathological criteria. In the past few years, several attempts have been made to identify prognostic markers, among them TP53 mutations and immunostaining of p53 and recently cytokeratin 19 (CK19). In a previous study using conventional comparative genomic hybridization (CGH) we have shown that chromosomal instability (CIN) is associated with metastatic disease in insulinomas. It was our aim to evaluate these potential parameters in a single study. For the determination of CIN, we applied CGH to microarrays because it allows a high-resolution detection of DNA copy number changes in comparison with conventional CGH as well as the analysis of chromosomal regions close to the centromeres and telomeres, and at 1pter-->p32, 16p, 19 and 22. These regions are usually excluded from conventional CGH analysis, because they may show DNA gains in negative control hybridizations. Array CGH analysis of 30 insulinomas (15 tumors of benign, eight tumors of uncertain and seven tumors of malignant behavior) revealed that >or=20 chromosomal alterations and >or=6 telomeric losses were the best predictors of malignant progression. A subset of 22 insulinomas was further investigated for TP53 exon 5-8 gene mutations, and p53 and CK19 expression. Only one malignant tumor was shown to harbor an arginine 273 serine mutation and immunopositivity for p53. CK19 immunopositivity was detected in three malignant tumors and one tumor with uncertain behavior. In conclusion, our results indicate that CIN as well as telomeric loss are very powerful indicators for malignant progression in sporadic insulinomas. Our data do not support a critical role for p53 and CK19 as molecular parameters for this purpose.     

Genetics of Bladder Malignant Tumors in Childhood

Bladder masses are represented by either benign or malignant entities. Malignant bladder tumors are frequent causes of disease and death in western countries. However, in children they are less common. Additionally, different features are found in childhood, in which non epithelial tumors are more common than epithelial ones. Rhabdomyosarcoma is the most common pediatric bladder tumor, but many other types of lesions may be found, such as malignant rhabdoid tumor (MRT), inflammatory myofibroblastic tumor and neuroblastoma. Other rarer tumors described in literature include urothelial carcinoma and other epithelial neoplasms. Rhabdomyosarcoma is associated to a variety of genetic syndromes and many genes are involved in tumor development. PAX3-FKHR and PAX7-FKHR (P-F) fusion state has important implications in the pathogenesis and biology of RMS, and different genes alterations are involved in the pathogenesis of P-F negative and embryonal RMS, which are the subsets of tumors most frequently affecting the bladder. These genes include p53, MEF2, MYOG, Ptch1, Gli1, Gli3, Myf5, MyoD1, NF1, NRAS, KRAS, HRAS, FGFR4, PIK3CA, CTNNB1, FBXW7, IGF1R, PDGFRA, ERBB2/4, MET, BCOR. Malignant rhabdoid tumor (MRT) usually shows SMARCB1/INI1 alterations. Anaplastic lymphoma kinase (ALK) gene translocations are the most frequently associated alterations in inflammatory myofibroblastic tumor (IMT). Few genes alterations in urothelial neoplasms have been reported in the paediatric population, which are mainly related to deletion of p16/lnk4, overexpression of CK20 and overexpression of p53. Here, we reviewed available literature to identify genes associated to bladder malignancies in children and discussed their possible relationships with these tumors.     

Folate Receptor-α (FOLR1) Expression and Function in Triple Negative Tumors

Folate receptor alpha (FOLR1) has been identified as a potential prognostic and therapeutic target in a number of cancers. A correlation has been shown between intense overexpression of FOLR1 in breast tumors and poor prognosis, yet there is limited examination of the distribution of FOLR1 across clinically relevant breast cancer subtypes. To explore this further, we used RNA-seq data from multiple patient cohorts to analyze the distribution of FOLR1 mRNA across breast cancer subtypes comprised of estrogen receptor positive (ER+), human epidermal growth factor receptor positive (HER2+), and triple negative (TNBC) tumors. FOLR1 expression varied within breast tumor subtypes; triple negative/basal tumors were significantly associated with increased expression of FOLR1 mRNA, compared to ER+ and HER2+ tumors. However, subsets of high level FOLR1 expressing tumors were observed in all clinical subtypes. These observations were supported by immunohistochemical analysis of tissue microarrays, with the largest number of 3+ positive tumors and highest H-scores of any subtype represented by triple negatives, and lowest by ER+ tumors. FOLR1 expression did not correlate to common clinicopathological parameters such as tumor stage and nodal status. To delineate the importance of FOLR1 overexpression in triple negative cancers, RNA-interference was used to deplete FOLR1 in overexpressing triple negative cell breast lines. Loss of FOLR1 resulted in growth inhibition, whereas FOLR1 overexpression promoted folate uptake and growth advantage in low folate conditions. Taken together, our data suggests patients with triple negative cancers expressing high FOLR1 expression represent an important population of patients that may benefit from targeted anti-FOLR1 therapy. This may prove particularly helpful for a large number of patients who would typically be classified as triple negative and who to this point have been left without any targeted treatment options.     

Childhood liver tumor in Hungary: two interesting clinical cases

Hepatic tumors account for 0.5-2% of all childhood tumors in Hungary, based of the data last ten years. More than half of the cases were histologically malignant. The worldwide incidence of malignant hepatic tumors is 1.6 / 1 million. Here we present two patients with hepatoblastoma. In the first case the size of the initially inoperable tumor diminished following the chemotherapy and total surgical resection became possible. No sign of relapse occurred so far. The second case included a congenital hepatic tumor which was remarkable because of its unusual clinical presentation and histology.     

Tailgut cyst associated with a carcinoid tumor: case report and review of the literature

We report the case of a 49-year-old woman who presented a tailgut cyst lined by a variety of epithelium including squamous, columnar and transitional. Fortuitously a microscopic carcinoid tumor expressing immunohistochemically neuroendocrine markers was identified in the cystic wall. Tailgut cysts are congenital abnormalities located in the presacrococcygeal area occurring usually in adult patients. Clinical diagnosis is difficult because they are often asymptomatic. Patients may present symptoms resulting from local mass effects or complications. The differential diagnoses include rectal duplication cysts, cystic sacrococcygeal teratomas, epidermal cysts, epidermoid cysts, anal duct or gland cysts. Magnetic resonance imaging has recently become the modality of choice to image the cyst. Malignant transformation is rare; 23 cases including 10 carcinoid tumors have been reported in the literature. To our knowledge, this is the eleventh case of carcinoid tumor arising in a tailgut cyst.     

Biological and molecular aspects of radiation carcinogenesis in mouse skin

The process of mouse skin carcinogenesis can be operationally subdivided into at least three stages which have been termed initiation, promotion, and progression. Ionizing radiation has been found to be a weak initiator of malignant squamous cell carcinomas (SCCs) when radiation was followed by repeated treatments of the skin with the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Besides SCCs, ionizing radiation was found to induce, independent of tumor promoters, basal cell carcinomas (BCCs), a tumor histology not normally seen with chemical carcinogens and mouse skin. Fractionated doses of 1 MeV electrons were found to enhance the conversion of chemically induced benign papillomas to malignant SCCs. In addition to the biological studies, questions related to dominant transforming genes and differential gene expression in the radiation-initiated mouse skin tumors have been explored. Distinct non-ras dominant transforming gene(s) have been detected in radiation-initiated, TPA-promoted SCCs. Differences in the expression pattern of tumor-associated genes were seen in comparing chemically to radiation-induced benign and malignant skin tumors. Therefore, ionizing radiation has been shown to be active in the initiation of malignant skin tumors and progression of benign to malignant tumors in the mouse skin. The ability to divide the process of carcinogenesis into multiple stages in the mouse skin model has facilitated mechanistic studies that may elucidate the molecular pathways involved in radiation-versus chemically induced tumor development.     

Incidentally Identified Adrenal Lipoma: Case Report and Review of Related Literature

ObjectiveTo report a case of an incidentally identified adrenal lipoma in a 68-year-old man with flank pain and hypertension.MethodsThe clinical, computed tomographic, and magnetic resonance imaging findings in this patient are described, and the pathologic features of the tumor are characterized. Moreover, the related literature is reviewed and summarized.ResultsThe patient had undergone coronary artery bypass grafting, had a prosthetic heart valve, and required systemic anticoagulation. Computed tomography showed a well-circumscribed left adrenal lesion with evidence of scattered foci of macroscopic fat; these findings were confirmed on magnetic resonance imaging. After laparoscopic left adrenalectomy, pathologic examination revealed a well-circumscribed, fatty, 7-cm adrenocortical-based tumor, which weighed 135 g. Histologic sampling disclosed mature adipose tissue without evidence of myeloid heterotopy or features of malignant involvement, and adrenal lipoma was diagnosed. On the basis of our review of the English-language literature, this tumor is the 11th reported case of adrenal lipoma. The vast majority of these tumors have been asymptomatic and identified incidentally on imaging or at autopsy. A minority of patients have had a history of hypertension.ConclusionWith the increased utilization and sensitivity of abdominal imaging techniques, identification of nonfunctional adrenal tumors has become more frequent. Adrenal lipoma should be included in the differential diagnosis of lipomatous adrenal tumors. (Endocr Pract. 2008; 14:209-212)     

Large Adrenal Oncocytoma with Uncertain Malignant Potential: Case Report and Review of Literature

ObjectiveTo report a case of oncocytoma, a relatively rare adrenal tumor, which most commonly is detected as an adrenal incidentaloma.MethodsWe present a case report, including laboratory, imaging, and pathologic findings, of a 47-year-old obese woman who had hypertension and an incidentally found large, left adrenal mass.ResultsOn the basis of the hormonal evaluation, this mass was a nonsecreting adrenal tumor, which histologically proved to be an oncocytoma with borderline malignant characteristics. A collective analysis of the few cases of adrenal oncocytoma published in the medical literature showed that our case corresponded to the previously published cases in preponderant location (left side) as well as the general size (11.4 cm in the largest dimension) and weight (372 g).ConclusionAdrenal oncocytoma should be included in the differential diagnosis of adrenal incidentalomas, especially if large tumors are detected. In addition, a longterm follow-up is suggested because there are no certain clues about the true potential of this tumor. (Endocr Pract. 2010;16:641-645)     

Transgenic mouse models of hormonal mammary carcinogenesis: advantages and limitations

Mouse models of breast cancer, especially transgenic and knockout mice, have been established as valuable tools in shedding light on factors involved in preneoplastic changes, tumor development and malignant progression. The majority of mouse transgenic models develop estrogen receptor (ER) negative tumors. This is seen as a drawback because the majority of human breast cancers present an ER positive phenotype. On the other hand, several transgenic mouse models have been developed that produce ER positive mammary tumors. These include mice over-expressing aromatase, ERα, PELP-1 and AIB-1. In this review, we will discuss the value of these models as physiologically relevant in vivo systems to understand breast cancer as well as some of the pitfalls involving these models. In all, we argue that the use of transgenic models has improved our understanding of the molecular aspects and biology of breast cancer.     

Minireview: branded from the start-distinct oncogenic initiating events may determine tumor fate in the thyroid

Thyroid follicular neoplasms commonly have aneuploidy, presumably due to chromosomal instability. This property is associated with a greater malignant potential and worse prognosis. Recently, there has been considerable progress in our understanding of mechanisms that may account for chromosomal instability in cancer cells. Many tumors with chromosomal instability have abnormalities in the cell cycle checkpoint that monitors the fidelity of mitosis. Mutations of Bub1 or BubR1, genes coding for kinases involved in mitotic spindle assembly checkpoint signaling, are found in a small subset of aneuploid tumors. Other components of protein complexes responsible for attachment of kinetochores to microtubules, or for cohesion between sister chromatids, may also be subject to alterations during tumor progression. Here, we also discuss the evidence that certain oncogenic events, such as Ras mutations, may predispose cells to chromosomal instability by favoring inappropriate posttranslational changes in mitotic checkpoint components through activation of upstream kinases during tumor initiation or progression.     

Second primary malignant tumors in patients with ocular melanoma

Multiple primary malignant tumors have been documented with increased frequency over the last two decades. Continuously increasing success of modern oncotherapy has led to long-term remissions in many cases, but this success rate poses a growing risk for the development of second primary malignancies. The incidence of those involving an intraocular tumor is relatively rare. In the present study we report five ocular melanoma patients with second primary malignant tumors diagnosed during a fourteen-year period in our department. We wish to emphasize that an intraocular mass lesion in a patient with a history of a previous malignancy should not be dismissed as a metastatic lesion. The diagnosis of an intraocular lesion as a separate primary tumor drastically changes the prognosis and the therapeutic approach.     

Malignant mesenchymal tumors in two white-tailed jack rabbits (Lepus townsendii)

Two white-tailed jack rabbits (Lepus townsendii) with proliferative lesions in their internal organs were submitted to the Canadian Cooperative Wildlife Health Centre (Saskatoon, Saskatchewan, Canada) for necropsy because of concern that dogs that had contact with the hares might have been exposed to an infectious disease. In both hares, the primary diagnosis was neoplasia. One hare had metastatic leiomyosarcoma and uterine fibroma, the other had metastatic mesenchymal tumors involving the liver and mesentery. These cases represent the only reports of malignant mesenchymal tumors in white-tailed jack rabbits that we have found in the literature.     

血小板升高与妇科恶性肿瘤的影响

血小板升高与多种实体肿瘤的发生发展密切相关,研究表明14%-38%的恶性肿瘤患者伴有血小板升高。虽然目前国内外学者对于定义血小板升高的具体标准尚未完全统一,但大致范围在血小板计数大于220-400×109/L。大量的临床研究证实恶性肿瘤细胞可以分泌多种生长因子及细胞因子促进血小板升高,而升高的血小板又产生促进肿瘤细胞增殖、血管生长及转移的细胞因子。回顾相关文献在许多妇科恶性肿瘤研究中,除外阴癌外,治疗前的血小板升高多与疾病预后不良有关,由于血小板升高可以通过阻断血栓形成细胞因子来预防,因此对其评估在未来可能具有治疗意义。本文将就妇科恶性肿瘤与血小板升高的具体关联性进行探究。     

Astrocyte-specific neurofibromatosis 1 gene deletion is insufficient for astrocytoma formation in mice

To gain insight into the role of the NF1 (Neurofibromatosis type 1) gene during neural development and in tumorigenesis, we have utilized the bacteriophage P1, Cre/loxP system to generate a conditional allele at the NF1 locus (NF1 flox) that permits temporal and spatial ablation of function through Cre-mediated recombination. We have been using these mice to assess the scope of NF1 requirement in distinct cell types. At the center of this approach is to identify the cells that give origin to the tumors most frequently found in NF1 patients: neurofibromas, neurofibrosarcomas, and astrocytomas. We have hypothesized that specific stem cells must lose NF1 by LOH to begin this process. I will discuss the consequences of NF1 loss in neurons, Schwann cells, and neural precursors. Distinct tumor phenotypes appear in each case. In malignant tumors, our mouse models indicate that the p53 pathway must also become mutated to cooperate with loss of NF1. Additionally, we have genetic evidence that the haploin-sufficient state is essential for tumor appearance. These data suggest that profilactic therapies preceding tumor appearance should be considered for NF1. Acknowledgements:  Funded by NINDS, NNFF, and DOD.     

Symposium 2: The Genetic,Molecular and Cellular Bases of Neurofibromatosis Type 1. A role of NF1 as a tumor suppressor

To gain insight into the role of the NF1 (Neurofibromatosis type 1) gene during neural development and in tumorigenesis, we have utilized the bacteriophage P1, Cre/loxP system to generate a conditional allele at the NF1 locus (NF1 flox) that permits temporal and spatial ablation of function through Cre‐mediated recombination. We have been using these mice to assess the scope of NF1 requirement in distinct cell types. At the center of this approach is to identify the cells that give origin to the tumors most frequently found in NF1 patients: neurofibromas, neurofibrosarcomas, and astrocytomas. We have hypothesized that specific stem cells must lose NF1 by LOH to begin this process. I will discuss the consequences of NF1 loss in neurons, Schwann cells, and neural precursors. Distinct tumor phenotypes appear in each case. In malignant tumors, our mouse models indicate that the p53 pathway must also become mutated to cooperate with loss of NF1. Additionally, we have genetic evidence that the haploin‐sufficient state is essential for tumor appearance. These data suggest that profilactic therapies preceding tumor appearance should be considered for NF1. Acknowledgements: Funded by NINDS, NNFF, and DOD.     

Thematic Review Series: Calorie Restriction and Ketogenic Diets: The ketogenic diet for the treatment of malignant glioma

Advances in our understanding of glioma biology has led to an increase in targeted therapies in preclinical and clinical trials; however, cellular heterogeneity often precludes the targeted molecules from being found on all glioma cells, thus reducing the efficacy of these treatments. In contrast, one trait shared by virtually all tumor cells is altered (dysregulated) metabolism. Tumor cells have an increased reliance on glucose, suggesting that treatments affecting cellular metabolism may be an effective method to improve current therapies. Indeed, metabolism has been a focus of cancer research in the last few years, as many pathways long associated with tumor growth have been found to intersect metabolic pathways in the cell. The ketogenic diet (high fat, low carbohydrate and protein), caloric restriction, and fasting all cause a metabolic change, specifically, a reduction in blood glucose and an increase in blood ketones. We, and others, have demonstrated that these metabolic changes improve survival in animal models of malignant gliomas and can potentiate the anti-tumor effect of chemotherapies and radiation treatment. In this review we discuss the use of metabolic alteration for the treatment of malignant brain tumors.