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High-Throughput Mutation Profiling of Primary and Metastatic Endometrial Cancers Identifies KRAS, FGFR2 and PIK3CA to Be Frequently Mutated  [PDF]
Camilla Krakstad, Even Birkeland, Danila Seidel, Kanthida Kusonmano, Kjell Petersen, Siv Mj?s, Erling A. Hoivik, Elisabeth Wik, Mari Kylles? Halle, Anne M. ?yan, Karl-Henning Kalland, Henrica Maria Johanna Werner, Jone Trovik, Helga Salvesen
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0052795
Abstract: Background Despite being the most common pelvic gynecologic malignancy in industrialized countries, no targeted therapies are available for patients with metastatic endometrial carcinoma. In order to improve treatment, underlying molecular characteristics of primary and metastatic disease must be explored. Methodology/Principal Findings We utilized the mass spectrometric-based mutation detection technology OncoMap to define the types and frequency of point somatic mutations in endometrial cancer. 67 primary tumors, 15 metastases corresponding to 7 of the included primary tumors and 11 endometrial cancer cell lines were screened for point mutations in 28 known oncogenes. We found that 27 (40.3%) of 67 primary tumors harbored one or more mutations with no increase in metastatic lesions. FGFR2, KRAS and PIK3CA were consistently the most frequently mutated genes in primary tumors, metastatic lesions and cell lines. Conclusions/Significance Our results emphasize the potential for targeting FGFR2, KRAS and PIK3CA mutations in endometrial cancer for development of novel therapeutic strategies.
Molecular Profiling of Endometrial Malignancies  [PDF]
Norasate Samarnthai,Kevin Hall,I-Tien Yeh
Obstetrics and Gynecology International , 2010, DOI: 10.1155/2010/162363
Abstract: Molecular profiling of endometrial neoplasms reveals genetic changes in endometrial carcinomas that support the dualistic model, in which type I carcinomas are estrogen-dependent, low grade lesions and type II carcinomas are nonestrogen dependent and high grade. The molecular changes in type I endometrial carcinomas include mutations in PTEN, PIK3CA, KRAS, and -catenin, along with microsatellite instability, whereas type II endometrial carcinomas are characterized by genetic alterations in p53, HER2/neu, p16, and E-cadherin. For endometrial neoplasms with a malignant mesenchymal component, C-MYC mutations and loss of heterozygosity are frequently seen in carcinosarcomas, and a fusion gene, JAZF1/JJAZ1, is distinctive for endometrial stromal sarcoma. In addition, p53 mutations may play an important role in tumorigenesis of undifferentiated endometrial sarcoma. These molecular changes can help in the diagnosis of endometrial neoplasms, as well as form the basis of molecular targeted therapy. 1. Introduction Endometrial malignancies can be categorized into two main groups based on the cell of origin: (i) endometrial carcinoma including carcinosarcoma and (ii) endometrial stromal sarcoma. Endometrial carcinomas show a broad spectrum of phenotypes which show various histologic appearances for example, endometrioid, serous, mucinous, squamous, urothelial, or clear cell, reflecting the differentiation potential of the müllerian epithelium and the difference in the tumorigenetic pathways of each tumor type. Women with an inherited predisposition for endometrial neoplasm have been reported, associated with autosomal dominant disorders such as hereditary nonpolyposis colorectal carcinoma (HNPCC) and Cowden syndrome. Some endometrial carcinomas undergo mesenchymal differentiation and are termed carcinosarcomas (formerly termed malignant mixed müllerian tumors). Pathogenetically and clinically, two distinct forms of endometrial adenocarcinoma, type I and type II, have been described. The molecular alterations driving endometrial carcinogenesis may follow a sequence similar to Vogelstein’s model for the progression of colorectal adenoma to carcinoma. This process is accompanied by stepwise genetic changes of oncogenes and tumor suppressor genes. Endometrial stroma may give rise to neoplasms that resemble normal endometrial stromal cells. The spectrum of endometrial stromal tumors ranges from the benign stromal nodule to the malignant endometrial stromal sarcoma. An oncogenic fusion gene, plays a significant role in tumor development of endometrial stromal sarcomas
Atypical presentations and rare metastatic sites of renal cell carcinoma: a review of case reports
Petros Sountoulides, Linda Metaxa, Luca Cindolo
Journal of Medical Case Reports , 2011, DOI: 10.1186/1752-1947-5-429
Abstract: Renal cell carcinoma (RCC) is a lethal tumor that accounts for approximately 3% of all adult malignancies and is associated with approximately 13,000 deaths annually [1]. The introduction and widespread use of sophisticated imaging modalities has resulted in a significant increase in the incidental detection of kidney tumors. Nowadays more than 70% of all renal cancer cases are "screen detected" as incidental findings on imaging studies obtained for unrelated reasons [2]. Therefore the classical teaching that renal cancer presents with signs and symptoms such as hematuria, flank pain and palpable mass is more of the exception rather than the rule. This trend has also resulted in a significant shift in the staging of renal cancer since lesser cases initially present with advanced metastatic disease and more cases of renal tumors are confined to the kidney at the time of diagnosis.Still, renal cancers have a strong tendency to metastasize following occasionally unpredictable patterns of spread. There have been several reports of late metastases from RCC even decades after potentially curative surgical excision of the primary tumor. There is evidence that distant metastatic disease will eventually develop in about one out of three patients with RCC and in these cases the disease is considered incurable. Even despite recent therapeutic advances in the management of metastatic renal cancer such as immunotherapy and mTOR kinase inhibitors, long-term survival in patients with metastatic RCC is limited to months [3-5].With regard to the histologic subtypes of RCC and their relationship to prognosis, the most common subtype, which is clear cell renal cancer, accounts for 70-80% of all RCCs. Chromophobe cell carcinoma accounts for only 3-5% of all RCCs and carries a better prognosis than clear cell RCC with a five-year survival rate between 92-94% [6,7]. The pathologic stage of RCC at the time of presentation has been demonstrated to correlate most closely with survival [8].T
Brain Metastases from Endometrial Carcinoma  [PDF]
Ettie Piura,Benjamin Piura
ISRN Oncology , 2012, DOI: 10.5402/2012/581749
Abstract: This paper will focus on knowledge related to brain metastases from endometrial carcinoma. To date, 115 cases were documented in the literature with an incidence of 0.6% among endometrial carcinoma patients. The endometrial carcinoma was usually an advanced-stage and high-grade tumor. In most patients (~90%), brain metastasis was detected after diagnosis of endometrial carcinoma with a median interval from diagnosis of endometrial carcinoma to diagnosis of brain metastases of 17 months. Brain metastasis from endometrial carcinoma was either an isolated disease limited to the brain only (~50%) or part of a disseminated disease involving also other parts of the body (~50%). Most often, brain metastasis from endometrial carcinoma affected the cerebrum (~75%) and was solitary (~60%). The median survival after diagnosis of brain metastases from endometrial carcinoma was 5 months; however, a significantly better survival was achieved with multimodal therapy including surgical resection or stereotactic radiosurgery followed by whole brain radiotherapy (WBRT) and/or chemotherapy compared to WBRT alone. It is suggested that brain imaging studies should be considered in the routine follow up of patients with endometrial carcinoma and that the search for a primary source in females with brain metastases of unknown primary should include endometrial biopsy. 1. Introduction The brain, along with the bone, liver, and lung, is one of the most common sites of metastases with about 170,000 patients newly diagnosed with brain metastases each year in USA, a figure which is 10-fold higher than that of patients newly diagnosed with primary brain malignancy [1–3]. Common sources of brain metastases are lung, breast, renal, and colorectal carcinoma and malignant melanoma; it has been estimated that about 15% of patients with these cancers develop brain metastases in the course of their disease [1, 3–5]. Female genital tract cancers, however, are considered “neurophobic” since brain metastases from female genital tract cancers, apart from choriocarcinoma, are rare and usually develop as part of a widespread disseminated disease. The primary mechanism of metastatic spread from genital tract cancers to the brain is by the hematogenous rout. Detached tumor cells are carried from the genital tract by the blood stream through the inferior vena cava, right atrium, right ventricle, pulmonary artery, lungs, pulmonary veins, left atrium, left ventricle, and aorta to the brain [6]. It has been speculated that tumor cells from the genital tract may also travel to the brain via the Batson
Genetics of Endometrial Cancers  [PDF]
Tsuyoshi Okuda,Akihiko Sekizawa,Yuditiya Purwosunu,Masaaki Nagatsuka,Miki Morioka,Masaki Hayashi,Takashi Okai
Obstetrics and Gynecology International , 2010, DOI: 10.1155/2010/984013
Abstract: Endometrial cancers exhibit a different mechanism of tumorigenesis and progression depending on histopathological and clinical types. The most frequently altered gene in estrogen-dependent endometrioid endometrial carcinoma tumors is PTEN. Microsatellite instability is another important genetic event in this type of tumor. In contrast, p53 mutations or Her2/neu overexpression are more frequent in non-endometrioid tumors. On the other hand, it is possible that the clear cell type may arise from a unique pathway which appears similar to the ovarian clear cell carcinoma. K-ras mutations are detected in approximately 15%–30% of endometrioid carcinomas, are unrelated to the existence of endometrial hyperplasia. A -catenin mutation was detected in about 20% of endometrioid carcinomas, but is rare in serous carcinoma. Telomere shortening is another important type of genomic instability observed in endometrial cancer. Only non-endometrioid endometrial carcinoma tumors were significantly associated with critical telomere shortening in the adjacent morphologically normal epithelium. Lynch syndrome, which is an autosomal dominantly inherited disorder of cancer susceptibility and is characterized by a MSH2/MSH6 protein complex deficiency, is associated with the development of non-endometrioid carcinomas. 1. Introduction Endometrial cancer is the most common cancer of the female reproductive tract with 150,000 new cases diagnosed annually worldwide. Approximately 90% of endometrial cancers are sporadic, and the remaining 10% are hereditary. Bokhman have generally categorized endometrial cancer into two broad groups of tumors using both clinical and histopathological variables: estrogen-dependent endometrioid endometrial carcinomas (EECs), or type I, and non-endometrioid endometrial carcinomas (NEECs), or type II tumors (Table 1) [1]. It should be noted that this model is not strict, and only a minority of endometrial cancer may exhibit shared characteristics. For example, mixed serous and endometrioid tumors are being increasingly recognized. Approximately 70% to 80% of new cases are classified as EECs, and other 10% to 20% are designated as NEEC tumors [1]. EECs are strongly associated with the estrogen-related pathway and arise in association with unopposed estrogen stimulation [2]. In contrast, NEECs are unrelated to the estrogen pathways and arise in the background of atrophic endometrium [3]. EECs typically occur in premenopausal and younger postmenopausal women and are usually low-grade and have a favorable outcome, whereas NEECs occur in older postmenopausal
Sperm protein 17 is highly expressed in endometrial and cervical cancers
Fang-qiu Li, Qun Liu, Yan-ling Han, Bo Wu, Hong-lin Yin
BMC Cancer , 2010, DOI: 10.1186/1471-2407-10-429
Abstract: The monoclonal antibodies against human Sp17 were produced as reagents for the analysis and immunohistochemistry was used to study two major kinds of paraffin-embedded gynecological cancer specimens, including 50 cases of endometrial cancer (44 adenous and 6 adenosquamous) and 31 cases of cervical cancer (15 adenous and 16 squamous). Normal peripheral endometrial and cervical tissues were used as controls.Sp17 was found in 66% (33/50) of the patients with endometrial cancer and 61% (19/31) of those with cervical cancer. Its expression was found in a heterogeneous pattern in the cancer tissues. The expression was not correlated with the histological subtype and grade of malignancy, but the staining patterns were different in endometrial and cervical cancers. The hyperplastic glands were positive for Sp17 in the normal peripheral endometrial and cervical tissues in 10% (8/81) of the patients.Sp17 is highly expressed in human endometrial and cervical cancers in a heterogeneous pattern. Although the expression frequency of Sp17 is not correlated with the histological subtype, the staining pattern may help to define endometrial and cervical cancers. Sp17 targeted immunotherapy of tumors needs more accurate validation.Endometrial cancer and cervical cancer are two of the most common malignancies among females globally [1]. Some of them have a poor prognosis due to their chemoresistance and early metastasis. No specific molecular markers are currently available for the early diagnosis and immunotherapy of these aggressive malignancies [2]. Therefore, there is an urgent need to identify tumor antigens associated with chemoresistance and early metastasis which can then be used as suitable targets for immunotherapy.The immunogenic protein, Sperm protein 17 (Sp17), is a member of the cancer testis antigen (CTA) family and has been extensively characterized [3-12]. Sp17 is a highly conserved mammalian protein in the testis and spermatozoa of humans and animals including rabbits
Endometrial Adenocarcinoma Metastatic to the Colon Masquerading as a Primary Colon Cancer  [cached]
Michael J. Anstadt,Margo Shoup,Shawn R. Lapetino,Umesh Kapur
Journal of Gastroenterology and Hepatology Research , 2012, DOI: 10.6051/j.issn.2224-3992.2012.01.020
Abstract: While the majority of colonic malignancies represent primarytumors, secondary tumors are not uncommon. We present a case ofendometrial cancer metastatic to the colon masquerading as a primarycolonic adenocarcinoma. The clinical and pathologic characteristicsof each disease are discussed. To our knowledge, this is the firstreported case of endometrial cancer metastasis to the colon in theabsence of endometriosis. It demonstrates the importance of usingimmunohistochemistry to distinguish morphologically similar tumorsin a patient who seemingly presents with more than one primarymalignancy.
Endometrial Glandular Dysplasia (EmGD): morphologically and biologically distinctive putative precursor lesions of Type II endometrial cancers
Oluwole Fadare, Wenxin Zheng
Diagnostic Pathology , 2008, DOI: 10.1186/1746-1596-3-6
Abstract: Endometrial cancers are the most frequently diagnosed malignancies of the female genital tract in the United States, with 39,080 new cases projected for 2007 [1]. Since 1983, two broad clinicopathologic subtypes of endometrial carcinomas have been recognized [2]. This conceptual classification has largely been supported by subsequent molecular-cytogenetic data, which has facilitated the acceptance of the so-called dualistic model of endometrial carcinogenesis [3-8]. Type I cancers, the prototype of which is the endometrioid histotype, occur in comparatively younger age group [3-8], appear to be related to unopposed estrogen stimulation [9-14], frequently express the estrogen and progesterone receptors [7,13,14], arise in a background of glandular hyperplasia [5,7,13,14], and has a relatively favorable prognostic profile [15]. Genetic alterations in Type 1 cancers include PTEN inactivation [16-19], beta-catenin (CTNNB1) mutations [17], and less frequently, microsatellite instability (related to inactivation of the MLH1 gene) [20,21], and activational mutations of the K-ras gene [22]. Type II cancers, the prototype of which is the endometrial serous carcinoma (ESC), and which was previously termed uterine papillary serous carcinoma (UPSC), typically occur in an older age group [3-8], frequently arise in a background of inactive or resting endometrium [3-8], and display a low frequency of expression of hormonal receptors [13,14,23,24]. Type II cancers also display frequent mutation and overexpression of the p53 [24-26] and HER2/neu [27,28] genes and proteins respectively, and have a comparatively poor prognosis independent of other factors [29-32]. This model has provided a valuable framework for the study of various aspects of endometrial carcinogenesis and for the potential development of therapeutic modalities that are pathway specific. Nonetheless, approximately 7400 deaths attributable to uterine corpus malignancies are projected for 2007 [1]. This relatively high
Cutaneous umbilical metastases in post-menopausal females with gynaecological malignancies  [cached]
Modupeola Omotara Samaila,Adebiyi Gbadebo Adesiyun,Garba Dahiru Waziri,Korede Afolabi Koledade
Journal of the Turkish-German Gynecological Association , 2012,
Abstract: Gynaecological malignancies frequently metastasize to contiguous structures, internal organs and bones. Cutaneous metastasis as a primary or recurrent presentation of these malignancies is rare and only a few cases have been reported in the literature. A twenty year (1991-2010) retrospective search for umbilical metastasis from gynaecological malignancies in our departmental case records showed only four cases. Four post-menopausal females presented with painful cutaneous umbilical (Sister Joseph’s) nodules. The clinical examinations of all four patients revealed well delineated nodules of varying sizes and degrees of ulceration. Other findings were matted axillary and inguinal lymph node enlargement, intra-abdominal and pelvic masses, vaginal discharge and vaginal bleeding. Incisional tissue biopsies from the nodules were processed in paraffin wax and stained with haematoxylin and eosin. Histology of the sections showed pigmented skin overlying metastatic malignant tumours consistent with adenocarcinoma from the endometrium and ovary in three cases, and squamous cell carcinoma, large cell keratinizing from the cervix uteri in the fourth case. Gynaecological cancers have a global spread and varied geographic distribution. Cervical cancer is the commonest in our setting and patients often present to hospital with advanced stage disease. Ovarian and endometrial cancers are infrequent and their diagnosis may be delayed by non- specificity of presenting clinical symptoms from other benign tumours at these sites. Although umbilical metastasis is commonly associated with gastro-intestinal malignancies, its presence may be the first harbinger of occult gynaecologic cancer.
Hospital-Based Study of Epithelial Malignancies of Endometrial Cancer Frequency in Lahore, Pakistan, and Common Diagnostic Pitfalls  [PDF]
Imrana Tanvir,Sabiha Riaz,Afshan Hussain,Riffat Mehboob,M. Usman Shams,Haseeb Ahmad Khan
Pathology Research International , 2014, DOI: 10.1155/2014/179384
Abstract: The current study was conducted to see the frequency of epithelial malignancies of endometrium with focus on the common diagnostic pitfalls and identify morphological and immunohistochemical markers helpful in the differential diagnosis between different subtypes. It is a retrospective descriptive study carried out on 52 specimens of endometrial tumors received in Fatima Memorial Hospital, Lahore, Pakistan, during three years (2010–2012). Patients were divided into 5 age groups: <40, 41–50, 51–60, 61–70, and >70?yrs. Tissues were fixed in 10% formalin and processed and stained with haematoxylin-eosin. Stained slides were examined to determine the histological types by WHO classification, and immunohistochemistry for WT1, p53, ER/PR, and MIB1 was done in cases where morphology alone was not helpful in making a confirmed diagnosis. 80% of specimens were of endometrioid adenocarcinomas, 11% of serous tumors, 4% of clear cell carcinoma, and 4% of squamous cell carcinomas involving both cervix and endometrium. Most of the patients (28.84%) with endometrial carcinomas fall in the age range of 51–60?yrs. Endometrioid adenocarcinoma is the most common type of epithelial endometrial malignancies. Morphology is the keystone in the evaluation of these tumors, but immunohistochemistry can also be helpful in establishing the correct diagnosis. 1. Introduction Endometrial cancer is the most common gynecologic malignancy in western women with 41,000 new cases projected in the United States for 2006 [1], whereas rates in developing countries and Japan are four to five times lower. In India, the rates are as low as 4.3 per 100,000 [2]. Ninety-seven percent of all cancers of the uterus arise from the glands of the endometrium and are known as endometrial carcinomas [3]. Its annual incidence is estimated at 10–20 per 100,000 women and it is increasing [4, 5]. Approximately, 75% of cases are diagnosed at an early stage with a tumor confined to the uterine corpus [6]. It is the fourth most common cancer in women after carcinomas of breast, colorectum, and lung [7]. In the United States, endometrial carcinoma accounts for approximately 6000 deaths per year [4]. The median age of patients at the diagnosis of endometrial carcinoma is 63 years [8]. The incidence of endometrial carcinoma is highly dependent on age; there are 12 cases per 100,000 women at 40 years of age and 84 per 100,000 at 60 years [3]. Five percent of women with endometrial cancer are less than 40 years of age. Seventy-five percent of women with endometrial carcinoma are postmenopausal [9]. Historical
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