Overexpression of PELP1 in Lung Adenocarcinoma Promoted E2 Induced Proliferation, Migration and Invasion of the Tumor Cells and Predicted a Worse Outcome of the Patients.

The expression of Proline-, glutamic acid-, and leucine-rich protein 1 (PELP1) has been reported to be dysregulated in non-small cell lung carcinoma, especially in lung adenocarcinoma (LUAD). Therefore, we aimed to investigate the functional and prognostic roles of PELP1 in LUAD in this study. We first immunolocalized PELP1 in 76 cases of LUAD and 17 non-pathological or tumorous lung (NTL) tissue specimens and correlated the findings with the clinicopathological parameters of the patients. We then performed in vitro analysis including MTT, flow cytometry, wound healing, and transwell assays in order to further explore the biological roles of PELP1 in 17-ß-estradiol (E2) induced cell proliferation, migration, and invasion of LUAD cells. We subsequently evaluated the prognostic significance of PELP1 in LUAD patients using the online survival analysis tool Kaplan-Meier Plotter. The status of PELP1 immunoreactivity in LUAD was significantly higher than that in the NTL tissues and significantly positively correlated with less differentiated features of carcinoma cells, positive lymph node metastasis, higher clinical stage as well as the status of ERα, ERß, and PCNA. In vitro study did reveal that E2 promoted cell proliferation and migration and elevated PELP1 protein level in PELP1-high A549 and H1975 cells but not in PELP1-low H-1299 cells. Knock down of PELP1 significantly attenuated E2 induced cell proliferation, colony formation, cell cycle progress as well as migration and invasion of A549 and H1975 cells. Kaplan-Meier Plotter revealed that LUAD cases harboring higher PELP1 expression had significantly shorter overall survival. In summary, PELP1 played a pivotal role in the estrogen-induced aggressive transformation of LUAD and could represent adverse clinical outcome of the LUAD patients.

Histological and immunohistochemical characteristics and p16 status studied by FISH in six incidentally detected cases of well-differentiated papillary mesothelioma of the peritoneum.

Well-differentiated papillary mesothelioma (WDPM) is an uncommon mesothelial neoplasm, which is generally regarded as benign or indolent in terms of its clinical behavior. However, details about WDPM have remained relatively unknown. Therefore, in this study, we examined six incidentally detected cases of WDPM of the peritoneum. All six cases were surgically excised, without any additional therapeutic measures. None of the cases showed recurrence. All six cases presented single lesions and the tumor sizes ranged from 2 to 10 mm. Histologically, all six cases exhibited papillary proliferation of cytologically bland mesothelial cells with a fibroconnective tissue core. One of the cases (Case 6) presented small invasive foci in the stalk. The tumor cells were immunohistochemically positive for mesothelial markers and negative for GLUT-1, p53, and CD146. The Ki-67 labeling index of the tumor cells was lower than 5% at the hot spots. All samples were BAP1-positive. None of the samples presented p16 homozygous deletion, as assessed by fluorescence in situ hybridization (FISH). None of the patients deceased due to WDPM. However, in Case 3, death occurred due to pancreatic cancer. The results of this study indicate the importance of analyzing immunohistochemical markers and p16 status to diagnose WDPM accurately.

Androgen Receptor Is a Non-canonical Inhibitor of Wild-Type and Mutant Estrogen Receptors in Hormone Receptor-Positive Breast Cancers.

Sustained treatment of estrogen receptor (ER)-positive breast cancer with ER-targeting drugs results in ER mutations and refractory unresponsive cancers. Androgen receptor (AR), which is expressed in 80%-95% of ER-positive breast cancers, could serve as an alternate therapeutic target. Although AR agonists were used in the past to treat breast cancer, their use is currently infrequent due to virilizing side effects. Discovery of tissue-selective AR modulators (SARMs) has renewed interest in using AR agonists to treat breast cancer. Using translational models, we show that AR agonist and SARM, but not antagonist, inhibit the proliferation and growth of ER-positive breast cancer cells, patient-derived tissues, and patient-derived xenografts (PDX). Ligand-activated AR inhibits wild-type and mutant ER activity by reprogramming the ER and FOXA1 cistrome and rendering tumor growth inhibition. These findings suggest that ligand-activated AR may function as a non-canonical inhibitor of ER and that AR agonists may offer a safe and effective treatment for ER-positive breast cancer.

Therapeutic advances in hormone-dependent cancers: focus on prostate, breast and ovarian cancers.

Hormonal cancers affect over 400,000 men and women and contribute collectively to over 100,000 deaths in the United States alone. Thanks to advances in the understanding of these cancers at the molecular level and to the discovery of several disease-modifying therapeutics, the last decade has seen a plateauing or even a decreasing trend in the number of deaths from these cancers. These advanced therapeutics not only effectively slow the growth of hormonal cancers, but also provide an insight on how these cancers become refractory and evolve as an altogether distinct subset. This review summarizes the current therapeutic trends in hormonal cancers, with focus on prostate, breast and ovarian cancers. The review discusses the clinical drugs being used now, promising molecules that are going through various stages of development and makes some predictions on how the therapeutic landscape will shift in the next decade.

In breast cancer subtypes steroid sulfatase (STS) is associated with less aggressive tumour characteristics.

BACKGROUND: The majority of breast cancer cases are steroid dependent neoplasms, with hormonal manipulation of either CYP19/aromatase or oestrogen receptor alpha axis being the most common therapy. Alternate pathways of steroid actions are documented, but their interconnections and correlations to BC subtypes and clinical outcome could be further explored. METHODS: We evaluated selected steroid receptors (Androgen Receptor, Oestrogen Receptor alpha and Beta, Glucocorticoid Receptor) and oestrogen pathways (steroid sulfatase (STS), 17ß-hydroxysteroid dehydrogenase 2 (17ßHSD2) and aromatase) in a cohort of 139 BC cases from Norway. Using logistic and cox regression analysis, we examined interactions between these and clinical outcomes such as distant metastasis, local relapse and survival. RESULTS: Our principal finding is an impact of STS expression on the risk for distant metastasis (p<0.001) and local relapses (p <0.001), HER2 subtype (p<0.015), and survival (p<0.001). The suggestion of a beneficial effect of alternative oestrogen synthesis pathways was strengthened by inverted, but non-significant findings for 17ßHSD2. CONCLUSIONS: Increased intratumoural metabolism of oestrogens through STS is associated with significantly lower incidence of relapse and/or distant metastasis and correspondingly improved prognosis. The enrichment of STS in the HER2 overexpressing subtype is intriguing, especially given the possible role of HER-2 over-expression in endocrine resistance.

Possible roles for glucocorticoid signalling in breast cancer.

Our understanding of breast cancer biology, and our ability to manipulate breast cancers have grown exponentially in the last 20 years. Much of that expansion has focused on the roles of steroids in driving these neoplasms. Initially this research focused on estrogens and progesterone receptors, and more recently on androgen actions in breast cancers. This review aims to make the case for glucocorticoids as the next essential steroid subclass that contributes significantly to our understanding of steroidogenic regulation of these neoplasms. Glucocorticoids have the potential to play multiple roles in the regulation of breast cancers including their control of cellular differentiation, apoptosis and proliferation. Beyond this they also act as a master integrator of organ homeostats in relation to such as circadian rhythms and stress responses. Therefore a better understanding of glucocorticoids and breast cancer could help to explain some of the epidemiological links between circadian disruption and/or stress and breast cancer development. Finally glucocorticoids are currently used during chemotherapeutic treatment in breast cancer therapy and yet results of various studies suggest that this may have an adverse impact on treatment success. This review aims to summarise the current evidence for glucocorticoids as actors in breast cancer and then suggest future essential approaches in order to determine the roles of glucocorticoids in this disease.

Virilism and Ectopic Expression of HSD17B5 in Mature Cystic Teratoma.

Mature cystic teratoma (MCT) is rarely involved in the overproduction of steroid hormones in contrast to sex cord stromal tumors. A 31-year-old woman visited our hospital with hirsutism, hoarseness, and hair loss from the scalp. Serum testosterone and free-testosterone levels were 7.3 ng/ml and 2.3 pg/ml, respectively, which were markedly in excess of the age adjusted female standard levels. Basal blood levels of steroid hormones and serum levels of 17-hydroxyprogesterone at 1 h after intravenous injection of adrenocorticotropic hormone demonstrated that 21-hydroxylase deficiency was not the underlying cause of her virilization. A subsequent chromosomal test with G-banding revealed a karyotype of 46XX. Magnetic resonance imaging revealed a mass in the left ovary, which was subsequently diagnosed as MCT. Detailed pathological analysis of the tumor indicated that it was comprised of skin components, sweat glands, with hair and fat texture, glandular epithelium and fibrous connective tissue, consistent with the characteristic composition of MCT. Immunohistochemical analysis demonstrated marked immunoreactivity of 17beta-hydroxysteroid dehydrogenase (HSD17B5), an enzyme that can convert androstenedione to testosterone. Following surgical removal of the tumor, testosterone and free testosterone levels were markedly decreased (0.3 ng/ml and 0.4 pg/ml, respectively) and other symptoms abated. In conclusion, this is the first report of an ovarian MCT associated with clinical virilization caused by the ectopic production of testosterone possibly because of an overexpression of intratumoral HSD17B5.

Serotonin receptor 4 (5-hydroxytryptamine receptor Type 4) regulates expression of estrogen receptor beta and cell migration in hormone-naive prostate cancer.

BACKGROUND: Estrogens are considered to potentially play some roles in the development and progression of prostate cancer through estrogen receptor beta (ERß). However, additional factors which could influence the clinical outcome of the patients through modulating these steroid signalings have also been proposed. Among these, increased expression of serotonin receptor especially that of 5-hydroxytryptamine receptor Type 4 (5-HTR4) has been recently proposed to be involved in autocrine/paracrine mechanisms of castration-resistant prostate cancer, but the presence and clinical significance of 5-HTR4 in hormone-naive prostate cancer (HNPC) and its interaction with hormonal signaling pathways have remained virtually unknown. MATERIALS AND METHODS: We evaluated the status of 5-HTR4 in 112 human HNPC cases (acinar adenocarcinoma) using immunohistochemistry and correlated the findings with clinicopathological features of individual patients and the status of androgen receptor (AR) and ERß. To further elucidate its underlying mechanisms, androgen-dependent human prostate carcinoma cell line, LNCaP, expressing 5-HTR4, was treated by 5-HTR4 agonist. RESULTS: 5-HTR4 immunoreactivity was detected in 34% of prostate cancer cases examined (38/112) and was significantly correlated with the status of ERß but not with that of AR and other clinicopathological factors of the patients. Results of in vitro studies demonstrated that 24 h incubation with 5-HTR4 agonist (10 nM) increased the expression level of ERß messenger RNA compared to controls. 5-HTR4 agonist (100 nM) significantly inhibited LNCaP carcinoma cell migration (P < 0.05). CONCLUSION: Results of our present study indicated that 5-HTR4 signaling upregulated ERß expression in HNPCs and could impact on biological processes in HNPC.

Estrogen receptor ß in Merkel cell carcinoma: its possible roles in pathogenesis.

Sex steroids have been postulated to influence skin development and functions as well as its pathogenesis. MCC occurs in both sexes; however, the specific differences in pathogenesis among sexes have yet to be conclusively defined. The detailed status of sex steroid receptors (AR, PRA and PRB, and ERα, ERß) are also unknown in MCC patients. We first immunolocalized sex steroid receptors and compared the results with immunolocalization of relevant transcription factors including SOX2, FOXA1, and Bcl-2 and Ki-67 in 18 cases of MCCs. AR, PRA, PRB, ERα, ERß, Bcl-2, SOX2, and FOXA1 immunoreactivity was evaluated by using the modified H score method, and Ki-67 was quantified using labeling index. ERß immunoreactivity was markedly present in all the cases of MCC examined, with relatively weak immunoreactivity of ERα, AR, PRA, and PRB. The status of ERß immunoreactivity was also significantly correlated with Ki-67 labeling index and Bcl-2 score. These results demonstrated that ERß could be associated with regulation of both cell proliferation and apoptosis in MCCs.

Androgen and breast cancer: an update.

PURPOSE OF REVIEW: The review is targeted at describing the advances in our understanding of androgen actions in the breast over the last 18 months. Androgens are current 'hot topics' in breast cancer because of their potential as therapeutics in situations where we currently do not have good clinical options. This is true for both estrogen receptor alpha (ERα) negative and ERα positive cancers. RECENT FINDINGS: The review has focused on examining associations between androgen receptor and patient prognosis and outcomes in different breast cancer subtypes. A logical extension of this is covering the timely topic of the use of androgen-directed therapy in these patients. The principle settings in which this is being considered is in ERα positive cancer with therapeutic resistance to ER-directed therapies and in ERα negative breast cancer that lack current standard targeted therapies. Finally interactions between mutations, and the potential role of androgen in the normal hierarchy of mammary cell differentiation and the relationship of this to cancer, are considered. SUMMARY: Androgens are firmly established as important factors across multiple breast cancer subtypes. The future challenge for basic researchers and important development for clinicians is going to be translating this understanding into effective therapeutics for the benefit of breast cancer patients.

The Role of Androgen Under Normal and Pathological Conditions in Sebaceous Glands: The Possibility of Target Therapy.

The androgen receptor plays a pivotal role in the sebaceous glands. Its primary function is to stimulate cell proliferation and differentiation in the sebaceous and its associate with acne. Previous studies have demonstrated expression of AR and steroidogenic enzymes in normal sebaceous glands and in all sebaceous disorders present evidence that androgen receptor may be a sensitive marker of sebaceous differentiation. It has been previously suggested that AR and steroidogenic enzymes immunohistochemistry may be useful particularly in identifying poorly sebaceous carcinoma. This review will provide an overview of the AR functions in the sebaceous glands and discussion of the therapeutic targets in acne and carcinoma.

Prognostic significance of proline, glutamic acid, leucine rich protein 1 (PELP1) in triple-negative breast cancer: a retrospective study on 129 cases.

BACKGROUND: Triple-negative breast cancer (TNBC) is associated with an aggressive clinical course due to the lack of therapeutic targets. Therefore, identifying reliable prognostic biomarkers and novel therapeutic targets for patients with TNBC is required. Proline, glutamic acid, leucine rich protein 1 (PELP1) is a novel steroidal receptor co-regulator, functioning as an oncogene and its expression is maintained in estrogen receptor (ER) negative breast cancers. PELP1 has been proposed as a prognostic biomarker in hormone-related cancers, including luminal-type breast cancers, but its significance in TNBC has not been studied. METHODS: PELP1 immunoreactivity was evaluated using immunohistochemistry in 129 patients with TNBC. Results were correlated with clinicopathological variables including patient's age, tumor size, lymph node stage, tumor grade, clinical stage, histological type, Ki-67 LI, as well as clinical outcome of the patients, including disease-free survival (DFS) and overall survival (OS). RESULTS: PELP1 was localized predominantly in the nuclei of carcinoma cells in TNBC. With the exception of a positive correlation between PELP1 protein expression and lymph node stage (p = 0.027), no significant associations between PELP1 protein expression and other clinicopathological variables, including DFS and OS, were found. However, when PELP1 and Ki-67 LI were grouped together, we found that patients in the PELP1/Ki-67 double high group (n = 48) demonstrated significantly reduced DFS (p = 0.005, log rank test) and OS (p = 0.002, log rank test) than others (n = 81). Multivariable analysis supported PELP1/Ki-67 double high expression as an independent prognostic factor in patients with TNBC, with an adjusted hazard ratio of 2.020 for recurrence (95 % CL, 1.022-3.990; p = 0.043) and of 2.380 for death (95 % CL, 1.138-4.978; p = 0.021). CONCLUSIONS: We found that evaluating both PELP1 and Ki-67 expression in TNBC could enhance the prognostic sensitivity of the two biomarkers. Therefore, we propose that PELP1/Ki-67 double high expression in tumors is an independent prognostic factor for predicting a poor outcome for patients with TNBC.

Androgen receptor, androgen-producing enzymes and their transcription factors in extramammary Paget disease.

Extramammary Paget disease (EMPD) has been known to frequently express androgen receptor (AR). Therefore, androgens could play roles in the biological behavior of Paget cells. 5α-Reductase (5α-red) types 1 and 2 and 17ß-hydroxysteroid dehydrogenase type 5 (17ß-HSD5) are pivotal in situ regulators of androgen production in androgen-responsive tissues including androgen-dependent neoplasms. Therefore, in this study, we immunolocalized AR, androgen-producing enzymes, and their transcription factors to assess the state of in situ androgen production and actions and its correlation of invasiveness in EMPD. We studied 51 cases of EMPD with known clinicopathological status. AR, 5α-red1, 17ß-HSD5, and ß-catenin immunoreactivity was evaluated by using the modified H-score method while cyclin D1, p53, forkhead box protein P1, and a proliferation marker, Ki-67, were quantified using labeling index. The mean scores of AR, 5α-red1, and 17ß-HSD5 in invasive EMPD were all significantly higher than noninvasive EMPD (P < .0001). Ki-67 labeling index as well as the cyclin D1 score was also significantly higher in invasive than noninvasive lesions of EMPD. These results demonstrated that androgen receptor and androgen-producing enzymes were both associated with cell cycle regulation and subsequently the invasiveness of EMPD lesions and could also indicate those above as potential markers of invasive potentials in EMPD.

Hypoelectrolytic isoosmotic solution for infusion prevents saline-induced ultrastuructural artifacts of renal biopsy specimens.

Artifacts in the process of specimen preparation are frequent in ultrastructural evaluation of renal biopsy. We hypothesized that the common practice of wrapping kidney biopsy specimens in saline-soaked gauze to prevent the drying of the specimens could be the major factor of artifacts. In this study, whole kidneys from two male Sprague-Dawley rats were used. Before fixation, fresh small cubes of kidney tissue were macerated in saline (Saline group) or hypoelectrolytic isoosmotic solution for infusion (HISI group) (Sorita T3 or SOLDEM 3A) for 10 or 30 min. Then, the specimens were processed by 1% OsO(4) in 0.1 M phosphate buffer (pH 7.4) and embedded by EPON 812 for ultramicroscopic analysis. In the Saline group, ultrastructural examination revealed swollen podocyte, swollen capillary protuberance of the mesangium into the glomerular capillary loop, tubular cells with swollen mitochondria and microvilli, and the smooth muscle cells in the arteriolar wall with marked vacuolar degeneration were detected after 10 min maceration in saline and these findings become more pronounced after 30 min maceration. However, in the HISI group, these artifacts were not identified or limited within 30 min. It is postulated that HISI solution could prevent the artifacts, and be used for soaking and wrapping instead of physiologic saline solution.

Clinical significance of subtype classification in metastatic lymph nodes of breast cancer patients undergoing neoadjuvant chemotherapy.

BACKGROUND: Neoadjuvant chemotherapy has been increasingly utilized in the treatment of breast cancer patients. However, there are no established surrogate markers predicting the response to subsequent adjuvant therapy and clinical outcome of patients. In particular, whether primary or lymph nodes metastasis should be evaluated for these analyses has remained unknown. Therefore, in this study, we first evaluated the differences in biomarkers between primary and metastatic cancer tissues in the patients undergoing neoadjuvant chemotherapy. We then correlated the findings with the clinical outcomes of these patients. METHODS: We examined 49 patients receiving neoadjuvant chemotherapy and subsequent surgery with lymph node metastasis. Estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2) and Ki-67 were all immunohistochemically evaluated in core needle biopsy samples from primary and metastatic tumors following chemotherapy. RESULTS: No statistically significant differences in these markers were detected between the primary tumor and metastatic lymph nodes following therapy, but the Ki-67 labeling index was significantly higher in metastatic lymph nodes than in primary tumor (p = 0.017). The patients associated with luminal A type carcinoma in their lymph nodes following chemotherapy demonstrated significantly better clinical outcomes (disease-free survival: p = 0.0045, overall survival: p = 0.0006) than those who were not. CONCLUSION: These data indicate that subtype classification following chemotherapy, in the metastatic lymph nodes rather than primary tumor could predict long-term outcomes of patients undergoing neoadjuvant chemotherapy.

3ßHSD and CYB5A double positive adrenocortical cells during adrenal development/aging.

Androstenedione is a common precursor of sex steroids produced and secreted in the human adrenal gland and produced by 3ß-hydroxysteroid dehydrogenase (3ßHSD), 17ß-hydroxylase/17,20-lyase (CYP17) and cytochrome b5 (CYB5A). 3ßHSD is expressed in the zona glomerulosa (ZG) and fasciculata (ZF), CYP17 in the ZF and zona reticularis (ZR) and CYB5A in the ZR, respectively. We previously demonstrated the presence of cortical parenchymal cells co-expressing 3ßHSD and CYB5A with hybrid features of both ZF and ZR in human adrenal cortex and hypothesized that these cells may play an important role in androstenedione production in human adrenal gland. Age-related morphologic development of these hybrid cells has, however, not been studied. Therefore, in this study, 48 human adrenal specimens from various age groups were retrieved. Double-immunohistochemical analyses were used in order to study the correlation between this hybrid cell type and age. In both male and female adrenal cortex, the means of total adrenocortical area, the area positive for CYB5A and its ratio reached highest peak in the 21-40-year-old (y.o.) group. The greatest overlap between 3ßHSD and CYB5A in both total and relative area was present in the 13-20 y.o. group. For all the markers mentioned above, statistically significant differences were detected among the different age groups examined (p < 0.05). These findings indicated that both area and ratio of 3ßHSD and CYB5A double positive cells, which could represent the hybrid cells of ZF and ZR, are correlated with human adrenal development and could subsequently influence age-related serum androstenedione levels.

Steroidogenic enzymes, their related transcription factors and nuclear receptors in human sebaceous glands under normal and pathological conditions.

The sebaceous gland is a major site of steroid synthesis in human skin, but details of the status of steroidogenic enzymes and their regulation in human sebaceous glands under normal and pathological conditions have rarely been reported. Therefore, in this study, we examined the status of steroidogenic enzymes, sex steroid receptors and transcription factors in human sebaceous glands under normal and pathological conditions to explore their possible roles in in situ steroid production in human skin. Immunohistochemical analysis was performed in a total of 59 human skin specimens, including 22 normal human sebaceous glands, 12 with sebaceous nevus, 12 with sebaceous gland hyperplasia, 3 with sebaceoma and 10 with sebaceous carcinoma. Immortalised human SZ95 sebocytes were treated with forskolin or vehicle for 3h, 6h, 12h or 24h, and the mRNA levels of steroidogenic enzymes were evaluated at each time point using quantitative RT-PCR (qPCR). The results of immunohistochemistry demonstrated the immunoreactivity of 3ß-HSD1, CYP11A1, StAR, 17ß-HSD5, CYP17A1, 5α-red1, PRB, AR and NGFI-B in normal human sebaceous gland, with lower levels of expression in pathological sebaceous glands. The results of the in vitro study also indicated that the expression levels of 3ß-HSD1, CYP11A1, StAR, 5α-red1 and NGFI-B were elevated by forskolin. 3ß-HSD1 and other steroidogenic enzymes were expressed in sebaceous glands resulting in in situ androgen and progesterone synthesis and their functions.

Complexities of androgen receptor signalling in breast cancer.

While the clinical benefit of androgen-based therapeutics in breast cancer has been known since the 1940s, we have only recently begun to fully understand the mechanisms of androgen action in breast cancer. Androgen signalling pathways can have either beneficial or deleterious effects in breast cancer depending on the breast cancer subtype and intracellular context. This review discusses our current knowledge of androgen signalling in breast cancer, including the relationship between serum androgens and breast cancer risk, the prognostic significance of androgen receptor (AR) expression in different breast cancer subtypes and the downstream molecular pathways mediating androgen action in breast cancer cells. Intracrine androgen metabolism has also been discussed and proposed as a potential mechanism that may explain some of the reported differences regarding dichotomous androgen actions in breast cancers. A better understanding of AR signalling in this disease is critical given the current resurgence in interest in utilising contemporary AR-directed therapies for breast cancer and the need for biomarkers that will accurately predict clinical response.

Renal epithelioid angiomyolipoma with malignant features: Histological evaluation and novel immunohistochemical findings.

Renal epithelioid angiomyolipoma (EAML) is a potentially malignant tumor type whose characteristics and biomarkers predictive of malignant behavior have not been elucidated. Here, we report three cases of renal EAML with malignant features but without histories of tuberous sclerosis complex. Case 1 involved a 29-year-old man with a 12-cm solid mass in the right kidney who underwent radical right nephrectomy. Case 2 involved a 22-year-old woman with a retroperitoneal mass who underwent radical right nephrectomy and retroperitoneal tumorectomy. Local recurrence was detected 7 years post-surgery. Case 3 involved a 23-year-old man with a 14-cm solid mass in the left kidney who underwent radical left nephrectomy. Microscopically, the tumors in all cases demonstrated proliferation of epithelioid cells with atypia, mitotic activity, necrosis, hemorrhage, and vascular invasion. Epithelioid cells in all cases were immunohistochemically positive for melanocytic and myoid markers and weakly positive for E-cadherin and ß-catenin. Immunohistochemistry revealed activation of the mammalian target of rapamycin pathway. Here, we report the morphological and immunohistochemical features of clinically or histologically malignant renal EAML.