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Tuberous sclerosis complex (TSC) tumors are presently incurable despite a cytostatic response to mTOR pathway inhibition because recurrence of disease occurs after treatment is discontinued. Here, we explored the hypothesis that inhibiting tyrosine kinase activity in mesenchymal lineage-specific platelet-derived growth factor receptor β (PDGFRβ) signaling in TSC tumors is cytocidal and attenuates tumorigenesis at significantly higher levels than treatment with an mTOR inhibitor. Rapamycin-induced versus tyrosine kinase inhibitor (TKI)-induced renal angiomyolipoma (AML) and pulmonary lymphangioleiomyomatosis (LAM) tumor cells were comparatively analyzed using cell survival assays, RNA sequencing, and bioinformatics to distinguish tumoricidal mechanisms adopted by each drug type. The efficacy of imatinib therapy was validated against spontaneously developing renal cystadenomas in tuberous sclerosis Tsc2+/- mouse models (C57BL/6J mice; N = 6; 400 mg/kg/d; oral gavage) compared with Tsc2+/- mice treated with PBS (C57BL/6J mice; N = 6). Our study revealed that TKIs imatinib and nilotinib were cytocidal to both pulmonary LAM and renal AML cell cultures through the downregulation of the glycoprotein GPVI pathway and resultant disruption in mitochondrial permeability, increased cytosolic cytochrome C, and caspase 3 activation. Importantly, renal tumor growth was significantly attenuated in imatinib-treated Tsc2+/- mice compared with PBS treatment. The preclinical studies reported here provide evidence documenting the effectiveness of TKIs in limiting LAM and AML cell growth and viability with important clinical potential. Furthermore, these drugs elicit their effects by targeting a PDGF pathway-dependent apoptotic mechanism supporting the investigation of these drugs as a novel class of TSC therapeutics., (©2023 The Authors; Published by the American Association for Cancer Research.)

The renal angiomyolipoma (AML) is a benign tumor characteristically composed of fat, smooth muscle tissue, and vessels. We collected AMLs from our nephrectomy database, reclassified them according to their histological appearance, recorded the demographic, clinical, and pathological parameters, and compared them with oncocytoma (RO) and renal cell carcinoma (RCC). Immunohistochemistry was ordered in 41 cases. In 2224 nephrectomies, we found 52 AMLs with a 53 mm median size. The mean age was 52.76. Forty-eight tumors were sporadic, while four were hereditary. The revision resulted in 31 classic, 13 leiomyoma-like, five lipoma-like, two epithelioid, and one AML with epithelial cysts. SMA was diffusely positive, except for the epithelioid type, while MelanA harbored stronger expression than HMB45. AML was more frequent in females and appeared ten and 7 years earlier than RO and RCC, respectively. The follow-up time was 7.42 years, and neither tumor-related death nor relapse occurred. AML is rare in nephrectomies and develops primarily in females in their 50s with an average size of 50-60 mm at the surgery. The histological appearance in order of frequency is classic, leiomyoma-like, lipoma-like, epithelioid, and cystic. The MelanA, HMB45, and SMA immunohistochemistry can support the light-microscopic findings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Fejes, Sánta, Jenei, Király, Varga and Kuthi.)

Tuberous sclerosis complex (TSC) is a rare autosomal dominant disorder involving multiple organ systems. TSC2 gene plays an important role in the development of TSC. The most common kidney manifestation of TSC is renal angiomyolipoma (RAML). TSC-RAML is more likely to be bilateral multiple tumors and tends to destroy the renal structure and damages renal function severely. As a result, patients with TSC-RAML often miss the opportunity for surgical treatment when TSC-RAML is diagnosed, causing difficulty in obtaining tumor specimens through surgery. Due to this difficulty, model cell lines must be constructed for scientific research. In this paper, TSC2 was knocked out in NIH-3T3 cell lines by CRISPR/Cas9 system. PCR, WB and mTOR inhibitor drug sensitivity test showed that the TSC2 knockout NIH-3T3 cells were successfully constructed. The ability of proliferation and invasion in TSC2 KO NIH-3T3 cells were higher than those in wild type group. The constructed KO cell line lay the foundation for further study of TSC., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Histological examination of liver biopsies and resection specimens remains the gold standard to establish a definitive diagnosis of liver lesions. While hepatocellular carcinoma remains the most commonly encountered liver lesion on mass-directed biopsies, surgical pathologists must be aware of other entities that may pose diagnostic challenges, as an accurate diagnosis is key for patient management. Mesenchymal tumours of the liver are relatively uncommon, therefore many pathologists are unfamiliar with these tumours. While the clinical presentation and radiological features of these lesions often overlap, careful attention to histological clues can assist in weeding out various congeners to arrive at the most accurate diagnosis. An additional challenge when diagnosing mesenchymal tumours is the specimen type, as mass-directed core biopsies are limited and have become standard clinical practice. Besides careful attention to histological features, radiological findings and clinical history, immunohistochemical analysis and molecular studies have become of immense diagnostic value. In this review, we discuss several common and rare mesenchymal hepatic lesions as defined in the current World Health Organization (WHO) classification and most up-to-date literature. We also discuss immunohistochemistry panels and relevant molecular findings that may assist in rendering an accurate diagnosis when encountering these lesions in daily practice., (Copyright © 2021 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Tuberous sclerosis complex (TSC) is caused by mutations of either the TSC1 or TSC2 tumor suppressor gene. TSC causes tumors of the brain, heart, kidney, skin and lymphangioleiomyomatosis (LAM). Here we report that the TSC2 protein physically binds to high-density lipoprotein binding protein (HDLBP), also called vigilin, a core stress granule (SG) protein, and that TSC2 localizes to SGs. SGs contain mRNAs and translation initiation complexes, and regulate gene expression by sequestering specific transcripts, thereby serving a cytoprotective role. TSC2 has never before been shown to localize to SGs and knocking down vigilin impacts SG translocation of TSC2. TSC2-deficient cells showed a striking increase in the number of SGs after thermal shock and arsenite treatment relative to Tsc2-expressing cells. Our findings also show that murine kidney lysates from a model of TSC have increased levels of SG components including G3BP1 and Caprin1. G3BP1 and Caprin are elevated in renal angiomyolipomas (a renal tumor common in patients with TSC) compared with control normal kidney. G3BP1 is also elevated in TSC-associated subependymal giant cell astrocytomas. We found that genetic inhibition of G3BP1 inhibits the proliferation of TSC2-deficient cells in vitro . Finally, in a mouse model of TSC, genetic inhibition of SGs suppresses cell growth, suggesting that targeting SGs may have efficacy in the therapy of TSC. IMPLICATIONS: This study demonstrates that TSC2 physically interacts with HDLBP/vigilin, a component of SGs, that TSC2 localizes to SG and that TSC2-deficient cells have more SGs, suggesting that SGs represent a novel therapeutic target in TSC., (©2021 American Association for Cancer Research.)

Tuberous sclerosis complex (TSC) is an autosomal dominant tumor suppressor syndrome, characterized by tumor development in multiple organs, including renal angiomyolipoma. Biallelic loss of TSC1 or TSC2 is a known genetic driver of angiomyolipoma development, however, whether an altered transcriptional repertoire contributes to TSC-associated tumorigenesis is unknown. RNA-seq analyses showed that MITF A isoform (MITF-A) was consistently highly expressed in angiomyolipoma, immunohistochemistry showed microphthalmia-associated transcription factor nuclear localization, and Chromatin immuno-Precipitation Sequencing analysis showed that the MITF-A transcriptional start site was highly enriched with H3K27ac marks. Using the angiomyolipoma cell line 621-101, MITF knockout (MITF.KO) and MITF-A overexpressing (MITF.OE) cell lines were generated. MITF.KO cells showed markedly reduced growth and invasion in vitro, and were unable to form xenografted tumors. In contrast, MITF.OE cells grew faster in vitro and as xenografted tumors compared to control cells. RNA-Seq analysis showed that both ID2 and Cysteine-rich angiogenic inducer 61 (CYR61) expression levels were increased in the MITF.OE cells and reduced in the MITF.KO cells, and luciferase assays showed this was due to transcriptional effects. Importantly, CYR61 overexpression rescued MITF.KO cell growth in vitro and tumor growth in vivo. These findings suggest that MITF-A is a transcriptional oncogenic driver of angiomyolipoma tumor development, acting through regulation of CYR61.

Ga-FAPI (Ga-labeled fibroblast activation protein inhibitor) PET imaging has been recently introduced for the diagnosis and staging in various malignant tumors. However, the reports about the utility of FAPI imaging in benign tumor are relatively rare. Here we report a case of pathologically proven recurrent angiomyolipoma in the left retroperitoneal area with low F-FDG uptake but diffuse heterogeneous intense Ga-FAPI uptake together with suspected lung metastases in a 53-year-old woman. Our case illustrates FAPI imaging could be helpful not only for detecting various malignant tumors but also for benign tumor like this case due to fibrotic activity in the disease.

Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by multiorgan hamartomas, including renal angiomyolipomas and pulmonary lymphangioleiomyomatosis (LAM). TSC2 deficiency leads to hyperactivation of mTOR Complex 1 (mTORC1), a master regulator of cell growth and metabolism. Phospholipid metabolism is dysregulated upon TSC2 loss, causing enhanced production of lysophosphatidylcholine (LPC) species by TSC2-deficient tumor cells. LPC is the major substrate of the secreted lysophospholipase D autotaxin (ATX), which generates two bioactive lipids, lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P). We report here that ATX expression is upregulated in human renal angiomyolipoma-derived TSC2-deficient cells compared with TSC2 add-back cells. Inhibition of ATX via the clinically developed compound GLPG1690 suppressed TSC2-loss associated oncogenicity in vitro and in vivo and induced apoptosis in TSC2-deficient cells. GLPG1690 suppressed AKT and ERK1/2 signaling and profoundly impacted the transcriptome of these cells while inducing minor gene expression changes in TSC2 add-back cells. RNA-sequencing studies revealed transcriptomic signatures of LPA and S1P, suggesting an LPA/S1P-mediated reprogramming of the TSC lipidome. In addition, supplementation of LPA or S1P rescued proliferation and viability, neutral lipid content, and AKT or ERK1/2 signaling in human TSC2-deficient cells treated with GLPG1690. Importantly, TSC-associated renal angiomyolipomas have higher expression of LPA receptor 1 and S1P receptor 3 compared with normal kidney. These studies increase our understanding of TSC2-deficient cell metabolism, leading to novel potential therapeutic opportunities for TSC and LAM. SIGNIFICANCE: This study identifies activation of the ATX-LPA/S1P pathway as a novel mode of metabolic dysregulation upon TSC2 loss, highlighting critical roles for ATX in TSC2-deficient cell fitness and in TSC tumorigenesis., (©2020 American Association for Cancer Research.)

Aim: The discrimination of renal cell carcinoma from renal angiomyolipoma (RAML) is crucial for the effective treatment of each. Materials & methods: Serum samples were analyzed by nuclear magnetic resonance spectroscopy-based metabolomics and a number of metabolites were further quantified by HPLC-UV. Results: Clear-cell renal carcinoma (ccRCC) was characterized by drastic disruptions in energy, amino acids, creatinine and uric acid metabolic pathways. A logistic model for the differential diagnosis of RAML from ccRCC was established using the combination of serum levels of uric acid, the ratio of uric acid to hypoxanthine and the ratio of hypoxanthine to creatinine as variables with area under the curve of the receiver operating characteristic curve value of 0.907. Conclusion: Alterations in serum purine metabolites may be used as potential metabolic markers for the differential diagnosis of ccRCC and RAML.

Angiomyolipoma (AML) earlier thought to be a hamartomatous lesion is now considered as a rare neoplasm of the kidney. A 6-year-old child presented with an abdominal mass. CT scans showed a multiloculated mass with variable attenuation raising the possibility of AML. FNAC done from the lesion also suggested possibility of AML, which was later confirmed on the histology of the resected specimen. There is sparse literature available describing the cytologic diagnosis of AML in children. Hence, we take this opportunity to describe the cytological findings of a case of pediatric renal AML., (© 2019 Wiley Periodicals, Inc.)

We discovered that 90.3% of patients with angiomyolipomas, lymphangioleiomyomatosis (LAM), and tuberous sclerosis complex (TSC) carry the arginine variant of codon 72 (R72) of TP53 and that R72 increases the risk for angiomyolipoma. R72 transactivates NOTCH1 and NODAL better than the proline variant of codon 72 (P72); therefore, the expression of NOTCH1 and NODAL is increased in angiomyolipoma cells that carry R72. The loss of Tp53 and Tsc1 within nestin-expressing cells in mice resulted in the development of renal cell carcinomas (RCC) with high Notch1 and Nodal expression, suggesting that similar downstream mechanisms contribute to tumorigenesis as a result of p53 loss in mice and p53 polymorphism in humans. The loss of murine Tp53 or expression of human R72 contributes to tumorigenesis via enhancing epithelial-to-mesenchymal transition and motility of tumor cells through the Notch and Nodal pathways. IMPLICATIONS: This work revealed unexpected contributions of the p53 polymorphism to the pathogenesis of TSC and established signaling alterations caused by this polymorphism as a target for therapy. We found that the codon 72 TP53 polymorphism contributes to TSC-associated tumorigenesis via Notch and Nodal signaling., (©2019 American Association for Cancer Research.)

Epithelioid angiomyolipoma (EAML) has been known as a potentially malignant tumor which occasionally recur and/or metastasize to other organs, and clinically and pathologically recognized as distinct entity. However, the mechanisms of recurrence and/or metastasis (recurrence/metastasis) has still remained unknown. Here, we report two cases of renal EAML associated with recurrence/metastasis, and three cases of EAML in kidney or liver without recurrence/metastasis. According to the previous histological predictive models of EAML, the primary tumor was classified as low risk group in one of the cases with recurrence/metastasis in spite of its malignant behavior. Therefore, we considered that further investigation about the mechanisms of recurrence/metastasis in EAML is required for a malignancy prediction. We focused on some cell-cycle modulators, including mouse double minute 2 homolog (MDM2), which is ubiquitin ligase well-known to promote malignant behaviors by p53 ubiquitination and degradation, and also other cellular processes including genomic instability and epithelial-mesenchymal transition in p53-independent manners in various human malignancies. Immunohistochemical evaluation revealed that MDM2 protein expression increased stepwise throughout every steps of metastasis/recurrence in both cases, although it was negative in primary tumors. In conclusion, this is the first study demonstrating that MDM2 could play an important role in the molecular mechanisms of recurrence/metastasis of EAML. Further analyses focusing on MDM2 pathway could contribute to the identification of novel prognostic factors and/or therapeutic targets in EAML patients.

Background: Hepatic angiomyolipoma (HAML) is a rare and difficult-to-diagnose liver tumour. The aim of this study was to summarize experiences in the management of HAML and to recommend a practical treatment strategy., Methods: We retrospectively studied 92 patients who were diagnosed with HAML and analysed the clinical presentation, histopathological features and treatment of the tumours encountered at our institute from May 2009 to June 2016., Results: The patients included 67 females and 25 males who underwent at least one radiographic examination. Sixty-eight patients underwent radical hepatectomy, two patients underwent liver biopsy, and 22 patients were treated with radiofrequency ablation after liver biopsy. The tumour cells correspondingly expressed both melanoma cell markers (HMB45, MART-1) and smooth muscle cell markers. Two patients were found to have tumour recurrence (2/92, 2.2%) after radical hepatectomy, and none of the patients died., Conclusion: Diagnosis of HAML depends on pathological findings. The treatment strategy for HAML should be selected according to the tumour size, liver biopsy, location and clinical symptoms of HAML. Patients should be followed closely after surgery because of the malignant potential of HAML., (© 2017 Royal Australasian College of Surgeons.)

Tuberous sclerosis complex (TSC) is a genetic disorder characterized by tumor formation in multiple organs, with over 80% of TSC patients developing angiomyolipomas (TSC-AMLs). However, the molecular events that contribute to TSC-AMLs are not well understood. Recent reports have demonstrated that microRNAs (miRNAs) are critical in TSC cortical tubers. However, little is known about the role of miRNAs in TSC-AMLs. In the current study, we analyzed changes in the miRNA and mRNA profiles in TSC-AMLs and matched normal adjacent tissues. A total of 15 differentially expressed miRNAs and 2664 mRNAs were identified. Using quantitative real-time PCR, we confirmed the results of the miRNA and mRNA profile experiments. Through bioinformatic analysis and luciferase reporter assays, we found that BCL2L11, an apoptotic activator, was the direct target of miR-9-5p, miR-124-3p, and miR-132-3p. Engineered expression of miR-9-5p, miR-124-3p, or miR-132-3p significantly regulated proliferation and apoptosis in Tsc2 -/- cells. Manipulated expression of BCL2L11 also led to proliferation and apoptosis alterations in Tsc2 -/- cells, in agreement with the effects of the above three miRNAs. In addition, BCL2L11 rescued the proliferation and apoptotic inhibition induced by miR-9-5p, miR-124-3p, and miR-132-3p in Tsc2 -/- cells. This study provides supportive evidence that miR-9-5p, miR-124-3p, and miR-132-3p play a role in TSC-AMLs through the regulation of BCL2L11.

Background: Improving the knowledge of angiomyolipoma physiopathology might help in refining its pharmacological treatment. We investigated if angiomyolipoma cells have migratory properties, how their growth and motility can be influenced by the hormonal milieu, and if this can be related to a specific gender., Methods: Primary cells were isolated from angiomyolipomas surgically resected for therapeutical reasons in a female and in a male patient. The genetic control demonstrated no TSC2 deletion. Bi- (wound healing) and three-dimensional (transwell assay) migration were analyzed in vitro in basal conditions and under the influence of 17- β-estradiol and SDF-1α., Results: Treatment up to 72 hours with 17-β-estradiol (0.1-100 nM), tamoxifen (0.2-20 μM) or with both, does not modify angiomyolipoma cells proliferation. On the other hand, SDF-1α and 17-β-estradiol treatment induce a significant motility increase (both bi- and three-dimensional) which becomes evident already after 2 hours of incubation. Angiomyolipoma cells express mRNA coding for SDF-1α and 17-β-estradiol receptors and secrete both the metalloproteases principally involved in malignant phenotype acquisition, i.e. MMP-2 and MMP-9., Conclusion: Angiomyolipoma cells behave similarly, despite their different source. Primary angiomyolipoma cells migrate in response to hormonal milieu and soluble factors, and produce active metalloproteases, both aspects being consistent with the theory claiming they can migrate to the lungs (and/or other organs) and colonizing them. No main feature, among the aspects we analyzed, seems to be referable to the gender of origin., Competing Interests: The authors have declared that no competing interests exist.

The mechanism by which TSC2 inactivation or deficiency contributes to the pathology of tuberous sclerosis complex (TSC) is not fully clear. We show that renal angiomyolipomas from TSC patients and kidney cortex from Tsc2+/- mice exhibit elevated levels of reactive oxygen species (ROS). Downregulation of tuberin (protein encoded by TSC2 gene) in renal proximal tubular epithelial cells significantly increased ROS concomitant with enhanced Nox4. Similarly, we found elevated levels of Nox4 in the renal cortex of Tsc2+/- mice and in the renal angiomyolipomas from TSC patients. Tuberin deficiency is associated with activation of mTORC1. Rapamycin, shRNAs targeting raptor, or inhibition of S6 kinase significantly inhibited the expression of Nox4, resulting in attenuation of production of ROS in tuberin-downregulated proximal tubular epithelial cells. In contrast, activation of mTORC1 increased Nox4 and ROS. These results indicate that Nox4 may be a potential target for tuberin-deficiency-derived diseases. Using a xenograft model from tuberin-null tubular cells in nude mice, both anti-sense Nox4 and GKT137831, a specific inhibitor of Nox1/4, significantly inhibited the tumor growth. Thus, our results demonstrate the presence of an antagonistic relationship between tuberin and Nox4 to drive oncogenesis in the tuberin deficiency syndrome and identify Nox4 as a target to develop a therapy for TSC.

Lymphangioleiomyomatosis (LAM) is a fatal lung disease associated with germline or somatic inactivating mutations in tuberous sclerosis complex genes ( TSC1 or TSC2 ). LAM is characterized by neoplastic growth of smooth muscle-α-actin-positive cells that destroy lung parenchyma and by the formation of benign renal neoplasms called angiolipomas. The mammalian target of rapamycin complex 1 (mTORC1) inhibitor rapamycin slows progression of these diseases but is not curative and associated with notable toxicity at clinically effective doses, highlighting the need for better understanding LAM's molecular etiology. We report here that LAM lesions and angiomyolipomas overexpress urokinase-type plasminogen activator (uPA). Tsc1 -/- and Tsc2 -/- mouse embryonic fibroblasts expressed higher uPA levels than their WT counterparts, resulting from the TSC inactivation. Inhibition of uPA expression in Tsc2 -null cells reduced the growth and invasiveness and increased susceptibility to apoptosis. However, rapamycin further increased uPA expression in TSC2-null tumor cells and immortalized TSC2-null angiomyolipoma cells, but not in cells with intact TSC. Induction of glucocorticoid receptor signaling or forkhead box (FOXO) 1/3 inhibition abolished the rapamycin-induced uPA expression in TSC-compromised cells. Moreover, rapamycin-enhanced migration of TSC2-null cells was inhibited by the uPA inhibitor UK122, dexamethasone, and a FOXO inhibitor. uPA-knock-out mice developed fewer and smaller TSC2-null lung tumors, and introduction of uPA shRNA in tumor cells or amiloride-induced uPA inhibition reduced tumorigenesis in vivo These findings suggest that interference with the uPA-dependent pathway, when used along with rapamycin, might attenuate LAM progression and potentially other TSC-related disorders., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)

Differentiation abnormalities are a hallmark of tuberous sclerosis complex (TSC) manifestations; however, the genesis of these abnormalities remains unclear. Here we report on mechanisms controlling the multi-lineage, early neuronal progenitor and neural stem-like cell characteristics of lymphangioleiomyomatosis (LAM) and angiomyolipoma cells. These mechanisms include the activation of a previously unreported Rheb-Notch-Rheb regulatory loop, in which the cyclic binding of Notch1 to the Notch-responsive elements (NREs) on the Rheb promoter is a key event. This binding induces the transactivation of Rheb. The identified NRE2 and NRE3 on the Rheb promoter are important to Notch-dependent promoter activity. Notch cooperates with Rheb to block cell differentiation via similar mechanisms in mouse models of TSC. Cell-specific loss of Tsc1 within nestin-expressing cells in adult mice leads to the formation of kidney cysts, renal intraepithelial neoplasia, and invasive papillary renal carcinoma.

Tuberous sclerosis complex (TSC) is a tumor-suppressor syndrome affecting multiple organs, including the brain, skin, kidneys, heart, and lungs. TSC is associated with mutations in TSC1 or TSC2, resulting in hyperactivation of mTOR complex 1 (mTORC1). Clinical trials demonstrate that mTORC1 inhibitors decrease tumor volume and stabilize lung function in TSC patients; however, mTOR inhibitors are cytostatic not cytocidal, and long-term benefits and toxicities are uncertain. Previously, we identified rapamycin-insensitive upregulation of cyclooxygenase 2 (PTGS2/COX2) and prostaglandin E2 (PGE2) production in TSC2-deficient cells and postulated that the action of excess PGE2 and its cognate receptors (EP) contributes to cell survival. In this study, we identify upregulation of EP3 (PTGER3) expression in TSC2-deficient cells, TSC renal angiomyolipomas, lymphangioleiomyomatosis lung nodules, and epileptic brain tubers. TSC2 negatively regulated EP3 expression via Rheb in a rapamycin-insensitive manner. The EP3 antagonist, L-798106, selectively suppressed the viability of TSC2-deficient cells in vitro and decreased the lung colonization of TSC2-deficient cells. Collectively, these data reveal a novel function of TSC2 and Rheb in the regulation of EP3 expression and cell viability. Implications: Therapeutic targeting of an aberrant PGE2-EP3 signaling axis may have therapeutic benefit for TSC patients and for other mTOR-hyperactive neoplasms. Mol Cancer Res; 15(10); 1318-30. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Renal angiomyolipomas are the most common renal mesenchymal tumors. While classic angiomyolipomas are benign, there are a number of other subtypes. Epithelioid variants are potentially malignant and may be indistinguishable from renal cell carcinoma on imaging. We present a 52-year-old woman who underwent left nephrectomy for an aggressive-appearing malignant renal epithelioid angiomyolipoma. At 6 months postoperatively, restaging FDG PET/CT demonstrated a hypermetabolic left adrenal mass extending to the left adrenal vein, left renal vein, inferior vena cava, and right atrium (SUVmax = 12). Multiple hypermetabolic pulmonary metastases were also noted.

Angiomyofibroblastoma is a rare and benign tumor that usually involves vulvovaginal area in women of reproductive age and early menopause. We report a lipomatous angiomyofibroblastoma in a 55-year-old multigravid woman. This tumor measured 9 cm in size and contained prominent mature adipose tissue that comprised approximately 50% of the tumor.

Four resected specimens of hepatic angiomyolipoma in which uptake of Sonazoid was observed in the postvascular phase of Sonazoid-enhanced ultrasonography were analyzed. Macrophage localization in the tumor was revealed pathologically by immunohistochemical staining for CD68. CD68-positive cells were observed in the tumor in all cases. The density of CD68-positive cells was 100/mm2, and the ratio of CD68-positive cell density in the tumor to that in the surrounding parenchyma was 32-171%. These results suggested that the uptake of the contrast agent Sonazoid was related to the density of CD68-positive cells., (© 2016 S. Karger AG, Basel.)

Angiomyolipoma with epithelial cysts is a rare mesenchymal tumor of the kidney that enters in the differential diagnosis of adult cystic renal neoplasms. These tumors demonstrate a slight female predominance and can present either incidentally or with symptoms, commonly flank pain and hematuria. Unlike conventional angiomyolipoma, this variant is characterized grossly by both solid and cystic areas, and histologically by the presence of single or multiple cysts lined by epithelial cells, a subepithelial "cambium-like" layer of small stromal cells with a prominent capillary vasculature, and a thick exterior wall composed of poorly formed fascicles of smooth muscle and thick-walled dysplastic blood vessels. Tumors show a distinct immunohistochemical profile and are often reactive for melanocytic markers (HMB-45 and Melan-A), as well as estrogen receptor and progesterone receptor. These tumors have an indolent clinical course, with no reports of progression or metastasis in reported cases thus far.

Background: Angiomyolipoma is a benign mesenchymal tumor composed of variable amounts of smooth muscle, adipose tissue and thick-walled blood vessels, and usually named PEComas (perivascular epithelioid cell tumors). PEComas share overlapping histopathological features with epithelioid cells along a perivascular distribution and characteristic immunohistochemistry with coexpression of myoid and melanocytic markers (HMB-45 /or Melan-A). We report the first case of primary orbital angiomyolipoma with negative melanocytic marker., Case Presentation: An 80-year-old Asian woman had a 2-year history of progressive swelling in the left upper eyelid. External examination revealed 3 cm of relative proptosis of the left eye and a palpable mass in the left superonasal orbit. Computed tomographic scan demonstrated a circumscribed, heterogeneous orbital mass. Excision biopsy was done and the histological finding demonstrated the orbital mass was composed of mature adipocytes, intermingled with spindle or oval-shaped cells, and accompanied by thick-walled blood vessels. Immunohistochemically, tumor cells were positive for CD34 and HHF-35, but negative for cytokeratin, HMB-45 and Melan-A. The diagnosis of angiomyolipoma was made. No recurrence was noted at 2-year follow-up., Conclusion: In our case, the HMB-45 negativity may be explained by the rarity of the epithelioid cells, and the HMB-45 positivity is often weaker or absent in spindle cells. Angiomyolipoma, although rare, should be added to the differential diagnosis of space-occupying orbital lesion.

Objective: To study the immunohistochemical expression of S100A1, GLUT-1 and Cavolin-1 and its diagnostic significance in renal tumors with oncocytic features., Methods: Tissue microarray and immunohistochemical staining for S100A1, GLUT-1 and Cavolin-1 were carried out in 59 cases of renal tumors with oncocytic features, including 19 cases of renal oncocytoma, 15 cases of clear cell renal cell carcinoma (CCRCC) with eosinophilic cells, 11 cases of eosinophilic variant of chromophobe renal cell carcinoma, 7 cases of oncocytic papillary renal cell carcinoma and 7 cases of epithelioid angiomyolipoma., Results: S100A1 was expressed in renal oncocytoma, with a positive propotion of 16/19 (including 14 cases showing widespread and strong positivity). On the other hand, the rate of expression of S100A1 was 2/11 in eosinophilic variant of chromophobe renal cell carcinoma, 10/15 in CCRCC with eosinophilic cells, 3/7 in oncocytic papillary renal cell carcinoma and 6/7 in epithelioid angiomyolipoma (P>0.05). The difference of S100A1 expression between renal oncocytoma and eosinophilic variant of chromophobe renal cell carcinoma was statistically significant. GLUT-1 was located in cell membrane, with a positive rate of 13/15 in CCRCC with eosinophilic cells, 7/19 in renal oncocytoma, 4/7 (weak) in oncocytic papillary renal cell carcinoma, 1/11 in eosinophilic variant of chromophobe renal cell carcinoma and 0/7 in epithelioid angiomyolipoma. The rate of expression of Cav-1 was 6/15 in CCRCC with eosinophilic cells, 2/7 in oncocytic papillary renal cell carcinoma, 5/7 in epithelioid angiomyolipoma, 2/11 (weak) in eosinophilic variant of chromophobe renal cell carcinoma and 0/19 in renal oncocytoma. S100A1 showed high sensitivity and 50% specificity in the diagnosis of renal oncocytoma. GLUT-1 and Cav-1 showed high specificity and sensitivity in the diagnosis of CCRCC and epithelioid angiomyolipoma., Conclusions: S100A1 is widely expressed in various oncocytic renal neoplasms and helpful in differential diagnosis of renal oncocytoma from eosinophilic variant of chromophobe renal cell carcinoma, but not from other 3 oncocytic renal tumors. Overexpression of GLUT-1 can be used in distinction between CCRCC and renal oncocytoma. Cav-1 is widely expressed in CCRCC and epithelioid angiomyolipoma but not in renal oncocytoma. Cav-1 expression thus rules out renal oncocytoma.

Backgound: Renal epithelioid angiomyolipoma (EAML) is a rare variant of AML (angiomyolipoma) and is often associated with aggressive behaviors. The pathogenesis of EAML has been poorly understood. We analyzed the expression of p53 and Ki-67 by immunohistochemistry (IHC) and investigated p53 mutation analysis in 11 cases of EAML in comparison to classical AML., Methods: P53 and Ki-67 expression status were determined by IHC staining. P53 mutation analysis was performed using bi-directional sequencing., Results: Renal EAML tumors were significantly associated with more severe to moderate nuclear atypia (100% vs. 36.4%, P = 0.004) and mitotic activity (90.9% vs. 27.3%, P = 0.008) compared with AML tumors. Out of 11 cases of EAML, 8 were positive for p53. There was only 1 case with positive p53 expression in AML cases and expression of p53 protein showed significant difference between EAML and AML tumors (72.7% vs. 9.1%, P = 0.008). In addition, there were 7 AML and 6 EAML cases harbored P72R mutation (SNP) in exon 4 of p53. Compared with AML cases, 2 out of 11 cases of EMAL showed more than 10% positivity for ki-67. The finding of stronger p53 expression in renal EAML might have contributed to their malignant behavior. However, the abnormal p53 expression cannot be entirely explained by p53 mutations in the exons examined., Conclusions: Thus, the combination of immunohistochemical assessment of tumor antigens might improve our ability to predict the malignant outcome in EAML.

Aims: To determine the significance of the epithelioid type and the corresponding molecular alterations in hepatic angiomyolipoma (AML)., Methods and Results: We retrieved 24 samples of hepatic AML to delineate the clinicopathological features and the immunohistochemical expression of components in the mTOR pathway, and employed microsatellite markers to analyse allelic imbalances in the TSC1 and TSC2 regions. Myomatous AML was the most common type, and a predominantly epithelioid cell population was observed in 50% of the samples. Two-thirds of all samples contained <20% of fat tissue. Four cases of monotypic epithelioid AML were discovered without prognostic implications. Elevated phospho-p70S6 kinase expression was noted in 19 samples in the absence of phospho-AKT activity. Loss of heterogeneity (LOH) of TSC1/TSC2 was found in 15 samples. As compared wityh syndromic AML samples, sporadic AML samples showed LOH of microsatellite markers to a limited extent. Only four samples had increased β-catenin expression in the context of concurrent high expression of phospho-p70S6 kinase and phospho-S6 (P = 0.018)., Conclusions: The low fat content and epithelioid cytomorphology in hepatic AML potentially obstruct preoperative and pathological diagnosis. Alteration of the mTOR pathway and LOH of the tuberous sclerosis complex genes is a frequent pathogenesis in hepatic AMLs., (© 2014 John Wiley & Sons Ltd.)

Mutations in tuberous sclerosis (TSC) genes cause the genetic disorder TSC, as well as other neoplasms, including lymphangioleiomyomatosis (LAM) and angiomyolipomas (AMLs). AMLs are benign renal tumors occur both in sporadic LAM and in TSC. As they carry the same mutations, AML cell lines serve as a model for TSC and LAM. Rheb/mammalian target of rapamycin complex 1 (mTORC1) pathway is chronically activated in TSC-deficient cells, and this activation can be diminished using the appropriate inhibitors. Rapamycin (sirolimus) is a known specific inhibitor of mTORC1, whereas S-trans,trans-farnesylthiosalicylic acid (FTS; salirasib) has been shown to inhibit Rheb. To examine the effect of the Rheb/mTOR inhibition pathway, we used human TSC2-deficient AML cells, derived from a LAM patient. FTS indeed inhibited Rheb in these cells and attenuated their proliferation. After comparative treatments with FTS or rapamycin or by re-expression of TSC2, we carried out a gene array analysis. This yielded a substantial number of commonly altered genes, many of which we identified as downstream targets of the interferon (IFN) regulatory factor 7 (IRF7) transcription factor, a central activator of the IFN type 1 immune response. Furthermore, nuclear localization of IRF7 was impaired by each of the three treatments. Interestingly, the phenomena seen on FTS or rapamycin treatment were selective for TSC2-deficient cells. Moreover, knockdown of IRF7 by siRNA mimicked the decrease in number of the abovementioned genes and also inhibited AML cell proliferation. Altogether, these findings support FTS as a potential treatment for TSC and its related pathologies and IRF7 as a novel target for treatment.

Tuberous sclerosis syndrome (TSC) is an autosomal dominant tumor suppressor gene syndrome affecting multiple organs, including renal angiomyolipomas and pulmonary lymphangioleiomyomatosis (LAM). LAM is a female-predominant interstitial lung disease characterized by the progressive cyst formation and respiratory failure, which is also seen in sporadic patients without TSC. Mutations in TSC1 or TSC2 cause TSC, result in hyperactivation of mammalian target of rapamycin (mTOR), and are also seen in LAM cells in sporadic LAM. We recently reported that prostaglandin biosynthesis and cyclooxygenase-2 were deregulated in TSC and LAM. Phospholipase A2 (PLA2) is the rate-limiting enzyme that catalyzes the conversion of plasma membrane phospholipids into prostaglandins. In this study, we identified upregulation of adipocyte AdPLA2 (PLA2G16) in LAM nodule cells using publicly available expression data. We showed that the levels of AdPLA2 transcript and protein were higher in LAM lungs compared with control lungs. We then showed that TSC2 negatively regulates the expression of AdPLA2, and loss of TSC2 is associated with elevated production of prostaglandin E2 (PGE2) and prostacyclin (PGI2) in cell culture models. Mouse model studies also showed increased expression of AdPLA2 in xenograft tumors, estrogen-induced lung metastatic lesions of Tsc2 null leiomyoma-derived cells, and spontaneous renal cystadenomas from Tsc2+/- mice. Importantly, rapamycin treatment did not affect the expression of AdPLA2 and the production of PGE2 by TSC2-deficient mouse embryonic fibroblast (Tsc2-/-MEFs), rat uterine leiomyoma-derived ELT3 cells, and LAM patient-associated renal angiomyolipoma-derived "mesenchymal" cells. Furthermore, methyl arachidonyl fluorophosphate (MAFP), a potent irreversible PLA2 inhibitor, selectively suppressed the growth and induced apoptosis of TSC2-deficient LAM patient-derived cells relative to TSC2-addback cells. Our findings suggest that AdPLA2 plays an important role in promoting tumorigenesis and disease progression by modulating the production of prostaglandins and may serve as a potential therapeutic target in TSC and LAM.

Genetic studies have shown that the tuberous sclerosis complex (TSC) 1-TSC2-mammalian target of Rapamycin (mTOR) and the Hippo-Yes-associated protein 1 (YAP) pathways are master regulators of organ size, which are often involved in tumorigenesis. The crosstalk between these signal transduction pathways in coordinating environmental cues, such as nutritional status and mechanical constraints, is crucial for tissue growth. Whether and how mTOR regulates YAP remains elusive. Here we describe a novel mouse model of TSC which develops renal mesenchymal lesions recapitulating human perivascular epithelioid cell tumors (PEComas) from patients with TSC. We identify that YAP is up-regulated by mTOR in mouse and human PEComas. YAP inhibition blunts abnormal proliferation and induces apoptosis of TSC1-TSC2-deficient cells, both in culture and in mosaic Tsc1 mutant mice. We further delineate that YAP accumulation in TSC1/TSC2-deficient cells is due to impaired degradation of the protein by the autophagosome/lysosome system. Thus, the regulation of YAP by mTOR and autophagy is a novel mechanism of growth control, matching YAP activity with nutrient availability under growth-permissive conditions. YAP may serve as a potential therapeutic target for TSC and other diseases with dysregulated mTOR activity., (© 2014 Liang et al.)

We report the first case of inflammatory variant of hepatic angiomyolipoma (AML) with expression of transcription factor E3 (TFE3) protein but negativity for HMB45 and melan A in a 62-year-old female. Imaging studies revealed a tumor in the left lobe of liver, sized 5.8 cm in maximum diameter. Microscopically, the lesion was composed of large polygonal or epithelioid cells with copious eosinophilic granular cytoplasm. There was a very prominent stromal lymphoplasmacytic infiltrate. Immunohistochemically, the tumor cells showed very strong and diffuse positivity for smooth muscle actin, and cathepsin K, while S-100 protein, keratin, desmin, HMB45 and Melan-A are negative. However, there was multifocal and very convincing nuclear positivity for TFE3, thus confirms the diagnosis.

Objective: To study the clinicopathologic features, immunophenotype, histological diagnosis and prognosis of hepatic epithelioid angiomyolipoma., Methods: Clinical data of 25 cases of hepatic epithelioid angiomyolipoma were collected along with follow-up study of the patients. The pathological features were documented and immunohistochemical study of various markers was performed with an emphasis on diagnosis and differential diagnosis., Results: Hepatic epithelioid angiomyolipoma was more commonly found in young women without characteristic clinical symptoms. Its morphological features were characterized by marked cytological atypia, relatively rare mitotic figures; radial distribution of tumor cells around the thin-walled blood vessels or muscular vessels; and the presence of common multinucleated giant cells and large ganglion-like tumor cells. The tumor cells expressed both melanoma cell markers (HMB45, MART-1) and smooth muscle cell markers (SMA). Tumor cells expressed various other markers including ER 16% (4/25), PR 32% (8/25), TFE3 24% (6/25) and p53 60% (15/25)., Conclusions: Hepatic epithelioid angiomyolipoma has variable morphological features and characteristic immunohistochemical phenotype. The differential diagnoses include a variety of tumors. The biological behavior of the tumor tends to be benign.

Angiomyolipomas (AMLs) are associated with cell fibrosis in kidney of Tuberous Sclerosis Complex patients. The mechanism by which the fibrotic proteins accumulated in AMLs has not been explored. In the present study, we investigated the role of Akt/tuberin/mTOR pathway in the regulation cell fibrosis proteins. AML cells that expressed low levels of tuberin showed less expression of N-cadherin and higher of vimentin proteins compared to HEK293 cells. AML cells infected with Ad-tuberin showed a significant decrease in vimentin and an increase in N-cadherin protein expression. In addition, cells treated with rapamycin showed a significant increase in p-Akt and a decrease in p-p70S6K that was associated with a decrease expression of vimentin and a slight increase expression in N-cadherin. On the other hand, cells treated with Akt inhibitor revealed a significant decrease in p-Akt and p-p70S6K that was associated with a significant decrease in vimentin and an increase in N-cadherin expression. In addition, cells transfected with DN-Akt or DN-S6K show significant increase expression in N-cadherin and a decrease in vimentin. Moreover, cells transfected with siRNA against rictor or siRNA against raptor resulted in a decrease in vimentin and an increase N-cadherin expression. Kidney tumors from TSC patients showed significant decrease in N-cadherin and significant increased in vimentin protein expression compared to control kidney tissues. These data comprise the first report to provide the role of Akt/tuberin/mTORC1/2 in the regulation of N-cadherin and vimentin that are involved in the progression of fibrosis in kidney tumor of TSC patients.

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 β-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., (© 2014 The Authors. Pathology International © 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.)

Purpose: Concern regarding coexisting malignant pathology in benign renal tumors deters renal biopsy and questions its validity. We examined the rates of coexisting malignant and high grade pathology in resected benign solid solitary renal tumors., Materials and Methods: Using our prospectively maintained database we identified 1,829 patients with a solitary solid renal tumor who underwent surgical resection between 1994 and 2012. Lesions containing elements of renal oncocytoma, angiomyolipoma or another benign pathology formed the basis for this analysis. Patients with an oncocytic malignancy without classic oncocytoma and those with known hereditary syndromes were excluded from study., Results: We identified 147 patients with pathologically proven elements of renal oncocytoma (96), angiomyolipoma (44) or another solid benign pathology (7). Median tumor size was 3.0 cm (IQR 2.2-4.5). As quantified by the R.E.N.A.L. (radius, exophytic/endophytic, nearness to collecting system or sinus, anterior/posterior and location relative to polar lines) nephrometry score, tumor anatomical complexity was low in 28% of cases, moderate in 56% and high in 16%. Only 4 patients (2.7%) were documented as having hybrid malignant pathology, all involving chromophobe renal cell carcinoma in the setting of renal oncocytoma. At a median followup of 44 months (IQR 33-55) no patient with a hybrid tumor experienced regional or metastatic progression., Conclusions: In our cohort of patients with a solitary, sporadic, solid benign renal mass fewer than 3% of tumors showed coexisting hybrid malignancy. Importantly, no patient harbored coexisting high grade pathology. These data suggest that uncertainty regarding hybrid malignant pathology coexisting with benign pathological components should not deter renal biopsy, especially in the elderly and comorbid populations., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the clinicopathological characteristics of sporadic renal hemangioblastoma., Methods: Two cases of sporadic renal hemangioblastoma were studied by histological and immunohistochemical staining, along with review of the literature., Results: Both cases were presented with a renal mass during annual physical examination with an age of 40 and 45 years, respectively. The lesions located in the middle portion of the kidney with a sharp tumor border. Histopathologically, the tumors were characterized by two major components: capillary and stromal cells. Immunohistochemically, the stromal cells were positive for vimentin, NSE, S-100 protein and inhibin-α, and negative for CK, HMB45, Melan A, EMA, CD56 and syn. Both tumors showed a very low level of Ki-67 labeling. The endothelial cells were positive for CD34., Conclusion: Sporadic renal hemangioblastoma is a rare benign neoplasm, the diagnosis of which is based on the characteristic follicular architecture and an exclusion of other carcinomas of the kidney.

This study aimed to study the clinicopathologic characteristics of epithelioid angiomyolipoma, a variant of angiomyolipoma (AML) in the liver; and to discuss the diagnostic challenges. Five cases of primary liver epithelioid AML were retrieved from our archives from January 2003 to October 2012. The clinicopathologic features of each case were retrospectively reviewed. All 5 patients were female, with age ranging from 36 to 70 years (median, 41 years). The size of the tumor ranged from 1.2 to 25 cm. Histologically, the tumor comprised polygonal cells with granular eosinophilic cytoplasm and accompanied by immunohistochemical expression of HMB-45 ± Melan-A. Variations in growth pattern and cytology were observed. Estrogen receptor was negative in all 5 cases. None showed cytologic atypia, coagulative necrosis, increased mitotic count, or vascular invasion. Epithelioid AML is an uncommon primary liver tumor with a female predominance. The size of the tumor can be variable. This tumor might impose diagnostic difficulty both clinically and histologically. Immunohistochemical staining with melanocytic markers is a promising means to confirm the pathologic diagnosis. A careful assessment of aggressive histologic features is recommended to stratify the risk of aggressive behavior of this tumor., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Overview: Although angiomyolipoma (AML) is a relatively rare entity, it is the most common benign mesenchymal neoplasm of the kidney., The Aim of This Study: To highlight the clinicopathological characteristics of AML and to assess the role of Human Melanoma Black-45 (HMB-45), Melan-A, smooth muscle actin (SMA), S-100 and cytokeratin in its diagnosis., Materials and Methods: The study included 15 cases of AML. Clinical and radiological data were retrieved from the archival files and all cases were subjected to a histopathological evaluation as well as immunohistochemical staining for HMB-45, Melan-A, SMA, S-100, and cytokeratin., Results: AML was more common in females (female:male = 4:1), the mean age was 53.9 ± 6.45 years. 60% of patients were symptomatic while the remaining 40% were asymptomatic. A statistically significant relationship was found between size of the tumor and the presence of the symptoms (P = 0.02). Patients with tumor size less than 4 cm were asymptomatic, while those with tumor size larger than 4 cm had different symptoms. Thirteen cases were classic AML, while 2 cases were epithelioid AML. Classic AML demonstrated admixture of fatty tissue, thick-walled blood vessels, and smooth muscle, while epithelioid AML was composed mainly of epithelioid cells and contained no fat. HMB-45 was positive in all cases of AML (100%), Melan-A was positive in 13/15 (87%) while SMA was positive in 11/15 (73%) of AML with variable staining intensity. All cases of AML were negative for S-100 and cytokeratin., Conclusion: AMLs have characteristic clinicopathological and immunohistochemical features and their recognition is crucial for proper diagnosis and treatment., (Copyright © 2013. Production and hosting by Elsevier B.V.)

Over the last two decades, marked increase in detection of incidental or asymptomatic renal cell carcinoma (RCC) in developed countries was observed. The study included 268 patients aged from 25 to 92 years with RCC, which underwent evaluation and treatment in urology clinic MRSRCI for the past 5 years. There were no significant differences in the frequency of histological types of RCC between incidental and symptomatic tumors. Among incidental neoplasms with clear- cell structure, tumor with small size--up to 4 cm (T1a stage) and moderate to high degree of differentiation (G 1-2 according Fuhrman) were predominant. Papillary variant of RCC was detected at a higher stage of the disease and characterized by a high degree of nuclear atypia, which indicates its high malignant potential. Chromophobe RCC was usually diagnosed at T3 stage. The average age of men and women with chromophobe RCC was 46.5 +/- 6.8 years; there were no age difference in patients with symptomatic and incidental RCC. Among the benign tumors of the kidneys, angiomyolipoma was most commonly diagnosed--in 13 (53.8%) cases. Thus, incidental tumors have a better prognosis than symptomatic tumors.

Objective: To study the clinicopathologic features, immunophenotype and genetic changes of perivascular epithelioid cell neoplasms (PEComa)., Methods: A total of 25 cases of PEComa located in various anatomic sites were selected for immunohistochemical staining (SP or EnVision method). TFE3 fluorescence in-situ hybridization was also performed to determine the TFE3 gene status., Results: The age of patient ranged from 21 to 61 years (mean = 43 years). The male-to-female ratio was 1: 1.3. Histologically, 22 cases represented conventional angiomyolipomas, composed of a mixture of adipose tissue, spindle element, epithelioid smooth muscle cells and abnormal thick-walled blood vessels in various proportions. Three cases involving lung, soft tissue and broad ligament had subtle but distinctive morphologic features. Nested or sheet-like architecture with epithelioid or spindle cells was observed. Immunohistochemical study showed that HMB 45, melan A, smooth muscle actin and cathepsin K were expressed in 80% (20/25), 88% (22/25), 88% (22/25) and 100% (25/25) of PEComa, respectively. Within positive cases, the average proportion of positive tumor cells was 36%, 41%, 35% and 90% respectively for HMB 45, melan A, smooth muscle actin and cathepsin K. TFE3 was negative in all of the 22 renal and hepatic PEComa studied, while it was positive in the 3 cases of extra-hepatorenal PEComa. None of the 25 cases exhibited evidence of TFE3 gene fusion or amplification., Conclusions: Extra-hepatorenal PEComa have distinctive morphologic features and are associated with TFE3 overexpression. Cathepsin K immunostaining demonstrates high sensitivity and specificity in PEComa, better than other commonly employed immunomarkers. This marker is thus useful in diagnosis of PEComa and distinction with other neoplasms.

Aims:   Mesenchymal neoplasms of the kidney are rare, and most represent sporadic angiomyolipomas. A few haemangiomas have been reported in end-stage renal disease (ESRD) but, to date, no study has focused on the frequency and morphological spectrum of mesenchymal lesions in ESRD., Methods and Results:   We evaluated retrospectively 90 nephrectomy specimens with ESRD. Haemangiomas were detected in eight cases (8.8%; six males and two females; mean age: 55 years); four were multifocal and four had concurrent renal epithelial neoplasms. Lesions involved the medulla (three), cortex (two) or both (three), and the size range was 1-25 mm (mean 4.8 mm). Histologically, all were capillary haemangiomas with an at least focally detectable spleen-like anastomosing pattern. All tumours stained positively for CD31 and FLI-1, but none expressed pankeratin (KL-1), podoplanin/D2-40, HHV8 or GLUT-1. Minute angiomyolipomas (mean size 2.3 mm) were detected in four patients (mean age 49.5 years). Tumour-like smooth muscle proliferations were seen surrounding muscular arteries (eight), occasionally admixed with fat extending from the renal sinus mimicking angiomyolipoma. No similar tumours were found in 105 control kidneys., Conclusions:   Benign haemangiomas are not uncommon in ESRD, but may be under-recognized. They display distinctive morphology and should be distinguished from angiosarcomas and capillary-rich renal cell carcinomas., (© 2012 Blackwell Publishing Limited.)

Angiomyolipoma is the most common member of perivascular epithelioid cell tumors that characteristically express myogenic and melanocytic markers. E-cadherin is a calcium-dependent cell-cell adhesion molecule that is repressed in epithelial to mesenchymal transition occurring in carcinomas. E-cadherin has not, thus far, been systematically studied in angiomyolipoma. We analyzed a series of 42 angiomyolipomas with E-cadherin and discussed its clinicopathologic significance. Forty-two cases of angiomyolipomas (35 renal, 5 hepatic, and 2 retroperitoneal) were examined histologically. E-cadherin was investigated immunohistochemically and compared with other significant markers found in angiomyolipoma in all cases. The percentages of tumors staining positively were E-cadherin (98%), smooth muscle actin (98%), actin (93%), HMB-45 (93%), Melan-A (90%), S-100 (38%), and CD117 (60%). The intensity of E-cadherin staining was moderate to strong in 30 cases (71%). E-cadherin stained both the cytoplasm and cell membrane of tumor cells, but membrane staining was stronger in the epithelioid tumor cells than in the spindle-shaped tumor cells. E-cadherin may serve as an additional diagnostic marker for angiomyolipoma. Angiomyolipoma should be included in the differential diagnosis of E-cadherin-positive tumors. Stronger membrane immunoreactivity for E-cadherin in epithelioid tumor cells is possibly related to constitution of their epithelioid architecture, but the pathogenetic significance of E-cadherin in angiomyolipoma remains to be further studied., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Aims: The aim of this study was to characterize and delineate the broad histological spectrum of hepatic angiomyolipoma (AML) and to obtain a better understanding of its clinicopathological diagnosis by reviewing a large series of AMLs., Methods and Results: According to the proportions of three histological components, AML could be classified into 10 types; 36 of 55 tumours (65%) were classified as myomatous, eight as myoangiomatous, six as mixed (conventional), two as lipomatous, two as myolipomatous, and one as lipomyomatous. The morphology of smooth muscle cells (SMCs) in AML was quite variable, giving a wide variety of growth patterns. Fourteen (25%) of 55 tumours showed severe cellular atypia, and invasive growth of tumour cells was found in 69% of the tumours. However, except for two autopsy cases, all of the patients were in good health at follow-up, without metastases. Immunostaining for HMB-45 was positive in all cases. We found frequent lymphocyte infiltration, and the occasional presence of abnormally large blood vessels around the tumour at the tumour-background liver interface, features which have not been reported previously., Conclusions: The majority of hepatic AMLs were myomatous in type, showing variable cellular morphology and growth patterns. Cellular atypia and invasive growth were frequent, indicating that hepatic AMLs often show malignancy-like histological features. Although the majority of cases behave as benign tumours, AML should be considered to have uncertain malignant potential, and careful follow-up of patients is recommended. Immunostaining for HMB-45 is specific for AML, and establishes the diagnosis. The occasional presence of abnormally large blood vessels around the tumour may give new insights into the evaluation of findings from imaging., (© 2012 Blackwell Publishing Limited.)

Renal angiomyolipoma (AML) may present as rare variants such as epithelioid and AML with epithelial cysts posing difficulties for the diagnosis to the surgical pathologist. We report a case of a 46-year-old male patient presenting a 5-cm solid tumor in the lower pole of the left kidney, with cystic changes at cut surface. The tumor exhibited 95% of epithelioid cells with atypical nuclei. A small focus of typical AML was observed. The immunoprofile of tumor cells was classical of AML including expression of melanocytic markers such as HMB45 and Melan A. We report the immunohistochemical study of the cystic component in an epithelioid AML. In contrast to the immunoreactivity reported in typical AML, the present case shows obvious expression of melanocytic markers in the cystic epithelial lining. This is strong evidence that these cysts are neoplastic and derived from AML, rather than entrapped native collecting duct epithelium., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background/aims: Hepatic angiomyolipoma (AML) is a rare mesenchymal tumor of the liver and demonstrates a marked histologic diversity. HMB-45 is a promising immunomarker for this tumor and especially helpful to diagnosis of some AMLs with unusual morphology. The purpose of this study was to better define the variable histologic feature of hepatic AML., Methods: Eight hepatic AMLs were examined, and all of that were resection specimens. The diagnosis was confirmed by the presence of HMB-45 positive cells. Median age was 41.5 years old, and mean size of tumor was 8.94 cm., Results: Conventional mixed type was 5 cases which showed myomatous, angiomatous and lipomatous component, and 3 cases were myomatous predominant. Variable patterns including spider web cell morphology, solid sheet-like and trabecular pattern were identified on myomatous component and variable amount and patterns of inflammatory cell infiltration was identified., Conclusions: With only histologic features, it is difficult to distinguish hepatic AML from other hepatic tumor including hepatocellular carcinoma or inflammatory pseudotumor. A correct diagnosis of hepatic AML is possible by a close histologic examination with immunohistochemical stainings such as HMB-45 which is important to patient's prognosis.

Tuberous sclerosis complex (TSC), an inherited tumor predisposition syndrome associated with mutations in TSC1 or TSC2, affects ∼1 in 6,000 individuals. Eighty percent of TSC patients develop renal angiomyolipomas, and renal involvement is a major contributor to patient morbidity and mortality. Recent work has shown that mammalian target of rapamycin complex 1 (mTORC1) inhibition caused angiomyolipoma shrinkage but that this treatment may cause cytostatic not a cytotoxic effect. Endoplasmic reticulum (ER) stress can develop in TSC-associated cells due to mTORC1-driven protein translation. We hypothesized that renal angiomyolipoma cells experience ER stress that can be leveraged to result in targeted cytotoxicity. We used immortalized human angiomyolipoma cells stably transfected with empty vector or TSC2 (encoding tuberin). Using cell number quantification and cell death assays, we found that mTORC1 inhibition with RAD001 suppressed angiomyolipoma cell proliferation in a cytostatic manner. Angiomyolipoma cells exhibited enhanced sensitivity to proteasome inhibitor-induced ER stress compared with TSC2-rescued cells. After proteasome inhibition with MG-132, Western blot analyses showed greater induction of C/EBP-homologous protein (CHOP) and more poly (ADP-ribose) polymerase (PARP) and caspase-3 cleavage, supporting ER stress-induced apoptosis. Live cell numbers also were decreased and cell death increased by MG-132 in angiomyolipoma cells compared with TSC2 rescued. Intriguingly, while pretreatment of angiomyolipoma cells with RAD001 attenuated CHOP and BiP induction, apoptotic markers cleaved PARP and caspase-3 and eukaryotic translation initiation factor 2α phosphorylation were increased, along with evidence of increased autophagy. These results suggest that human angiomyolipoma cells are uniquely susceptible to agents that exacerbate ER stress and that additional synergy may be achievable with targeted combination therapy.