Differentiation of Sporadic Versus Tuberous Sclerosis Complex-Associated Angiomyolipoma.

OBJECTIVE: We review the imaging of renal angiomyolipomas, including differentiation of tuberous sclerosis complex (TSC)-associated and sporadic renal angiomyolipomas and other solid renal tumors. We also focus on radiologic interventions and molecular targeting of the TSC genetic pathway. CONCLUSION: Imaging plays a central role in the diagnosis and management of renal angiomyolipomas. It provides essential information to make the best therapeutic decisions about the interventional and pharmacologic options to help prevent bleeding and preserve functional parenchyma.

Evidence for pericyte origin of TSC-associated renal angiomyolipomas and implications for angiotensin receptor inhibition therapy.

Nearly all patients with tuberous sclerosis complex (TSC) develop renal angiomyolipomas, although the tumor cell of origin is unknown. We observed decreased renal angiomyolipoma development in patients with TSC2- polycystic kidney disease 1 deletion syndrome and hypertension that were treated from an early age with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers compared with patients who did not receive this therapy. TSC-associated renal angiomyolipomas expressed ANG II type 1 receptors, platelet-derived growth factor receptor-ß, desmin, α-smooth muscle actin, and VEGF receptor 2 but did not express the adipocyte marker S100 or the endothelial marker CD31. Sera of TSC patients exhibited increased vascular mural cell-secreted peptides, such as VEGF-A, VEGF-D, soluble VEGF receptor 2, and collagen type IV. These findings suggest that angiomyolipomas may arise from renal pericytes. ANG II treatment of angiomyolipoma cells in vitro resulted in an exaggerated intracellular Ca(2+) response and increased proliferation, which were blocked by the ANG II type 2 receptor antagonist valsartan. Blockade of ANG II signaling may have preventative therapeutic potential for angiomyolipomas.

Changes in lung function and chylous effusions in patients with lymphangioleiomyomatosis treated with sirolimus.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a disorder that affects women and is characterized by cystic lung destruction, chylous effusions, lymphangioleiomyomas, and angiomyolipomas. It is caused by proliferation of abnormal smooth muscle-like cells. Sirolimus is a mammalian target of rapamycin inhibitor that has been reported to decrease the size of neoplastic growths in animal models of tuberous sclerosis complex and to reduce the size of angiomyolipomas and stabilize lung function in humans. OBJECTIVE: To assess whether sirolimus therapy is associated with improvement in lung function and a decrease in the size of chylous effusions and lymphangioleiomyomas in patients with LAM. DESIGN: Observational study. SETTING: The National Institutes of Health Clinical Center. PATIENTS: 19 patients with rapidly progressing LAM or chylous effusions. INTERVENTION: Treatment with sirolimus. MEASUREMENTS: Lung function and the size of chylous effusions and lymphangioleiomyomas before and during sirolimus therapy. RESULTS: Over a mean of 2.5 years before beginning sirolimus therapy, the mean (±SE) FEV1 decreased by 2.8%±0.8% predicted and diffusing capacity of the lung for carbon monoxide (Dlco) decreased by 4.8%±0.9% predicted per year. In contrast, over a mean of 2.6 years of sirolimus therapy, the mean (±SE) FEV1 increased by 1.8%±0.5% predicted and Dlco increased by 0.8%±0.5% predicted per year (P<0.001). After beginning sirolimus therapy, 12 patients with chylous effusions and 11 patients with lymphangioleiomyomas experienced almost complete resolution of these conditions. In 2 of the 12 patients, sirolimus therapy enabled discontinuation of pleural fluid drainage. LIMITATIONS: This was an observational study. The resolution of effusions may have affected improvements in lung function. CONCLUSION: Sirolimus therapy is associated with improvement or stabilization of lung function and reduction in the size of chylous effusions and lymphangioleiomyomas in patients with LAM. PRIMARY FUNDING SOURCE: Intramural Research Program, National Heart, Lung, and Blood Institute, National Institutes of Health.

[Rupture of renal angiomyolipoma during pregnancy: a case report].

A 39-year-old woman, who was followed because of a 4 cm asymptomatic angiomyolipoma (AML) in the left kidney, presented with an acute onset of lower left back pain in the 38th week of her first pregnancy. An ultrasound revealed an 8 cm mass suggestive of AML rupture and retroperitoneal hemorrhage. An emergency caesarean delivery was performed. A post-delivery computed tomographic scan confirmed the AML rupture and selective embolization was performed. This was a case in which the AML grew rapidly during the pregnancy ; therefore, we discuss the relationship between AML and pregnancy.

Analysis of the oestrogen response in an angiomyolipoma derived xenograft model.

Angiomyolipomas are benign mesenchymal tumours of smooth muscle, blood vessels and fat which occur sporadically or associated with tuberous sclerosis and lymphangioleiomyomatosis (LAM), a rare cystic lung disease. Angiomyolipoma and LAM are caused by loss of function of either the tuberous sclerosis-1 or -2 genes resulting in activation of p70S6kinase (S6K1) and uncontrolled cellular proliferation. LAM and angiomyolipoma can be exacerbated by oestrogens but how this occurs is not understood. To address this question, we created a xenograft tumour system in nude mice using immortalised angiomyolipoma cells. Angiomyolipoma xenografts had active S6K1, p38, p42/44 MAPK and Akt; they grew more rapidly and had greater Akt phosphorylation after oestrogen treatment of tumour-bearing mice. Transcriptional profiling showed oestrogen induced 300 genes including extracellular matrix proteins, proteases, cell cycle regulatory proteins and growth factors including platelet derived growth factor-C (PDGF-C). Biologically active PDGF-C was produced by primary angiomyolipoma cells in culture and PDGF-C protein was present in the neoplastic smooth muscle cells of 5/5 human angiomyolipoma and 4/5 LAM tissues examined by immunohistochemistry. These findings suggest that the response to oestrogen in this model is mediated by activation of Akt and transcriptional events. This model may prove useful for studying the biology and effect of drugs on angiomyolipoma and diseases related to TSC.

Evaluation of renal function of angiomyolipoma patients after selective transcatheter arterial embolization.

BACKGROUND: Angiomyolipoma patients may have renal insufficiency before selective transcatheter arterial embolization (TAE) or may undergo subsequent surgery after TAE. Therefore, this retrospective study examined our experience with TAE or TAE and subsequent surgery on renal function of angiomyolipoma patients with and without preexisting renal insufficiency. METHODS: 25 patients who had undergone TAE for renal angiomyolipoma over a 7-year period were reviewed. The 25 patients were grouped according to whether or not they had undergone further surgery. Preexisting renal insufficiency was compared between the 2 groups. The TAE and surgery group was further subdivided into 2 subgroups according to total nephrectomy or not. The TAE-alone group was further subdivided into 2 subgroups by presence of preexisting renal insufficiency or not. In each group and subgroup, pre-TAE and post-TAE renal function, including serum creatinine and creatinine clearance were compared. RESULTS: TAE rather than TAE and surgery was more likely chosen in the presence of preexisting renal insufficiency (6/13 versus 1/12, P=0.035). In TAE-alone patients, no statistical differences were noted between serum creatinine and creatinine clearance before and after TAE. Conversely, TAE and surgery patients who had undergone total nephrectomy rather than nephron-sparing surgery differed significantly in preand post-TAE serum creatinine (0.77 versus 1.07, P=0.014) and creatinine clearance (98.1 versus 70.7, P=0.032). CONCLUSIONS: This study demonstrated that TAE alone for treating renal angiomyolipomas was able to preserve renal function, despite the presence of mild preexisting renal insufficiency. Conversely, surgery after TAE, particularly total nephrectomy, should be avoided whenever possible.

[Renal epithelioid angiomyolipoma]. / Angiomyolipome épithélioïde rénal.

Renal epithelioid angiomyolipomas (ReAML) are rare tumors (identified in less than 0,1 per thousand in general population) and represent 8% of operated angiomolipomas (AML). The diagnostic is histological, with an epithelioid cell component among the typical AML cells. ReAML are tumors derived from perivascular epithelioid cells (PEComa). There are benign PEComas, potentially aggressive PEComas and malignant PEComas. Most malignant PEComas are ReAML. There are two ReAML clinical entities, sporadic or associated to Tuberous Sclerosis Complex (TSC). ReAML are unique, localized and sporadic solid tumors of the kidney of variable size that can be revealed as classical AML with local symptoms or a complication (hemorrhage). Revelation mode is mostly radiologic. ReAML are fat-poor on CT-scan. They can be misdiagnosed with renal cell carcinoma (RCC). (One third of ReAML are malignant with a locoregional, nodal or metastatic evolution that can lead to death. ReAML treatments are multimodal depending of histology, clinical-radiological entity, evolution and the patient. Partial nephrectomy or follow-up are the benign entity treatment. Radical nephrectomy eventually followed by doxorubicine or rapamycine treatments are recommended for potentially aggressive and malignant entities.

Evaluation of ABO blood groups and blood-based biomarkers as a predictor of growth kinetics of renal angiomyolipoma.

PURPOSE: The aim of our study was to investigate the impact of the ABO blood groups and blood-based biomarkers on the growth kinetics of renal angiomyolipoma (AML). METHODS: A total of 124 patients with AML who were followed-up between 2010 and 2018 were retrospectively reviewed. The patients' characteristics were recorded, including age, body mass index (BMI), blood pressure, smoking history, and ABO blood group. Baseline laboratory test results, including serum creatinine, AST, ALT, platelet, neutrophil and lymphocyte count, were used to calculate the estimated glomerular filtration rate (eGFR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and De Ritis ratio. The Cox regression analysis was used to evaluate the relationship between variables and tumor growth. RESULTS: The study population comprised 71 women and 44 men with a median age of 47.3 (28-65) years. Among patients classified according to the blood groups, no significant differences were observed regarding age, BMI, smoking history, co-morbidities, NLR, PLR, De Ritis ratio, eGFR, or tumor size and localisation. The mean growth rate from baseline to the last scan was 0.36 ± 0.27 cm, 0.21 ± 0.21 cm, 0.14 ± 0.11 cm, and 0.19 ± 0.17 cm for blood type O, A, B, and AB, respectively. In multivariate analysis, eGFR < 60 (p = 0.044), central tumor localisation (p = 0.030), presence of blood group-0 (p = 0.038), and De Ritis ratio ≥ 1.24 (p = 0.047) were statistically associated with tumor growth. CONCLUSION: Our study demonstrates that both the ABO blood groups and the De Ritis ratio might represent independent predictors of tumor growth rate in patients with renal AML.

Observational study of characteristics and clinical outcomes of Dutch patients with tuberous sclerosis complex and renal angiomyolipoma treated with everolimus.

OBJECTIVE: To compare kidney size (used as proxy for total renal angiomyolipoma [rAML] size) and kidney function outcomes between patients with tuberous sclerosis complex (TSC) and rAML treated and not treated with everolimus. METHODS: Medical charts of adults with TSC-associated rAML followed at a specialty medical center in the Netherlands (1990-2015). Included patients treated with everolimus (n = 33, of which 27 were included in the kidney size analyses and 27 in the kidney function analyses [21 patients in both]; index date = everolimus initiation) and non-treated patients (n = 39, of which 29 were included in the kidney size analyses and 33 in the kidney function analyses [23 patients in both]; index date = one date among all dates with outcome measurement).Percent change in kidney size and kidney function from the index date to the best measurement in the two years post-index date (best response) compared between patients treated and not treated with everolimus. RESULTS: Compared with non-treated patients, significantly more everolimus-treated patients experienced a reduction in the size of their largest kidney in the two years post-index date (85.2% vs. 37.9%, p < 0.01). Also, there was a tendency towards more improvement in the estimated glomerular filtration rate (eGFR) among the everolimus-treated patients (55.6% vs. 33.3%, p = 0.08). CONCLUSIONS: The study results suggest that everolimus is effective in controlling and even reversing the growth of the kidneys, used as a proxy for rAML size, as well as preserving or improving kidney function in patients with TSC and rAML treated in a real-world, observational setting.

Trauma-induced adiposis dolorosa (Dercum's disease).

We present a case of a 39-year-old man who presented with chronic bilateral upper extremity pain associated with innumerable angiomyolipomas that developed 5 years after a motor vehicle accident involving his upper extremities. Our case notes the rare nature of painful adipose tissue deposits and the diagnostic challenges.

The impact of renal angiomyolipoma on estimated glomerular filtration rate in patients with tuberous sclerosis complex.

BACKGROUND: There is a growing concern that renal impairment may develop in patients with renal angiomyolipomas (AMLs) associated with tuberous sclerosis complex (TSC) as a consequence of the disease itself and/or the interventions to mitigate the risk of hemorrhage. OBJECTIVE: To assess the estimated glomerular filtration rate (eGFR) in patients with bilateral renal AMLs and the impact of tumor burden and intervention on renal function. DESIGN: Retrospective study. SETTING: Urology department of a tertiary care hospital. PATIENTS AND METHODS: All adult patients (>=18 years of age) with TSC-associated renal AMLs seen from October 1998 to June 2015. We included only patients with bilateral tumors or solitary kidneys at the last follow-up. MAIN OUTCOME MEASURES: The eGFR, renal volume, and number and type of interventions. RESULTS: We identified 12 patients (median age 27.6, interquartile range 23.7-39.9 years), a median follow-up period of 1266 days (33-3133), and a median renal size of 454.7 mL (interquartile range 344.7-1016.9 on the right side; 558.1 mL, interquartile range 253.7-1001.4 on the left). In 11 (91.7%) patients, the eGFR was > 60 mL/min/1.77 m2. Six patients had three total nephrectomies, one had a contralateral partial nephrectomy, and seven had selective arterial embolizations. Intervention was associated with a significantly reduced eGFR. The renal size did not correlate with the eGFR. CONCLUSIONS: TSC-associated renal AMLs may attain a large size but normal renal function is maintained in 92% of patients. Interventions to mitigate the risk of hemorrhage are associated with decreased renal function. LIMITATIONS: The renal size was used as a surrogate for tumor size. Other limitations were the limited number of patients and lack of split renal function testing.

Review of the Tuberous Sclerosis Renal Guidelines from the 2012 Consensus Conference: Current Data and Future Study.

Renal-related disease is the most common cause of tuberous sclerosis complex (TSC)-related death in adults, and renal angiomyolipomas can lead to complications that include chronic kidney disease (CKD) and hemorrhage. International TSC guidelines recommend mammalian target of rapamycin (mTOR) inhibitors as first-line therapy for management of asymptomatic, growing angiomyolipomas >3 cm in diameter. This review discusses data regarding patient outcomes that were used to develop current guidelines for embolization of renal angiomyolipomas and presents recent data on 2 available mTOR inhibitors - sirolimus and everolimus - in the treatment of angiomyolipoma. TSC-associated renal angiomyolipomas can recur after embolization. Both sirolimus and everolimus have shown effectiveness in reduction of angiomyolipoma volume, with an acceptable safety profile that includes preservation of renal function with long-term therapy. The authors propose a hypothesis for mTORC1 haploinsufficiency as an additional mechanism for CKD and propose that preventive therapy with mTOR inhibitors might have a role in reducing the number of angiomyolipoma-related deaths. Because mTOR inhibitors target the underlying pathophysiology of TSC, patients might benefit from treatment of multiple manifestations with one systemic therapy. Based on recent evidence, new guidelines should be considered that support the earlier initiation of mTOR inhibitor therapy for the management of renal angiomyolipomas to prevent future serious complications, rather than try to rescue patients after the complications have occurred.

A case of renal cell carcinoma and angiomyolipoma in an adolescent girl.

We describe a case of renal cell carcinoma in the right kidney together with an angiomyolipoma in the left kidney, encountered in an adolescent girl at Potchefstroom Provincial Hospital, North West Province, South Africa.

Rheb/mTOR/p70s6k Cascade and TFE3 Expression in Conventional and Sclerosing PEComas of the Urinary Tract.

Perivascular epithelioid cell tumors (PEComas) are rarely found in the urinary tract. The clinicopathologic characteristics of 10 cases, retrospectively collected from 5 medical institutions in 3 different European countries, are presented in this study. Male/female ratio was 3:7 and the average age at diagnosis was 62.7 years. Nine cases were sporadic and 1 showed germline mutation of the TSC2 gene. Eight cases were located in the kidney, 1 in the left adrenal and 1 in the right ureter. All of the patients were alive and free of disease at the time of last contact (mean follow-up, 14.1 mo). Four cases displayed a conventional morphology and 6 showed a prominent sclerotic stroma. By immunohistochemistry, melanocytic markers were consistently expressed, especially HMB-45 (10 cases), MiTF (9 cases), and Melan-A (6 cases). Desmin was expressed in 6 cases; 2 cases were positive for CD117; a single case showed TFE3 expression. pMAPK, mTOR, and pAKT demonstrated variable immunostaining with focal positivity in 7, 4, and 2 cases, respectively. Cytokeratins were repeatedly negative in all cases. PEComas in the urinary tract, especially in the renal region, may show a relatively high frequency of the sclerosing histologic subtype. Knowledge of the distinct histology and immunohistochemical profile is vital to correctly diagnose this rare entity.

Renal angiomyolipoma: a clinicopathologic, immunohistochemical, and follow-up study of 46 cases.

We reviewed 46 cases of renal angiomyolipoma covering the period from 1977 to 1997. Eight cases were associated with tuberous sclerosis and one with lymphangiomyomatosis. Histologically, the lesions were most often classic with the three usual components, i.e., mature adipose tissue, thick-walled blood vessels, and smooth muscle. Seven cases were particularly misleading: three cases were entirely adipose mimicking liposarcoma: two cases had an exclusively smooth-muscle component, one mimicking lymphangiomyomatosis and one with epithelioid cells; another case had a monophasic epithelioid pleomorphic component ("REON": renal epithelioid oxyphilic neoplasm) and proved to be fatal; and another case was associated with collecting duct carcinoma. The immunohistochemical profile showed the coexpression of alpha-smooth-muscle actin and HMB45. Our study is the first to show positivity of estrogen and progesteron receptors or both in more than 25% of cases. Of 35 cases with follow-up information, only one patient died of malignant spread of angiomyolipoma.

Apparent renal cell carcinomas in tuberous sclerosis are heterogeneous: the identification of malignant epithelioid angiomyolipoma.

Renal epithelial tumors (carcinoma and oncocytoma) have been reported with higher a frequency than expected in patients with the tuberous sclerosis complex. However, the recent identification of a monotypic, epithelioid variant of angiomyolipoma, closely simulating renal cell carcinoma, has cast doubt on the real frequency of carcinoma. Immunohistochemical analysis with a panel of antibodies, including melanogenesis marker HMB45, can discriminate between carcinoma and carcinoma-like angiomyolipoma. We studied five tumors previously reported as carcinoma and found that only one of them showed an immunohistochemical phenotype indicative of an epithelial tumor (Ker+, HMB45-). Three tumors exhibited a phenotype compatible with the monotypic epithelioid variant of angiomyolipoma (HMB45+, Ker-), and two of the three patients died of metastatic disease. The last patient had unusual clinical features, and the tumor was positive both for HMB45 and keratin. It is concluded that (1) renal cell carcinoma is less common in tuberous sclerosis complex than previously believed, (2) some cases called renal cell carcinoma probably represent a monotypic, epithelioid variant of angiomyolipoma, and (3) epithelioid angiomyolipoma is a potentially malignant tumor with invasion and metastases. These findings indicate that all reported renal carcinomas in tuberous sclerosis complex, therefore, must be reevaluated.

Renal angiomyolipoma: optimal treatment based on size and symptoms.

The natural history of renal angiomyolipoma is not well delineated. Current management options include observation, embolization, and partial or total nephrectomy. Recommendations for treatment are usually based on the patient's symptoms or the size of the lesion. In an effort to help define the optimal treatment of renal angiomyolipomas, we reviewed our experience over the last 10 years with these tumors. We performed a retrospective study of 37 patients (48 renal units) diagnosed with renal angiomyolipoma over a ten year period at our medical center (mean follow-up 40 months, range 1 month-12 years). Lesions were classified as small (< 4 cm), medium (4-8 cm) or large (> 8 cm) based on the single largest lesion in each kidney. The relationship between the size, symptoms and treatment was reviewed. Patients were also analyzed with regard to the diagnosis of tuberous sclerosis. Our findings indicate renal angiomyolipomas less than 4 cm (21/37 patients) tend to be asymptomatic and generally do not require intervention. Angiomyolipomas greater than 8 cm were responsible for significant morbidity and generally require treatment (5/6). Patients with tuberous sclerosis made up one half (3/6) of the large lesions. Medium-sized lesions had a less predictable natural history, with 54% (7/13) requiring intervention to treat hemorrhagic complications. Small asymptomatic lesions (< 4 cm) tend to remain stable but should be periodically evaluated. Medium-sized lesions (4-8 cm) have the most variable behavior. These lesions should be followed closely with serial imaging studies, and if significant changes in size or symptoms are noted, or the patient is at risk for flank trauma, elective intervention should be initiated promptly to increase the chances of renal salvage. Large asymptomatic angiomyolipomas (> 8 cm) will most likely become symptomatic and should be treated electively prior to the development of symptoms and potential complications.

Sporadic angiomyolipomas of the kidneys silent and symptomatic: a report of three CT-scan diagnosed cases.

Three cases of sporadic angiomyolipomas (AML) of the kidneys presented to the department of radiology faculty of medicine. Two of them presented with sudden onset of flank pain and gross Hematuria and the other was asymptomatic. They had Ultrasound (US), Computerised Tomography (CT) scans with and with out intravenous urography (IVU). CT findings were diagnostic and correlated with the final histological diagnoses. The epidemiological and clinical features. US and CT findings, and the histology of this unusual case are briefly discussed.

[Erratic course of bilateral renal angiomyolipomas]. / Evolution erratique d'angiomyolipomes rénaux bilatéraux.

We report a case of multiple and bilateral renal angiomyolipomas demonstrated and followed up by urography, sonography, and computed tomography during a period of 17 years. The diagnosis has been made by computed tomography. Follow-up examinations showed first a stability of the lesions, and afterwards, a rather fast increase of the volume of various masses, without symptoms, followed by a new period of stabilization.