Patients' and physicians' awareness of clinical symptoms and disease severity in tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is a rare inherited disease with the potential to affect virtually every organ system. Clinical presentation is age- and partly sex-dependent and varies broadly with respect to disease manifestations including treatment-refractory epilepsy, intellectual disability and TSC-associated neuropsychiatric disorders, chronic kidney disease or progressive lung function decline. Given the complexity of this disease, multidisciplinary care in specialized TSC centres is recommended. We aimed to elucidate the state of knowledge of patients/caregivers and physicians on individual disease manifestations. We further examined whether the association to a TSC centre has an impact on the comprehensive consideration of potential disease manifestations. Therefore, a survey was performed in a cohort of German TSC patients and their physicians. Complete information was available for 94 patients with a median age of 18 years [range 1-55] and a sex distribution of 53.2% (male): 48.8% (female). Using almost identical questionnaires for patients/caregivers and their respective physician, there was a good correlation for disease assessments associated with relevant morbidity and mortality like epilepsy, renal angiomyolipoma, cardiac rhabdomyomas or intellectual disability. Correlation was moderate for several neuropsychiatric disorders and only poor for hypomelanotic macules, dental pits or retinal achromic patches. Estimation of overall disease severity using a numeric rating scale correlated highly significantly (Pearson correlation coefficient = 0.767; p < 0.001) between patients/caregivers and physicians. In general, physicians more likely quoted items as 'unknown' than patients (822 answers vs. 435 answers in the respective groups). Questionnaires completed by physicians who were associated with a specialized TSC centre declared a significantly lower proportion of items as unknown (mean 8.7% vs. 20.5%; p < 0.001). These findings indicate that patients treated by specialized TSC centres seem to obtain a more comprehensive surveillance. Furthermore, it shows that there were reasonable surveillance strategies in general and sufficient patient/caregiver interaction and education in the examined cohort. However, for the most prominent disease characteristics there was a good awareness within both the patients/caregivers and the physicians group.

Histopathological spectrum of adult renal tumours: A single center experience and review of literature.

Background: Renal tumors constitute approximately 3% of all malignancies in adults. They form a heterogenous group with variable morphological, immunohistochemical, and molecular features. Aim: The objective of this study was to analyze the spectrum of adult renal tumors at a tertiary care center and study the demographic and histomorphological features. Materials and Methods: In this study, 55/87 nephrectomy specimens resected for adult renal tumors during a 1-year period were analyzed retrospectively. Results: There were 4 benign (7.2%) and 51 (92.7%) malignant tumors. There was a male preponderance with a male: female ratio of 3.42:1. The tumors were seen to occur equally in both kidneys. The most common tumor was clear cell renal cell carcinoma (RCC), the conventional type accounting for 65.5% of our study group. There were one each of multilocular cystic renal neoplasm of low malignant potential, papillary RCC, chromophobe RCC, Mit family RCC, oncocytoma and angiomyolipoma and two clear cell papillary RCC during this 1-year period. Uncommon tumors included neuroendocrine carcinoma (1), epithelioid angiomyolipoma (1), mixed epithelial stromal tumor (1), Ewings sarcoma (2), and glomangioma (1). Five cases of urothelial carcinoma of renal pelvis/ureter also were present. Conclusion: This article gives an overview of the spectrum of adult renal tumors at a tertiary care center with an in-depth literature review providing recent advances in each category of tumors.

Incidence of Benign Renal Masses in a Contemporary Cohort of Patients Receiving Partial Nephrectomy for Presumed Renal Cell Carcinoma.

INTRODUCTION: Over the past decade and a half, advances in diagnostic imaging as well as an increased utilization of active surveillance (AS) and renal mass biopsy (RMB) have led to an improved ability to identify benign lesions prior to partial nephrectomy (PN). We seek to examine the incidence of benign pathology at the time of PN in a contemporary cohort of patients undergoing PN for presumed renal cell carcinoma (RCC). PATIENTS AND METHODS: We performed a chart review on a prospectively maintained database on a series of patients who underwent PN between January 1, 2006 and December 31, 2021 for solid renal masses concerning for RCC. RESULTS: One thousand two hundred twenty-nine patients were included in the analysis, with 240 patients (19.2%) identified to have benign disease on final pathology. Of patients with benign disease, (23%) of patients had angiomyolipoma (AML) and 64% had oncocytoma. Between 2006 and 2021, there was a significant increase in the incidence of benign pathology after PN. When examining 3-year rolling averages over this same time period, the incidence of oncocytoma appeared to increase while the incidence of AML decreased. CONCLUSION: Despite improvements in diagnostic tools and increased utilization of active surveillance, the overall incidence of benign pathology, particularly oncocytoma, did not decrease over time in this contemporary cohort of patients undergoing PN.

Prevalence of thoracoabdominal imaging findings in tuberous sclerosis complex.

BACKGROUND: Tuberous sclerosis complex (TSC) results in neurodevelopmental phenotypes, benign tumors, and cysts throughout the body. Recent studies show numerous rare findings in TSC. Guidelines suggest routine abdominal and chest imaging to monitor these thoracoabdominal findings, but imaging is not uniformly done across centers. Thus, the prevalence of many findings is unknown. To answer this, we categorized the clinical reads of 1398 thoracoabdominal scans from 649 patients of all ages in the Cincinnati Children's Hospital TSC Repository Database. RESULTS: Typical TSC findings were present in many patients: kidney cysts (72%), kidney fat-containing angiomyolipomas (51%), kidney lipid-poor angiomyolipomas (27%), liver angiomyolipomas (19%), and lung nodules thought to represent multifocal micronodular pneumocyte hyperplasia (MMPH) (18%). While many features were more common in TSC2 patients, TSC1 patients had a higher prevalence of MMPH than TSC2 patients (24% versus 13%, p = 0.05). Many rare findings (e.g., lymphatic malformations and liver masses) are more common in TSC than in the general population. Additionally, most thoracoabdominal imaging findings increased with age except kidney cysts which decreased, with the 0-10 years age group having the highest percentage (69% 0-10 years, 49% 10-21 years, 48% 21 + years, p < 0.001). Finally, in our population, no patients had renal cell carcinoma found on abdominal imaging. CONCLUSIONS: These results show that regular thoracoabdominal scans in TSC may show several findings that should not be ignored or, conversely, over-reacted to when found in patients with TSC. Female sex, TSC2 mutation, and age are risk factors for many thoracoabdominal findings. The data suggest novel interactions of genetic mutation with pulmonary nodules and age with renal cysts. Finally, in agreement with other works, these findings indicate that several rare thoracoabdominal imaging findings occur at higher rates in the TSC population than in the general population. This work supports obtaining detailed thoracoabdominal imaging in patients with TSC.

Adults with tuberous sclerosis complex: A distinct patient population.

OBJECTIVES: There are few data on adults living with tuberous sclerosis complex (TSC), with most studies focusing on pediatric populations. The objective of our study was to examine a large national cohort of adults with TSC, and to describe the clinical characteristics of these adults and the nature of the multidisciplinary care that they receive. METHODS: Six Canadian medical centers collaborated in this study. Data were collected using a standardized form, and descriptive statistics were used for the analyses. RESULTS: Our study included 181 adults with definite TSC (mean age = 33.6 years [SD = 13.7]). More than 40% (n = 75) had family members affected by TSC. Forty-six percent (n = 83) of individuals had intellectual disability. Nearly 30% (n = 52) of individuals reported living alone or with a partner/spouse. Seventy-six percent (n = 138) of people had epilepsy, 43% (n = 59) of whom had drug-resistant epilepsy, and 21% (n = 29) had undergone epilepsy surgery. Neuropsychiatric disease (n = 128) and renal angiomyolipomas (n = 130) were both present in approximately 70% of people. Renal imaging was performed in 75.7% (n = 137) of participants within the past 3 years. Renal and pulmonary function tests, as well as electrocardiograms, were recently performed in a minority of individuals. SIGNIFICANCE: Our cohort of adults with TSC showed that an important proportion have a milder phenotype, and are more frequently familial, as compared to children with TSC (and differing from prior reports in adult cohorts). Drug-resistant epilepsy, neuropsychiatric comorbidities, and renal angiomyolipoma are challenging factors in adults with TSC. Our participating medical centers generally followed recommended screening strategies, but there remain important gaps in care. Multidisciplinary and structured TSC care centers offering service to adults may help to improve the health of this important patient population.

Uterine angiomyolipoma: a clinical analysis of 8 cases and literature review.

PURPOSE: Uterine angiomyolipoma (AML) is a rare condition involving benign tumors composed of varying proportions of blood vessels, fat, and epithelioid or spindled smooth muscle cells. We analyzed the clinicopathological features, diagnosis and treatment methods, and prognosis of uterine AML. METHODS: We retrospectively analyzed the clinical-pathological data of eight patients with pathologically diagnosed uterine AML at a single center from January 2008 to July 2020. RESULTS: The mean age of the patients was 50 years (range, 41-62). One patient was asymptomatic; the main clinical manifestations of the others included vaginal bleeding (3), menorrhagia (2), abdominal pain (1), and dysmenorrhea with adenomyosis (1). In one case, fat components observed via abdominal computed tomography led to a diagnosis of uterine leiomyolipoma; the rest were diagnosed as uterine leiomyoma (4), uterine fibroid degeneration (2), and pelvic mass (1). The lesions were in the body of the uterus (6), the fundus of the uterus (1), and the broad ligament (1). Seven patients had a focal soft tumor texture, and one had a tough texture; the lesions were yellow (3), yellow-white (3), and pinkish white (2). Surgeries included transabdominal myomectomy (2), transabdominal hysterectomy (2), transabdominal hysterectomy/bilateral salpingo-oophorectomy (2), and laparoscopic total hysterectomy/bilateral salpingectomy (2). The median follow-up time was 72 months. No relapses were reported. CONCLUSION: Uterine AML has a low incidence rate and is most likely to occur in perimenopausal women. The clinical manifestations are similar to those of uterine leiomyomas, but AML should be suspected if the internal echo of the uterine tumor is uneven and contains adipose tissue.

From tuberous sclerosis complex to end stage renal disease: who are these patients?

In patients with tuberous sclerosis complex (TSC), renal complications are not limited to bleeding angiomyolipoma (AML); although rare, end-stage renal disease (ESRD) may occur. New treatments (e.g., mammalian target of rapamycin (m-Tor) inhibitors) for AML might influence the epidemiology of ESRD in patients with TSC. In France, 99 patients with TSC from the Renal Epidemiology and Information Network (REIN) registry and having undergone renal replacement therapy (RRT) between 2002 and 2016 were included in the present study. Additional data were collected from the patients' medical charts. The mean ± standard deviation age at RRT initiation was 48.4 ± 16.4 and 73.8% had a neurologic impairment. Fifty-four patients underwent kidney transplantation after an average of 23 ± 12.3 months on dialysis. Among the 61 patients with additional data the most common renal lesion was AML: 26.2% of the patients had isolated AML, and 26.2% had AML and renal cysts, 65.6% of patients had undergone nephrectomy, and 16.4% had undergone at least one embolization. None of the patients had been treated with an m-Tor inhibitor before dialysis. The graft survival rate was 92.5% at 5 years and 70.2% at 10 years. The present cohort study is the first to have assessed TSC patients on RRT from a national registry. Nephrectomy or embolization due to AML was the leading cause of ESRD in our cohort. By reducing the size of the AML, m-tor inhibitors might lower the risk of complications and thus reduce the number of patients with TSC requiring RRT.

Renal epithelioid angiomyolipoma: Incidence in a Japanese cohort and diagnostic utility of diffusion-weighted magnetic resonance imaging.

OBJECTIVES: To show the epidemiological characteristics of epithelioid angiomyolipoma in a Japanese population, and to establish the preoperative diagnosis method of epithelioid angiomyolipoma. METHODS: Among the 855 tumors of patients who underwent partial/radical nephrectomy or renal biopsy for presumed renal cell carcinoma between 2007 and 2018, 39 renal tumors were diagnosed as nonclassical angiomyolipoma, including epithelioid angiomyolipoma and fat-poor angiomyolipoma. We retrospectively evaluated the incidence of epithelioid angiomyolipoma. Furthermore, we analyzed computed tomography and magnetic resonance imaging results, including diffusion-weighted magnetic resonance imaging findings of epithelioid angiomyolipoma and fat-poor angiomyolipoma. RESULTS: The incidence of epithelioid angiomyolipoma (n = 7) was 17.9% of surgically resected non-classical angiomyolipoma. The radiological appearance of epithelioid angiomyolipoma was hyperattenuating on unenhanced computed tomography images with iso or low intensity on T2-weighted magnetic resonance imaging. The mean apparent diffusion coefficient value of the solid component in epithelioid angiomyolipoma was significantly lower than that in fat-poor angiomyolipoma (median 0.79 × 10-3 vs 1.07 × 10-3 mm2 /s, P = 0.0019). CONCLUSIONS: The proportion of epithelioid angiomyolipoma in our Japanese cohort was equivalent to that of the reported series in the USA. The apparent diffusion coefficient value is potentially useful to differentiate between epithelioid angiomyolipoma and fat-poor angiomyolipoma. Further research is required to establish the imaging diagnostic criteria for epithelioid angiomyolipoma.

Germline mutation of TSC1 or TSC2 gene in Chinese patients with bilateral renal angiomyolipomas and mutation spectrum of Chinese TSC patients.

The germline mutation of the TSC1/2 gene in bilateral renal angiomyolipomas is unclear. Meanwhile, the mutation spectrum of Chinese TSC patients has not been revealed. We recruited 78 patients diagnosed with bilateral renal AMLs. High-throughput sequencing was used to detect any variants in TSC1/2 genes. The results showed that 28.6% of patients diagnosed before 45 were with positive results of TSC1/2 test. The rate decreased to 14.3% for those with onset age over 45. For the 315 previously reported Chinese patients, TSC1 patients were more likely to be affected by nonsense mutations (51.1% vs. 20.7%, p<0.001) and had a significantly higher rate of family history than TSC2 patients (37.8% vs. 19.6%, p=0.0067). Moreover, exon8, 15, and 18 were the hotspot mutation regions for TSC1, and exon 29, 33 and 40 were the most common mutation regions for TSC2. Besides, Chinese TSC patients carried more TSC2 alterations (85.7% vs.76.2%, p<0.001), and were more likely to have a family history than those from TOSCA (22.2% vs. 13.9%, p<0.001). In conclusion, patients affected by bilateral renal AMLs should receive genetic testing of TSC ½ genes and Chinese TSC patients have relatively hotspot mutation regions, which are helpful to genetic counseling and clinical decision making.

[Small renal masses. Analysis of 152 cases]. / Masas renales pequeñas: predictores de malignidad en una serie de 10 años.

BACKGROUND: Small renal masses (SRM) are defined as complex organ-confined solid or cystic lesions < 4 cm. Up to 20% of these can be benign. A conservative management with active surveillance can be done in some patients. However, it is difficult to identify patients with a higher risk of malignancy. AIM: To characterize the clinical, radiological and histopathological aspects of patients with SRM, analyzing predictive factors for tumor aggressiveness. MATERIAL AND METHODS: Retrospective analysis of a cohort of patients undergoing partial or total nephrectomy for renal tumors between 2006 and 2016. All tumors of 4 cm or less were included. Four histological groups were defined: benign, favorable, intermediate and unfavorable. Two categories of risk were also defined: low and high. Preoperative clinical and radiological variables of these patients were analyzed. RESULTS: Data of 152 patients were analyzed. Six percent had a benign histology, and the majority was of intermediate risk (74%). According to histological type, clear cell carcinoma was the most common type (74%). Three percent were benign angiomyolipomas. No malignancy predictive variable was identified. CONCLUSIONS: In these patients, the percentage of benign SRM was low. No variable that could predict the presence of a benign or malignant lesion in the definitive biopsy was identified.

Masas renales pequeñas: predictores de malignidad en una serie de 10 años / Small renal masses: analysis of 152 cases

Background: Small renal masses (SRM) are defined as complex organ-confined solid or cystic lesions < 4 cm. Up to 20% of these can be benign. A conservative management with active surveillance can be done in some patients. However, it is difficult to identify patients with a higher risk of malignancy. Aim: To characterize the clinical, radiological and histopathological aspects of patients with SRM, analyzing predictive factors for tumor aggressiveness. Material and Methods: Retrospective analysis of a cohort of patients undergoing partial or total nephrectomy for renal tumors between 2006 and 2016. All tumors of 4 cm or less were included. Four histological groups were defined: benign, favorable, intermediate and unfavorable. Two categories of risk were also defined: low and high. Preoperative clinical and radiological variables of these patients were analyzed. Results: Data of 152 patients were analyzed. Six percent had a benign histology, and the majority was of intermediate risk (74%). According to histological type, clear cell carcinoma was the most common type (74%). Three percent were benign angiomyolipomas. No malignancy predictive variable was identified. Conclusions: In these patients, the percentage of benign SRM was low. No variable that could predict the presence of a benign or malignant lesion in the definitive biopsy was identified.

[Multiple hypochromic or achromic macules in children and risk of tuberous sclerosis]. / Macules hypochromiques ou achromiques multiples de l'enfant et risque de sclérose tubéreuse de Bourneville.

AIM: To describe in a large paediatric cohort the characteristics of hypopigmented and depigmented (hypochromatic and achromic) macules with no clear diagnosis but potentially evocative of tuberous sclerosis (TS). PATIENTS AND METHODS: This was a retrospective multicentre study performed between 2010 and 2017 at a reference centre for rare skin diseases; it included all children consulting for hypochromic and achromic macules. A descriptive analysis was made of the characteristics of macules with no clear diagnosis, enabling them to be classified in three secondary groups: TS certain, TS ruled out, TS uncertain. RESULTS: Of the 3300 children seen during this 7-year period 7,265 were consulting for hypochromic or achromic macules, with no clear diagnosis in 18 cases: 7 girls and 11 boys of median age at 7.21 years (range: 4 months to 16 years and 7 months). The lesions were congenital in 7 cases. The number of macules varied, with over 20 in some cases. The majority were in the form of ash-leaf spots, followed by the oval form. Two children were diagnosed at clinical examination, and 16 underwent it is not examinations, resulting in a diagnosis of certain ST in 6 of these cases. No particular characteristics of the macules appeared to guide the clinical examination towards ST or isolated lesions. Café-au-lait spots were more frequent in the group in which ST was ruled out than in the other two groups: 67% vs. 33% and 33%. Neurologic involvement was more common in children with certain or uncertain ST than in children in whom ST was ruled out (83% and 67% vs. 11%). CONCLUSION: No identified characteristics of stains enabled the clinical examination to confirm or rule out tuberous sclerosis. Screening for acute any signs of ST is essential. Diagnostic efficacy is enhanced by additional exams.

Renal progression factors in young patients with tuberous sclerosis complex: a retrospective cohort study.

BACKGROUND: Renal pathology in tuberous sclerosis complex (TSC) is characterized by the growth of angiomyolipoma and renal cysts, and in rare cases renal cell carcinoma. Other consequences of renal involvement in TSC, including hypertension, proteinuria, and hyperfiltration, are not well studied. We aimed to analyze the early manifestations of the renal TSC phenotype in a young TSC cohort and to explore common, modifiable risk factors. METHODS: In this retrospective cohort study, TSC patients attending the TSC clinics of two tertiary hospitals were included. Data on demographics, history, genotype, kidney function, hematuria, proteinuria, blood pressure, and renal imaging were collected. RESULTS: Eighty patients were included, with a median age of 0.8 years (0.0-63.0) at first presentation, and a median follow-up time of 10.2 (0.4-41.0) years. Mutation analysis was available in 64 patients (80%). Renal lesions (cysts or angiomyolipoma) were observed in 55/73 (75%). Thirty-two percent (19/60) were hypertensive, 8/51 (16%) had proteinuria, and 18/71 (25%) had hyperfiltration (median eGFR 154 ml/min/m2). Six (7.5%) patients had developed end stage renal disease at the last follow-up. No association was found between hyperfiltration, hypertension, or proteinuria and CKD ≥ 3. Cox regression showed a significant positive association between the presence of a renal intervention and CKD ≥ 3 (Hazard-Ratio 3.91, P < 0.05). CONCLUSIONS: Besides renal cysts and angiomyolipoma, the modifiable progression factors hypertension, proteinuria, and hyperfiltration occur frequently and early in TSC patients. This represents a preventive treatment target.

The Relationship Between Lithium and Cancer Proliferation: A Case-Based Review of the Literature.

BACKGROUND: The incidence and mortality rates of cancer in patients with Bipolar Disorder (BD) is higher compared with the general population. The role of Lithium (Li) in cancer proliferation/inhibition is still a controversial issue in the literature. OBJECTIVE: Based on a clinical case with lithium intake and development of a renal tumor, we aimed to explore the relationship between Li use and tumor proliferation, with regard to the mechanism of action of Li. METHOD: We present evidence of a female patient with bipolar disorder I, who had been on Li for several years, either as monotherapy or in combination with Valproate (VPA). While on Li monotherapy, the patient had undergone unilateral nephrectomy due to a chromophobe cell renal tumor. A literature search was performed using keywords bipolar disorder, medical comorbidity, cancer, renal tumor, lithium, mood stabilizers, valproate and mechanism of action. RESULTS: The limited data on the relationship between Li and cancer proliferation in clinical populations support neither a positive relationship between long-term Li use and increased urinary tract cancers nor an overall cancer risk. Growing evidence identifies effects of Li on cancer proliferation through inhibition of glycogen synthase kinase-3ß (GSK-3ß), modulations of redox status, inflammatory changes, pro-/anti-apoptotic mechanisms, and mitochondrial function changes. CONCLUSION: Despite the presence of contradictory data, a substantial body of evidence mainly from molecular studies points to Li's anti-carcinogenic effects. However, the underlying mechanistic pathways remain unclear. Mitochondrial dysfunction and redox modulations are potential areas for research on the relationship between Li and cancer proliferation.

Assessing the outcomes of everolimus on renal angiomyolipoma associated with tuberous sclerosis complex in China: a two years trial.

BACKGROUND: Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disorder characterized by the development of numerous benign tumors. Renal angiomyolipoma (RAML) occur in up to 80% of TSC patients, which is a leading cause of TSC-related death in adult patients. The aim of the study was to evaluate the efficacy and safety profiles of everolimus in Chinese patients of TSC associated with RAML(TSC-RAML). METHODS: In this 2-years, nonrandomized, open-label trial, 18 patients of TSC-RAML, with at least one RAML 3 cm or larger in its longest diameter, were enrolled to assess the efficacy and safety of everolimus therapy in Chinese patients. Everolimus was administered for the first 12 months only. The primary endpoint was a reduction of 50% or more relative in RAML volume to the baseline in the absence of new RAML ≥1 cm and no RAML-related bleeding of grade ≥ 2. The secondary endpoints included: safety, lung function and skin lesions response rate. Serial computed tomography of RAML, magnetic resonance imaging of brain lesions and pulmonary-function tests were performed. Adverse events were investigated using CTCAE v4.0. All analyses used a significance level of 0.05 and were generated in SPSS19.0 software. RESULTS: The proportion of patients who achieved ≥50% reduction from baseline in the sum of volumes of target lesions increased from 52.94% at 3 months, to 58.82% and 66.67% at months 6 and 12, respectively. During the period of everolimus therapy, among patients with lymphangioleiomyomatosis, the mean forced expiratory volume in 1 s (FEV1) increased by 276 ± 78 ml (P < 0.001), the forced vital capacity (FVC) increased by 433 ± 170 ml (P < 0.001), and the residual volume decreased by 408 ± 243 ml (P = 0.009), as compared with baseline values. The angiomyolipoma volume and the lung function approached, but did not completely return to, the baseline values. The skin lesions response rate was 37.5% after 12 months of therapy falling to 21.4% at 12 months after stopping everolimus. The most common adverse events were mucositis oral, irregular menstruation, abdominal pain, hypertriglyceridemia and headache. The most common grade 3 adverse events were irregular menstruation and mucositis oral. In addition, one patient died from RAML spontaneous haemorrhage during treatment with everolimus, even with reduction in RAML volume of 60.68% at 3 months. A second death was due to epithelioid RAML progression, with metastasis to multiple retroperitoneal lymph node, who died from severe infection one month after surgery. CONCLUSIONS: Angiomyolipomas regressed somewhat during everolimus therapy but tended to increase in volume after the therapy was stopped. Everolimus was well tolerated and showed promising activity in Chinese patients with TSC-RAML, however, we should alert the life-threatening hemorrhage of large RAML in the early period and the lymph node metastasis of epithelioid RAML. TRIAL REGISTRATION: ChiCTR-OPC-14005488 . Registered November 17, 2014.

Renal manifestations of tuberous sclerosis complex: patients' and parents' knowledge and routines for renal follow-up - a questionnaire study.

BACKGROUND: Renal angiomyolipomas (AMLs) are a major clinical feature in patients with tuberous sclerosis complex (TSC). Spontaneous bleeding can be life threatening, and appropriate information and proper surveillance and management are important to limit morbidity and mortality. Because TSC is a rare disease, patients are at risk of suboptimal medical management. Our aim was to investigate patients' and parents' knowledge about renal angiomyolipomas (AMLs) in Tuberous Sclerosis Complex (TSC) and to identify current routines for renal follow-up. METHODS: A questionnaire survey was initiated by the French Reference Centre on TSC. It was distributed in France through university hospitals and the patients' association (2009-2011), and to patients registered by the Norwegian National Centre for Rare Epilepsy-Related Disorders (2013-2014). Contingency tables with Chi-Square test for independence (with Yates Continuity Correction) and Pearson-Chi-Square value were used for correlation statistics. RESULTS: We included 357 patients (France, n=257; Norway n=100). Most participants knew that TSC is associated with AMLs. However, 42 % did not know about the risk of AMLrelated bleeding, and 37 % had been informed about the risk of bleeding only after the age of 15 years. Furthermore, 14 % did not know whether they themselves or their child had AMLs. Patients had less knowledge than parents. Medical consultations and patient associations were the main sources of information. Among 30 % of patients, renal imaging was not received at all, or not conducted every 1-3 years, as recommended by current guidelines. Regular imaging was more frequent in patients with AMLs < 15 years, than in patients with AMLs ≥ 15 years. Ultrasound was the most frequently used imaging modality. CONCLUSIONS: Knowledge of renal AML in TSC patients and their parents was lower than expected, and follow-up by renal imaging was suboptimal for a substantial proportion of patients. Patients and parents should be informed about the risk and symptoms of renal bleeding, at the latest when the patient is 15 years. Monitoring the growth of AMLs should be standardized to comply with guidelines. Transition between adolescence and adulthood is a high-risk period and ensuring appropriate follow-up at this time is particularly important.

Liver Angiomyolipomas in Tuberous Sclerosis Complex-Their Incidence and Course.

BACKGROUND: The purpose of this study was to evaluate the epidemiology and clinical significance of hepatic angiomyolipomas in patients with tuberous sclerosis complex. METHODS: We performed a retrospective analysis of clinical and imaging data from 187 patients with tuberous sclerosis complex. The prevalence, progression, and potential relationship between liver lesions and other clinical findings, including genetic associations, were assessed. RESULTS: Twenty-eight of 187 patients (14.9%) had hepatic lesions. There was a predominance of female over male patients in individuals with liver lesions (17 versus 11), with statistical significance in patients under five years of age (P < 0.05). All individuals having hepatic lesions who also had available genetic testing data (n = 20) were diagnosed with a TSC2 gene mutation. All patients with liver lesions had coexisting renal angiomyolipomas (AMLs) (P < 0.05). The age of onset of renal lesions was lower and their prevalence was significantly higher in patients with liver involvement (P < 0.05). In most instances, hepatic lesions measured several millimeters in diameter and were clinically asymptomatic. Progressive lesion growth was documented in six individuals but with no clinical consequences to date. CONCLUSIONS: This study confirms the association of hepatic lesions with TSC2 mutations, a common origin of liver and renal AMLs, as well as the predominance of female patients in this group. Hepatic AMLs are relatively common but mostly benign lesions.

[Clinical and pathologic analysis of 414 cases of renal angiomyolipomain in a single institution].

Objective: To study the different clinicopathological characteristics between classic and epithelioid renal angiomyolipoma, and the relationships between clinicopathological characteristics and biological behaviors as basis for clinical treatment. Methods: The clinicopathological and follow-up data for the patients diagnosed with renal angiomyolipoma between 2004 and 2011 were retrospectively reviewed and analyzed. Results: There were 414 cases of renal angiomyolipoma diagnosed over 8 years ago, accounting for 8.1% (414/5 287) of all renal parenchymal tumors. The patients included 122 male and 292 female (male-to-female ratio of 1.0∶2.4), mean age 44.0 years (range 15-74 years). Of these, 195(47.1%) tumors occurred in the left kidney, 212(51.2%) in the right kidney and seven (1.7%) were bilateral. Clinically, some cases presented with hypochondrial pain, hematuria or palpable masses. Histologically, 394(95.2%) were classic angiomyolipoma, 20(4.8%) were epithelioid angiomyolipoma; 54, 23 and 7 cases had hemorrhage, necrosis and cystic degeneration, respectively; and 5, 30 and 14 cases had perirenal fat invasion, atypical cells and polymorphic/giant tumor cell. There was a positive correlation between atypical cells and epithelioid tumor type, respectively. The other clinicopathological parameters did not correlate with histological type. Follow-up data was available in 360 patients, with follow-up period of 3 to 99 months. One case died from other causes. The remaining patients were free of disease. Conclusions: Angiomyolipoma is a common renal parenchyma tumor. Clinically, it is usually biologically benign. Histologically, it can be either classic or epithelioid types. The epithelioid type should be differentiated from the classic renal cell carcinoma, Mit family translocation renal tumor and renal hemangioblastoma. Atypical cells, more commonly found in the epithelioid angiomyolipoma, do not affect the clinical prognosis of patients.

Lipomatous tumours in adrenal gland: WHO updates and clinical implications.

Adrenal lipomatous tumour is a group of adrenal tumours with a significant component of adipose tissue. According to the current World Health Organization (WHO) classification of tumours of endocrine organs, adrenal myelolipoma is the only entity amongst the group of tumours being described. In the literature, other more recently documented adrenal lipomatous tumours included 24 lipomas, 32 teratomas and 16 angiomyolipomas. Rare fatty tumours of the adrenal gland comprised liposarcoma, hibernoma, adrenocortical tumours with fat component and rare adrenal tumours with fat component. Myelolipoma comprises approximately 3% of primary adrenal tumour. It is noted more commonly in females and in the right adrenal gland. Approximately 40 bilateral myelolipomas were reported. The tumour is most frequently recorded in patients between fifth and seventh decades of life. Adrenal lipomas are often seen in males and in the right adrenal gland. They were commonly noted in patients in the sixth decade of life. The diagnosis could only be possible on examination of the surgically removed specimen. Adrenal teratomas were more common in females and with a bimodal age distribution. Slightly over 60% of the patients with adrenal teratoma are symptomatic. Adrenal angiomyolipomas were often symptomatic, more common in females and in the fifth decades of life. To conclude, adrenal lipomatous tumour is uncommon. They are often benign and non-functional. It is important to recognize the features of this group of lipomatous tumours in the adrenal gland as they are being detected on increasing incidence as a result of the wide-spread use of modern imaging modalities.

Prevalence of Renal Angiomyolipomas and Spontaneous Bleeding Related to Angiomyolipomas in Tuberous Sclerosis Complex Patients in France and Norway-a Questionnaire Study.

OBJECTIVE: To estimate the prevalence of renal angiomyolipomas (AMLs) and AML-related bleedings among patients with tuberous sclerosis complex and to gather information about associated treatments. METHODS: A questionnaire survey was undertaken by the French Reference Centre for Tuberous Sclerosis Complex and distributed through university hospitals and the patients' association (2009-2011). The questionnaire was then distributed to patients registered by the Norwegian National Centre for Rare Epilepsy-Related Disorders (2013-2014). Risk of bleeding was estimated by Kaplan-Meier analysis. RESULTS: We included 357 patients (France, n = 257; Norway, n = 100); 189 (54%) reported having AMLs, 111 (32%) reported not having AMLs, and 50 (14%) reported not knowing whether they had AMLs. Twenty-five patients (France, n = 19; Norway, n = 6) reported that they have had bleeding. Age at first bleeding (known in 22 patients) was 27.6 ± 8.5 years. Fifteen patients (France, n = 11; Norway, n = 4) experienced first bleeding between 20 and 30 years. Bleeding-free survival was similar in France and Norway (P = .471). The bleeding-free survival rate at 72 years was 81% (95% confidence interval: 68-89) in the overall population and 66% (95% confidence interval: 43-82) in patients with AMLs. Bleeding treatment (known in 24 patients) consisted of conservative measures (n = 9), embolization (n = 8), nephrectomy (n = 4), embolization and nephrectomy (n = 2), or partial nephrectomy (n = 1). Fifteen French patients reported prophylactic treatment. In Norway, this information was known only in patients with renal bleeding and was reported in two. CONCLUSION: Fifty-four percent of the patients reported having AMLs and 7% (25/357) reported bleeding. Sixty-eight percent of first bleedings occurred between 20 and 30 years. Bleedings were managed conservatively in 38% of the patients and 62% needed active treatment.