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pS6 staining of normal human adult kidney (hAK) and AML tumors. (a-c) hAK demonstrates varying pS6 expression, seen mostly in distal tubules (DT) and collecting ducts (CD). (d-g) Sporadic AMLs demonstrate abundant pS6 expression. (h-k) Normal kidney borders of sporadic AML demonstrate varying pS6 expression in DT and CD, similarly to hAK. (l-n) TSC-related AML demonstrates a strong pS6 expression in both tumor (l,m) and normal kidney tissue (n). AML, renal angiomyolipoma; TSC, tuberous sclerosis complex.
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Introduction
Renal angiomyolipoma (AML) is the most common benign renal tumor. Despite a generally benign histology, AML can result in significant morbidity, from intra-abdominal hemorrhage and reduction in kidney function. While classically associated with the autosomal dominant disorder tuberous sclerosis complex (TSC) or with pulmonary lymphangi...
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Context 1
... as to validate that sporadic AML tumors show mTORC1 activation, which could serve as the basis for targeting this pathway in this group of patients, we first carried out immunohistochemical staining for pS6, a marker of mTORC1 activation in normal human adult kidneys (hAK), sporadic AML tumors, and TSC-related AML ( Figure 1). hAK demonstrated varying levels of pS6 expression, mostly in distal tubules (DT) and col- lecting ducts (CD) (Figure 1). ...
Context 2
... as to validate that sporadic AML tumors show mTORC1 activation, which could serve as the basis for targeting this pathway in this group of patients, we first carried out immunohistochemical staining for pS6, a marker of mTORC1 activation in normal human adult kidneys (hAK), sporadic AML tumors, and TSC-related AML ( Figure 1). hAK demonstrated varying levels of pS6 expression, mostly in distal tubules (DT) and col- lecting ducts (CD) (Figure 1). Within the tumor tissue of sporadic AML specimens we detected a strong pS6 expression, whereas the normal kidney borders exhibited an expression pattern similar to that of hAK, involving mostly DT and CD. ...
Context 3
... the tumor tissue of sporadic AML specimens we detected a strong pS6 expression, whereas the normal kidney borders exhibited an expression pattern similar to that of hAK, involving mostly DT and CD. As expected, TSC-related AML demonstrated a strong pS6 expression in both tumor tissue and within normal kidney tissue, reflect- ing the germline mutation in TSC1/2 leading to wide- spread mTORC1 activation ( Figure 1). Taken together, these results indicate that the tumor tissue of sporadic AML exhibits strong activation of the mTORC1 pathway. ...
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In tuberous sclerosis (TSC)-associated tumors, mutations in the TSC genes lead to aberrant activation of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway. mTORC1 signaling impacts many biological processes including the epithelial-mesenchymal transition (EMT), which is suggested to promote tumor progression and metastasis in...
Citations
... The mainstay of treatment for TSC is mTOR inhibition, which has been shown to be effective both in the sporadic and genetic form of the TSC-associated lesions [9]. Additionally, clinicians often used multiple different modalities to treat TSC patients who fail conventional anti-epileptic drugs, including the ketogenic diet, cannabidiol (CBD) oil, vagus nerve stimulation (VNS), and epilepsy surgery [10]. ...
AimWe aimed to describe the experience of a large single-center cohort for the clinical, radiological, and genetic characteristics, as well as to determine the efficacy of different anti-epileptic strategies in children and adults with tuberous sclerosis complex (TSC).Methods
We carried out a historical cohort study on 91 TSC patients treated in a single center between 2008 and 2018.ResultsOur cohort comprised 46 males and 45 females, with a median age of 15.6 years at the last follow-up. Mean follow-up time was 2.5 ± 0.75–5.5 years (range 0–9.5 years). Of those tested, a disease-causing mutation was identified in 90% of patients, 53% in TSC2, and 37% in TSC1. Epilepsy prevalence was similar among TSC1 and TSC2 mutated patients. The most common radiological finding were cortical tubers in 95% of patients, while subependymal giant cell astrocytoma (SEGA) were detected in 36% of patients. Notably, infantile spasms (IS) were diagnosed in 29%, with SEGA representing the only finding significantly different in prevalence between those with and without IS (62% vs. 28%, respectively, p = 0.009). Lastly, we did not find any difference in efficacy between three anti-epileptic treatments: Vagus nerve stimulation (VNS), CBD-based products, and the ketogenic diet, all showing approximately 30%–40% response rates.SignificanceAltogether, we provide a comprehensive description of our experience in treating TSC, which could serve to expand current knowledge of the disease and its treatments.
... With regard to AMLs, the first study demonstrating an antiproliferative effect of mTOR inhibitors was conducted in 20 patients. The results showed a significant reduction in AML size (80). The beneficial effects subsided once treatment stopped, indicating a reversible effect of mTOR inhibition. ...
Tuberous sclerosis complex (TSC) is a genetic condition caused by a mutation in either the TSC1 or TSC2 gene. Disruption of either of these genes leads to impaired production of hamartin or tuberin proteins, leading to the manifestation of skin lesions, tumors, and seizures. TSC can manifest in multiple organ systems with the cutaneous and renal systems being the most commonly affected. These manifestations can secondarily lead to the development of hypertension, chronic kidney disease, and neurocognitive declines. The renal pathologies most commonly seen in TSC are angiomyolipoma, renal cysts, and less commonly, oncocytomas. In this review, we highlight the current understanding on the renal manifestations of TSC along with current diagnosis and treatment guidelines.
... Korelacja pomiędzy mutacją konkretnego genu a przebiegiem klinicznym AML pozostaje niejasna [83]. Somatyczne delecje w locus TSC2 obserwuje się także w sporadycznych przypadkach naczyniakowłókniakotłuszczaków [84] i prowadzą one, podobnie jak w TSC, do zwiększonej aktywności kompleksu mTORC1 [85]. Wykazano ponadto, że 0,3% chorych z AML, naczyniakowatością limfatyczną i TSC jest nosicielem polimorfizmu kodonu 72 (R73) genu TP53 oraz że nosicielstwo tego polimorfizmu wiąże się z większym ryzykiem rozwoju AML [86]. ...
... W grupie chorych, którzy w 2. roku obserwacji nie przyjmowali już leku, stwierdzono utrzymanie obiektywnej odpowiedzi jedynie u 5% spośród nich. Nadmierną aktywację kompleksu mTORC1, związaną między innymi z somatycznymi mutacjami inaktywującymi genu TSC2, wykazano również w sporadycznych AML, a pojedyncze doniesienia wskazują na podobne korzyści z zastosowania inhibitorów mTOR u tych pacjentów [85]. Nie przeprowadzono jednak badań klinicznych dotyczących leczenia systemowego sporadycznych przypadków AML. ...
Angiomyolipoma (AML) is the most commonly occurring tumour from the PEComa family (PEC tumours; perivascular epithelioid cell tumours), a rare group of neoplasms of mesenchymal origin. AML may occur sporadically or in the course of tuberous sclerosis and lymphangioleiomyomatosis. The sporadic type form is the most common subtype of benign kidney tumours and is four times more frequent in women. Kid ney tumours of the angiomyolipoma type are most commonly detected by chance during an abdominal cavity ultrasound scan, during which they are visible as hyperechogenic tumours, and in most cases they are not a diagnostic problem. AML growth is slow, and complications are rare. The main AML complication can be bleeding to the retroperitoneal space or to the pelvicalyceal system. The typical method of AML care is active surveillance (AS). Asymptomatic tumours with a diameter under 4 cm require control by ultrasound examination every 12 months whereas tumours with a diameter of less than 2 cm are considered not to require control ultrasounds. AML with a diameter of over 4 cm require more frequent ultrasound scans — every six months. The size of the tumour, the presence of symptoms (e.g. pain in a tumour projection, haematuria), planned pregnancy, or suspicion of a malignant tumour are critical in therapeutic decisions. Active treatment options include: embolisation, ablation techniques, nephron-sparing surgery (NSS), and radical nephrectomy. In adult patients with tuberous sclerosis, who require treatment but do not require rapid surgical treatment, everolimus is used. In the case of AML, initially doses of 1 × 10 mg per day should be used (an appropriate dose decrease is required in the case of liver insufficiency), and subsequently treatment may be individualised after determining the lowest effective dose with acceptable adverse effects. A rare epithelioid variety of AML (EAML) shows the potential for a malignant course. The basis of EAML treatment is radical resection, ensuring a high percentage of cures. For non-resectable EAML, chemotherapy, mTOR inhibitors, and VEGFR inhibitors (pazopanib, apatinib) are used, but objective responses have been described only in a very small percentage of patients.
... 57 A recent study reported the effectiveness of mTOR inhibitors for sporadic AML, and treatment with rapamycin at 1 mg daily for sporadic AML in a 35-year-old female reduced the tumor volume by 22.2% and 42.3% after 5 and 13 months, respectively. 58 Thus, further studies are required to fully elucidate the efficacy of mTOR inhibitor treatment for sporadic AML. mTOR inhibitors have become a new treatment option for patients with TSC-associated AML who cannot undergo surgical treatment or TAE because of intellectual disability. ...
Renal angiomyolipoma (AML) is the most common benign tumor of the kidney. It consists of blood vessels, smooth muscle and fat components in varying proportions. AML is divided into the sporadic type and tuberous sclerosis complex (TSC)-associated type. TSC-associated AML develops at a younger age and tends to exhibit a much faster growth rate over time than sporadic AML. AMLs are classified as classic AML, fat-poor AML and epithelioid AML. Epithelioid AML, though rare, shows aggressive behavior leading to distant metastasis and mortality. TSC-associated AML is more likely to have an epithelioid component than sporadic AML. Active surveillance is the suggested management for small AML. Clinical intervention is mainly indicated when there is a substantial risk of rupture. Minimally invasive therapies, including partial nephrectomy, transcatheter arterial embolization, and mammalian target of rapamycin (mTOR) inhibitor treatment are employed for patients who require treatment. An updated algorithm for the management of AML is herein described. According to this algorithm, treatment intervention is recommended for TSC-associated AML >3 cm, even in asymptomatic cases. In cases with asymptomatic sporadic AML >4 cm in size or with an intra-tumoral aneurysm of >5 mm, treatment, including transcatheter arterial embolization or partial nephrectomy, is advised. The major complication of AML is intra-tumoral or retroperitoneal hemorrhage due to rupture that may be serious and life threatening. Thus, correct diagnosis, proper observation, and appropriate treatment are very important in the management of renal AML.
Sporadic Renal Angiomyolipoma (AML) is commonly managed through transcatheter arterial embolization (TAE) or surgical intervention. In this report, we present a remarkable case of tumor regression from Novick Classification level 2 to level 1 in a 54-year-old male with sporadic renal AML and inferior vena cava (IVC) involvement, treated with the administration of everolimus. Subsequently, laparoscopic nephrectomy without cavectomy was performed. Notably, the patient did not present with tuberous sclerosis complex (TSC). Our findings highlight the potential of everolimus in the treatment of sporadic AML, even in cases unrelated to TSC, offering a viable alternative to invasive therapeutic approaches.
Epidemiological studies document strong associations between acute or chronic kidney injury and kidney tumors. However, whether these associations are linked by causation, and in which direction, is unclear. Accumulating data from basic and clinical research now shed light on this issue and prompt us to propose a new pathophysiological concept with immanent implications in the management of patients with kidney disease and patients with kidney tumors. As a central paradigm, this review proposes the mechanisms of kidney damage and repair that are active during acute kidney injury but also during persistent injuries in chronic kidney disease as triggers of DNA damage promoting the expansion of (pre-)malignant cell clones. As renal progenitors have been identified by different studies as the cell of origin for several benign and malignant kidney tumors, we discuss how the different types of kidney tumors relate to renal progenitors at specific sites of injury and to germline or somatic mutations in distinct signaling pathways. We explain how known risk factors for kidney cancer rather represent risk factors for kidney injury as an upstream cause of cancer. Finally, we propose a new role for nephrologists in kidney cancer, i.e. the primary and secondary prevention and treatment of kidney injury to reduce incidence, prevalence, and recurrence of kidney cancer.
Renal angiomyolipomas (AMLs) were first described in the early 1900s by Gravitz, but it was not until 1951 that they were named renal AML. These kidney tumours are rare, occurring in 0.13%–0.44% of the population. These mesenchymal tumours are composed of smooth muscle-like, adipocyte-like and epithelioid cells. Depending on the predominant cell population, it can be further subclassified into classic, epithelioid and AML with epithelial cyst. A 32-year-old woman presented with mild, intermittent, epigastric and right upper quadrant abdominal pain. Abdominal ultrasound revealed an incidental lesion within the inferior vena cava (IVC). A CT scan showed a lesion within the left renal vein extending into the IVC with 40% narrowing and a fat-containing mass in the lower pole of the left kidney of 15 mm suggesting an AML. Thrombectomy was performed. The specimen resulted positive for classic variant renal AML. Initial diagnosis is centred on imagining studies, based in fatty tissue concentration. The AML expresses melanocytic markers. This helps differentiate from renal cell carcinoma. Although AML is considered a benign condition, there is evidence of malignant transformation. Active surveillance is recommended for lesions <4 cm. Nephron sparing surgery is the procedure of choice. Nephrectomy is recommended if there is a high probability of malignancy. Mammalian target of rapamycin (mTOR) inhibitors have been proposed to be an alternative treatment.
Background:
The perivascular epithelioid cell tumour (PEComa) family of tumours mainly includes renal and hepatic angiomyolipomas, pulmonary lymphangioleiomyomatosis and clear cell "sugar" tumour of the lung. Several uncommon tumours with similar morphological and immunophenotypical characteristics arising at a variety of sites (abdominal cavity, digestive tract, retroperitoneum, skin, soft tissue and bones) are also included in the PEComa family and are referred to as PEComas not otherwise specified.
Case summary:
We present a 37-year-old female patient who underwent resection of an 8.5 cm × 8 cm × 4 cm retroperitoneal tumour, which eventually was diagnosed as PEComa of uncertain biological behaviour. Three years after the operation, the patient remains without any evidence of recurrence. A search was performed in the Medline and EMBASE databases for articles published between 1996 and 2018, and we identified 31 articles related to retroperitoneal and perinephric PEComas. We focused on sex, age, maximum dimension, histological and immunohistochemical characteristics of the tumour, follow-up and long-term outcome. Thirty-four retroperitoneal (including the present one) and ten perinephric PEComas were identified, carrying a malignant potential rate of 44% and 60%, respectively. Nearly half of the potentially malignant PEComas presented with or developed metastases during the course of the disease.
Conclusion:
Retroperitoneal PEComas are not as indolent as they are supposed to be. Radical surgical resection constitutes the treatment of choice for localized disease, while mammalian target of the rapamycin (mTOR) inhibitors constitute the most promising therapy for disseminated disease. The role of mTOR inhibitors as adjuvant or neoadjuvant therapies needs to be evaluated in the future.
