Renal angiomyolipoma (RAML) is the most common form of angiomyolipoma, a benign neoplasm of largely unknown etiology. Patients suffering from tuberous sclerosis or sporadic lymphangioleiomyomatosis are predisposed for developing RAML. Most RAML grow slowly and don't require any specific therapy, but regular surveillance. If treatment is deemed necessary, the application of everolimus, cryoablation, radiofrequency ablation, embolization of the renal artery, and nephrectomy may be considered.
Presentation
Most RAML patients are asymptomatic. The mean size of tumors at the time of detection is 4 to 6 cm and the smaller the tumor, the lower the likelihood of it causing any complaints [1]. Occasionally, these benign renal neoplasms provoke back and flank pain. Furthermore, RAML may cause hematuria. It has been estimated that a palpable mass may be detected during a physical examination of the kidneys in about 10% of those individuals presenting with RAML-related hematuria. Additionally, these patients are predisposed for spontaneous retroperitoneal hemorrhages, a condition also known as Wunderlich syndrome. Pregnant women are particularly susceptible to this complication and may even suffer from life-threatening hemorrhagic shock [2] [3].
In patients suffering from tuberous sclerosis or lymphangioleiomyomatosis, symptoms caused by RAML are usually not the reason why medical attention is sought. Tuberous sclerosis is typically associated with mental retardation and epilepsy, which may manifest during infancy. Affected individuals are prone to a variety of mesenchymal tumors, with facial angiofibromas distributed in a butterfly-like pattern being the most characteristic ones. Angiomyolipomas may not only develop in the kidneys, but also in the liver and possibly in other organs. Lymphangioleiomyomatosis is usually part of the tuberous sclerosis complex, but may rarely occur as a sporadic disease not related to tuberous sclerosis. Lymphangioleiomyomatosis manifests in form of unspecific respiratory symptoms like chest pain, dyspnea, and cough.
Entire Body System
- Pain
flank pain, urinary tract infections, renal failure or hypertension. [ncbi.nlm.nih.gov]
Ultrasonography of the right kidney of twenty five years female patient with tuberous sclerosis presenting with right flank pain, fever and anemia showing renal angiomyolipomas. A. [oatext.com]
- Asymptomatic
The vast majority are sporadic, asymptomatic, and initially harmless, with a negligible growth rate. Our findings support a policy of initial active surveillance for all asymptomatic AMLs. [ncbi.nlm.nih.gov]
- Fever
Ultrasonography of the right kidney of twenty five years female patient with tuberous sclerosis presenting with right flank pain, fever and anemia showing renal angiomyolipomas. A. [oatext.com]
She subsequently developed recurrent fever and was suspected of having emphysematous pyelonephritis, for which she underwent a right nephrectomy. The entire kidney was replaced by a tan bulging, lobular mass, with scattered tan-yellow nodules. [ncbi.nlm.nih.gov]
Patients with renal angiomyolipoma often have flank pain, a palpable tender mass, abdominal discomfort, fever, and gross hematuria. [consultant360.com]
He recovered well after the operation with resolution of pain and fever. [ispub.com]
- Swelling
Get medical help right away if you have trouble breathing or develop swelling of your tongue, mouth, or throat during treatment with AFINITOR. You may develop kidney failure. In some people, this may be severe and can even lead to death. [us.afinitor.com]
Angioedema With Concomitant Use of Angiotensin-Converting Enzyme (ACE) Inhibitors: Patients taking concomitant ACE inhibitor with AFINITOR may be at increased risk for angioedema (eg, swelling of the airways or tongue, with or without respiratory impairment [hcp.novartis.com]
A palpable swelling in the lumbar area of spine. This is because of the enlargement of growing tumor. Red or brown colored urine due to passage of blood in urine. Frequent urinary tract infection. Raised blood pressure. [tandurust.com]
- Flank Mass
Shock due to a grave haemorrhage from AML rupture is called Wunderlich syndrome that is clinically characterized by the Lenk's triad: acute flank pain, a flank mass and hypovolemic shock.Other symptoms and signs may be present: haematuria, palpable mass [ncbi.nlm.nih.gov]
When symptomatic, AML typically presents as palpable flank mass, hematuria and flank pain. [hoajonline.com]
Gastrointestinal
- Abdominal Pain
A 68-year-old woman presented with abdominal pain, fatigue, anorexia and night sweats. [ncbi.nlm.nih.gov]
- Nausea
A 21-year-old woman was seen in the emergency unit at the 25th week of her pregnancy with complaints of sudden onset left flank pain radiating to the back, nausea and hematuria. [ncbi.nlm.nih.gov]
This includes new significant back or abdominal pain, nausea, vomiting, and fever. If these growths involve both kidneys, renal failure is a possibility. [tsalliance.org]
Other associated signs and symptoms include nausea, vomiting, hypertension, anemia, elevated white blood cell count, and renal insufficiency. [consultant360.com]
If the dilated blood vessels in an angiomyolipoma rupture, the resulting retroperitoneal haemorrhage causes sudden pain, accompanied with nausea and vomiting. [en.wikipedia.org]
Other adverse events occurring in at least 10% of everolimus patients, all of which were grade 1 or 2, were arthralgia (22%), acne (22%), headache (20%), nausea (16%), vomiting (15%), diarrhea (14%), peripheral edema (13%), arthralgia (13%), abdominal [ascopost.com]
- Vomiting
Other associated signs and symptoms include nausea, vomiting, hypertension, anemia, elevated white blood cell count, and renal insufficiency. [consultant360.com]
These symptoms most commonly included abdominal or back pain, nausea and vomiting and fever. For the individual who is non-verbal, this may be present as irritability and vomiting. [tsalliance.org]
If the dilated blood vessels in an angiomyolipoma rupture, the resulting retroperitoneal haemorrhage causes sudden pain, accompanied with nausea and vomiting. [en.wikipedia.org]
Other adverse events occurring in at least 10% of everolimus patients, all of which were grade 1 or 2, were arthralgia (22%), acne (22%), headache (20%), nausea (16%), vomiting (15%), diarrhea (14%), peripheral edema (13%), arthralgia (13%), abdominal [ascopost.com]
The usual symptoms are flank pain, palpable mass, nausea, vomiting, hematuria, anemia, hypertension, urinary tract infection, shock, or even kidney failure [3]. AMLs can be diagnosed by various imaging modalities. [urotoday.com]
- Diarrhea
Other adverse events occurring in at least 10% of everolimus patients, all of which were grade 1 or 2, were arthralgia (22%), acne (22%), headache (20%), nausea (16%), vomiting (15%), diarrhea (14%), peripheral edema (13%), arthralgia (13%), abdominal [ascopost.com]
These include stomatitis/mucositis, respiratory infection, diarrhea, hypertriglyceridemia, hypercholesterolemia, bone marrow suppression (anemia, mild neutropenia, and leukopenia), proteinuria, and joint pain ( 38, 41, 42 ). [cjasn.asnjournals.org]
Cardiovascular
- Hypertension
Renovascular hypertension should be considered in patients who present with accelerated hypertension, particularly if the hypertension is resistant to medical therapy and not associated with laboratory features of preeclampsia/eclampsia. [ncbi.nlm.nih.gov]
In addition, BP should be measured and followed closely, because the risk of hypertension increases with increasing burden of kidney lesions. [cjasn.asnjournals.org]
- Thrombosis
A preoperative inferior vena cava (IVC) filter is reported to be effective in surgical cases with proximal deep venous thrombosis (DVT) or in which pulmonary embolism (PE) has already developed, and considered to be at high risk of developing secondary [ncbi.nlm.nih.gov]
[…] of the superficial dorsal vein of the penis (Penile Mondor‘s Disease) Penile Mondor disease is a rare thrombosis of THE SIGNIFICANCE OF MRI IN DIAGNOSING PENILE FRACTURE IN A CASE REPORT OF A 16-YEAR-OLD BOY Penile fracture is the rupture of one or LEIOMYOMA [prolekare.cz]
Kaohsiung Journal of Medical Sciences, 27(2): 72-75 [ CR ] [ EČ ][ GS ] Mittal, V., Aulakh, B.S., Daga, G. (2011) Benign Renal Angiomyolipoma With Inferior Vena Cava Thrombosis. [scindeks.ceon.rs]
The largest AML in right mid portion kidney measured 9 cm x 8 cm x 9 cm and showed a central round nonenhancing area of pseudoaneurysm measuring 4.3 cm x 3.8 cm x 4.9 cm suggestive of spontaneous thrombosis. Minimal ascites was noted. [oatext.com]
By this method, we aimed to achieve complete occlusion of the ruptured vessel with maximal nephron sparing and also to help thrombosis of the aneurismal sac and reduction in size with time. [sjkdt.org]
Skin
- Flushing
The incidence of serious infections was reported at a higher frequency in patients Severe Hypersensitivity Reactions: Hypersensitivity reactions to AFINITOR have been observed and include anaphylaxis, dyspnea, flushing, chest pain, and angioedema (eg, [hcp.novartis.com]
Call your health care provider or get medical help right away if you get signs and symptoms of a severe allergic reaction including: rash, itching, hives, flushing, trouble breathing or swallowing, chest pain, or dizziness. [us.afinitor.com]
All diagnostic digital subtraction angiographic examinations started with a flush aortogram for evaluation of extrarenal arterial feeders to the tumor. After aortography, selective renal artery catheterization was performed. [hemodinamiadelsur.com.ar]
Musculoskeletal
- Back Pain
We report a case of a pregnant woman with 18 weeks of gestation admitted in the emergency room with an acute right low back pain with no other symptoms. [ncbi.nlm.nih.gov]
Clinical History: 59-year old woman with right lower back pain for more than one year Diagnosis: Right renal angiomyolipoma MR Technique: Upper abdominal imaging was performed on a 3T MR system. [clinical-mri.com]
This includes new significant back or abdominal pain, nausea, vomiting, and fever. If these growths involve both kidneys, renal failure is a possibility. [tsalliance.org]
In this situation, the signs and symptoms could be nausea, vomiting, back pain, sudden drop in blood pressure, and palpitations. [dovemed.com]
Urogenital
- Flank Pain
flank pain, urinary tract infections, renal failure or hypertension. [ncbi.nlm.nih.gov]
Ultrasonography of the right kidney of twenty five years female patient with tuberous sclerosis presenting with right flank pain, fever and anemia showing renal angiomyolipomas. A. [oatext.com]
- Hematuria
Although life-threatening complications related to retroperitoneal bleeding and massive hematuria are possible, it is often detected incidentally. Pulmonary embolism as the first symptom is extremely rare. [ncbi.nlm.nih.gov]
- Kidney Failure
Outcomes were incidence rates per 100 patient-years and number of months to development of hematuria, chronic kidney disease, renal hemorrhage, kidney failure, and inpatient death. [ncbi.nlm.nih.gov]
These growing tumors may lead to life-threatening complications, such as internal bleeding and kidney failure. TSC symptoms and manifestations vary from person to person and may change over time. [novartisoncology.com]
However, sometimes the kidney is filled with cysts, and this can lead to kidney impairment and even kidney failure, requiring dialysis or transplantation. [tsalliance.org]
This clinical condition is termed Wunderlich syndrome The presence of kidney cysts and more than one AML tumors in kidney can cause kidney failure, due to compression of the kidney tissue Chronic renal failure affecting kidney function, if tumors are [dovemed.com]
- Renal Insufficiency
Other associated signs and symptoms include nausea, vomiting, hypertension, anemia, elevated white blood cell count, and renal insufficiency. [consultant360.com]
Patients with lesions greater than 4cm with moderate to severe symptoms (bleeding or pain) should undergo renal sparing surgery or renal arterial embolization Although patients with angiomyolipomas may develop renal insufficiency or failure due to chronic [ispub.com]
However, alternative treatment options should be seriously considered before opting for surgery because of the high incidence of complications and an increased risk of future renal insufficiency and end-stage renal failure. [symptoma.com]
The 2012 consensus guidelines specifically state that “[n]ephrectomy is to be avoided because of the high incidence of complication and increased risk of future renal insufficiency, end-stage renal failure, and the poor prognosis that results from CKD [cjasn.asnjournals.org]
Multiple bilateral lesions cause renal insufficiency in approximately 15% patients with tuberous sclerosis and this contributes significantly to the mortality and morbidity. [8], [28] Renal angiomyolipoma very rarely invades into the renal venous ststem [indianjurol.com]
- Renal Function Impairment
No rebleeding and no renal function impairment occurred during follow-up. CONCLUSIONS: AML embolization with EVOH copolymer is feasible, safe, and effective. EVOH copolymer could be another embolic option for AML treatment. Copyright © 2017 SIR. [ncbi.nlm.nih.gov]
Workup
Because patients don't usually present symptoms related to the disease, most RAML are incidental findings. They are rather easily detected on images obtained by means of sonography, radiography, computer tomography and magnetic resonance imaging [1]. Their distinction from other renal neoplasms is largely facilitated by their increased content of fat, which accounts for their characteristic, heterogeneous appearance. However, proportions of vascular tissue, smooth musculature, and proliferating adipocytes vary and atypical, minimal-fat RAML have been described. Up to 5% of all cases fall into this category [4]. Contrary to typical, triphasic RAML, these tumors present as homogeneous masses and resemble renal cell carcinoma on images. Several studies have been conducted to define parameters that may help to distinguish both types of neoplasms.
A detailed comparison of imaging findings characteristic of minimal-fat RAML and distinct types of renal cell carcinoma has recently been published by Lim et al. [5]. These authors have proposed the combination of hypointensity on T2-weighted images, low apparent diffusion coefficients, and avid early enhancement and washout on contrast-enhanced computer tomography or magnetic resonance imaging have been proposed as valuable for recognizing RAML [5]. Elsewhere, it has been stated that calcified areas are to be expected in renal cell carcinomas only [6], although statements to the contrary can also been found in the literature [7]. Still, these conclusions have not yet been validated on a larger scale and it may occasionally not be possible to reliably distinguish RAML from renal cell carcinoma if only imaging data are available.
Anamnestic data, results obtained during the histological examination of percutaneous biopsy specimens, and those of genetic analyses may support a tentative diagnosis of RAML. RAML are typically found in young women, while renal cell carcinomas are most commonly diagnosed in patients aged 40 to 60 years, unless they are related to hereditary diseases predisposing for tumor growth. Those patients previously diagnosed with tuberous sclerosis or lymphangioleiomyomatosis are much more likely to repeatedly develop RAML than renal cell carcinomas. With regards to the histological examination of tissue samples, due to the heterogeneity of RAML, it may be difficult to obtain representative specimens. Immunohistochemical staining for specific tumor markers, e.g., smooth muscle actin and HMB-45 for RAML and CD10 and CD34 for renal cell carcinoma, may nevertheless yield conclusive results [8]. Finally, the presence of mutations of tumor suppressor genes TSC1 or TSC2, which are associated with tuberous sclerosis and lymphangioleiomyomatosis and may be revealed by means of molecular biological techniques, indicate RAML.
Treatment
Periodic clinical and imaging assessments are recommended in cases of asymptomatic RAML and small tumor size, if malignancy is not suspected. Generally, patients are to be re-examined yearly. Sporadic RAML are expected to grow slowly, but rapid growth may be observed in tuberous sclerosis-related cases. It is important to remember to realize regular blood pressure measurements, because renal neoplasms may interfere with the kidney's function in blood pressure regulation. At the same time, renal parameters should be evaluated by means of blood sample analysis [9].
Few years ago, everolimus, an inhibitor of the mTOR pathway, has been approved to treat tuberous sclerosis- and lymphangioleiomyomatosis -associated RAML. The mTOR pathway has been shown to play a crucial role in the pathogenesis of those diseases [7] [10]. Cryoablation, radiofrequency ablation, and embolization of the renal artery have also been carried out to treat RAML, irrespective of their association to multi-system pathologies. The latter is of particular importance to avert the risk of hemorrhages and hemorrhagic shock; the former are typically considered in cases of small, but symptomatic RAML [4]. While low complication rates and a good preservation of renal function have been reported for cryoablation [11], the risk of re-intervention was significantly higher after embolization than in patients that underwent any other treatment [12].
Surgical interventions have been recommended for patients with symptomatic RAML, for those with tumors that measure more than 4 cm in diameter or that contain aneurysms of more than 5 mm in diameter, for women of childbearing age, and if malignancy cannot be excluded [7]. However, alternative treatment options should be seriously considered before opting for surgery because of the high incidence of complications and an increased risk of future renal insufficiency and end-stage renal failure [13]. Partial, total, or radical nephrectomy may be conducted. If the situation warrants surgery but a patient's general condition renders them ineligible for surgery, either of the aforementioned approaches may be chosen to delay tumor growth and to avoid possibly life-threatening ruptures of aneurysms until general improvement.
Prognosis
RAML are benign neoplasms and are generally associated with a good prognosis. However, literature contains isolated reports of spread to adjacent tissues, to the renal vein and inferior vena cava, to regional lymph nodes and even to the large intestine [1]. Presumably, such growth behavior is more likely in RAML of the epithelioid variant, a rare form of RAML that has also been designated atypical or oncocytoma-like RAML [14]. Epithelioid RAML differ from typical, triphasic RAML in that they are missing the characteristic vascular structures and adipocytes.
Etiology
RAML have originally been classified as hamartomas because they were thought to develop due to an abnormal proliferation of certain components of renal tissue. This classification has been revised and RAML are now listed as perivascular epithelioid cell tumors or PEComas. These tumors may grow at a variety of visceral and soft tissue sites and arise from clonal proliferation of epithelioid cells surrounding blood vessels [15]. While tuberous sclerosis and sporadic lymphangioleiomyomatosis have been related to mutations in either of the two tumor suppressor genes TSC1 or TSC2, little is known about the causes of sporadic RAML.
Epidemiology
RAML are the most common solid, benign kidney tumors. RAML and other perivascular epithelioid cell tumors are more common in women [15]. The female-to-male ratio is approximately 2:1, as has been confirmed in a large screening study for renal neoplasms conducted in Japan: Almost 18,000 individuals have been screened and RAML were detected in 0.22% of females and 0.1% of males [16]. The overall prevalence of RAML has been calculated to 0.13% [16].
About 20% of RAML patients suffer from tuberous sclerosis. The proportion of individuals affected by sporadic lymphangioleiomyomatosis is considerably lower because it is a rare disease.
Pathophysiology
RAML develop within the renal parenchyma and are well-circumscribed tumors that usually don't spread to the renal capsule or the perirenal space [7]. They are mesenchymal neoplasms typically composed of abnormal, eccentric and thick-walled vessels, smooth muscle cells of different maturation stages and adipocytes. While hemorrhages may be visible macroscopically or upon histological examination, necrotic foci are not characteristic of RAML. However, necrotic foci are not uncommon in the rare epithelioid subtype of RAML. This subtype is further characterized by an increased number of mitotic figures per microscopic field, which may be atypical [14]. The histological hallmark of epithelioid RAML is the near absence of vascular structures and adipocytes. Malignant potential has been ascribed to about a third of all cases of epithelioid RAML, which distinguishes this subtype from all other forms of RAML [14].
Prevention
Few recommendations can be given to prevent RAML: About 80% of all cases are sporadic and while one in five RAML patients does suffer from tuberous sclerosis, a hereditary disorder, this disease is often triggered by de novo mutations.
However, those affected by tuberous sclerosis are recommended to undergo regular imaging assessments to detect RAML at an early stage [13]. This way, therapy can be initiated in a timely manner and the risk of possibly life-threatening hemorrhages can be reduced. This also applies for patients with lymphangioleiomyomatosis.
Summary
An angiomyolipoma is a benign neoplasm of mesenchymal origin that mainly consists of dysmorphic blood vessels, smooth muscle cells, and mature adipose tissue - the name of this tumor derives from that particular composition of tissues [1]. Angiomyolipomas most commonly develop in the kidneys, but they may also be detected in the liver and, very rarely, in other organs. It has been estimated that about 80% of these tumors are sporadic, while the remaining 20% are developed by patients suffering from tuberous sclerosis or sporadic lymphangioleiomyomatosis [17]. At the same time, most individuals affected by tuberous sclerosis and about 60% of lymphangioleiomyomatosis patients eventually develop RAML [17].
It is important to distinguish between sporadic RAML and cases associated to the pathological conditions mentioned above: The course of the disease varies considerably depending on its etiology. In sporadic cases, solitary tumors are much more common. By contrast, tuberous sclerosis patients usually develop multiple RAML that affect both kidneys [1]. Also, tuberous sclerosis-related RAML tend to grow more rapidly and a reach larger size and than those affecting the general population. Large size is associated with an increased risk of hemorrhages and possibly hemorrhagic shock. Therefore, it is important to assess, and possibly re-assess, a tumor's size and vascularization. Besides imaging and histological data, these parameters are most important when deciding on one of several treatment options: surveillance, pharmacotherapy, cryoablation, radiofrequency ablation, embolization of the renal artery, or nephrectomy.
Patient Information
Renal angiomyolipoma (RAML) is a benign tumor of the kidney. Most cases are sporadic, i.e., they are not associated with any hereditary condition or pre-existing diseases. Sporadic RAML grow very slowly and don't usually cause any symptoms. Indeed, they are most commonly detected when individuals undergo diagnostic imaging of the abdomen for non-related reasons. By contrast, patients suffering from tuberous sclerosis or lymphangioleiomyomatosis should undergo regular imaging assessments because those disorders are known to predispose for RAML. About one in five RAML cases is not sporadic but related to either of the aforementioned pathologies. In individuals suffering from tuberous sclerosis or lymphangioleiomyomatosis, RAML tend to grow faster and reach larger sizes. Because large RAML often contain abnormal blood vessels that may eventually rupture, causing possibly life-threatening hemorrhages, alternative therapeutic approaches may be chosen: In case of sporadic RAML, patients are generally recommended for surveillance and periodic re-imaging, but larger tumors like those frequently found in those affected by tuberous sclerosis or lymphangioleiomyomatosis may require pharmacological treatment, minimally invasive or conventional surgery. The patient's prognosis is generally good, even more so in case of sporadic RAML. Tuberous sclerosis and lymphangioleiomyomatosis predispose for the development of certain types of tumors and while the current problem may be solved, recurrence is more likely.
References
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- Katada Y, Umehara I, Ohki T, Kishino M, Shibuya H. Bilateral renal angiomyolipoma in a patient with tuberous sclerosis treated with resection of one kidney and transarterial embolization of other kidney using CT during selective arteriography: a case report. Cases J. 2009; 2:6351.
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