Angiomyolipoma (Angiomyolipomas)

Angiomyolipome der Niere CT[1]

Angiomyolipoma is a benign neoplasm of mesenchymal origin that primarily consists of proliferating adipocytes, smooth muscle cells, vascular structures, and macrophages. It most frequently affects the kidneys and may be associated with tuberous sclerosis.

Presentation

Most AML patients are asymptomatic. Here, AMLs are generally incidental findings, observed on images obtained for non-related reasons. In the case of symptomatic AML, patients may present with lower back and flank pain radiating from the affected kidney(s). Accordingly, hepatic AML may provoke upper abdominal pain, sensations of early satiety and fullness. Tumors may be palpable and sensitive to pressure. Renal AML may interfere with kidney function and affected individuals may claim hematuria.

Since about one in five AML patients suffers from TSC, symptoms related to this disease shall be briefly summarized here. Besides multiple mesenchymal tumors, mental retardation and epilepsy due to cortical dysplasia, as well as dermatological and dental anomalies, are typical of TSC. With regards to the former, numerous facial angiofibroma's distributed in a butterfly-like pattern are most characteristic of the disease, but patients may also present with ungual fibromas, retinal hamartoma, subependymal astrocytoma, rhabdomyoma, lymphangioleiomyomatosis and mesenchymal tumors of the kidneys and liver [14]. In this context, cysts are often observed in close proximity to multiple AML.

While tumor size upon the initial presentation of AML patients varies, TSC-associated AML is typically larger than those deemed sporadic. According to a retrospective study conducted in Egypt, TSC-related AML usually measure more than 15 cm in diameter at the time of diagnosis, while sporadic AML have a mean size of only 4 cm [7]. Similarly, growth rates differ largely (1.25 and 0.19 cm per year in the case of TSC-associated AML and sporadic tumor growth, respectively). As has been indicated above, sporadic cases of renal AML usually manifest in form of unilateral disease.

Vessels passing through AML are prone to aneurysm formation and rupture, and this particularly applies to larger tumors. Patients diagnosed with AML measuring more than 4 cm in diameter have a risk of more than 50% of spontaneous hemorrhages [15]. Such events may lead to anemia, but rupture of major vessels may also cause life-threatening blood loss. Affected patients may present with sudden-onset abdominal pain and hemorrhagic shock.

Workup

Diagnostic imaging allows for the detection of space-occupying masses in kidneys, liver or other tissues, and such findings often prompt a tentative diagnosis of tumor disease. Echography, magnetic resonance imaging, and computed tomography scans may also be carried out to determine the dimensions of such a mass and to ascertain which tissues are involved. Here, AML may appear as heterogenous tissue with a variable content of fat. It should be noted, though, that certain subtypes of AML have low-fat contents, and that malignant neoplasms may occasionally contain adipose tissue. These facts limit sensibility and specificity of imaging techniques for AML diagnosis, but renal or hepatic masses containing fat are considered highly suspicious of this type of tumor. Angiography may reveal those masses to be highly vascularized, another feature typical of AML. Arteries usually follow tortuous, irregular courses, and veins have been described to have a whorled, sunburst-like appearance [16]. Arteriovenous shunting and aneurysms are frequently observed.

Despite their characteristic appearance, AML are frequently misdiagnosed as lipoma, liposarcoma, renal cell carcinoma or hepatocellular carcinoma, or hemangioma. Thus, only histopathological analyses of tumor specimens, possibly combined with subsequent immunohistochemistry staining, allow for a definitive diagnosis of AML. Fine needle aspiration has been proposed to this end, but due to the heterogeneity of AML, findings largely depend on the site of sampling [17] [18].

Treatment

Treatment of AML depends on the overall condition of the patient, on whether the lesion is symptomatic or not, on the size of the tumor and angiographic findings. For small, asymptomatic AML, a conservative approach is usually recommended [17]. Cryoablation or radiofrequency ablation may be applied to this end; administration of mTOR inhibitors has also yielded promising results [19]. Either embolization of the renal artery or surgery may be indicated in case of larger, symptomatic renal AML. Embolization of the renal artery is a prophylactic measure aiming at reducing the threat imposed by spontaneous hemorrhages due to rupture of aneurysms. This minimally invasive procedure has traditionally been performed if the tumor size exceeded 4 cm, but angiographic findings should be considered when evaluating the possibility of embolization in the case of smaller tumors [20]. Similarly, larger tumors with low vascularity may not require embolization. Of note, embolization is less frequently used to treat hepatic AML. There is no general consensus as to the preference of embolization over early surgery or vice versa [21]. Removal of neoplastic tissue is usually curative, but patients diagnosed with epithelioid AML should be considered for adjuvant therapy [12]. With regards to renal AML, wedge resection or partial nephrectomy is preferred over total nephrectomy. Renal parenchyma should be preserved as much as possible.

Prognosis

Prognosis for AML patients is generally good. Retrospective studies have shown low rates of recurrence; malignant transformation and metastasis have only been described in occasional case reports. However, epithelioid AML may be associated with a less favorable prognosis. Literature holds contradictory information to that end: While in one study, all patients affected by epithelioid AML were found to have "died of neoplastic progression of the disease, with liver, lung and bone metastases" [12], other authors state the "the rate of aggressive behaviour among epithelioid angiomyolipomas (to be) very low" [13].

Etiology

AML are tumors mainly composed of adipose tissue, smooth muscle cells, vascular structures. Most cases are deemed sporadic, but about 20% of AML are encountered in TSC patients. TSC is a hereditary disease caused by mutations in either of the two tumor suppressor genes TSC1 and TSC2. These genes encode for hamartin and tuberin, respectively, and those proteins form a complex that inhibits the mTOR pathway. The respective signaling cascade has been shown to affect adipogenesis and angiogenesis, although it is more commonly related to the metabolism of striated muscle cells than to smooth musculature [4]. The mTOR pathway, more precisely the mTOR1 and mTOR2 pathways, depend on diverse stimulators and inhibitors, namely on nutrient and energy supply, the availability of oxygen, cytokines and growth factors, and regulate cell growth, division, differentiation, and death. Since histopathologically, there are no differences between sporadic and TSC-associated AML, it is tempting to speculate that at least part of those "sporadic cases" may be ascribed to gene defects associated with alterations of the mTOR signaling cascade [5]. Such has been proven for pulmonary lymphangioleiomyomatosis [6], a disease that may be accompanied by AML. Loss of heterogeneity of TSC1 and TSC2 has also been confirmed for hepatic AML [2].

Epidemiology

The overall incidence of AML has been estimated to be 0.3%, and this value is based on the detection of such tumors in autopsy studies. Women are affected more significantly than men [7].

About one in five cases can be related to TSC, with 80% and 30% of people diagnosed with this hereditary disorder developing renal and hepatic AML, respectively. Due to the prominent role of TSC in AML etiology, selected epidemiological data shall be presented in consideration of this disease: Most patients are middle-aged women, and the median age at diagnosis of sporadic AML is 49 years, while TSC patients developing AML have a median age of 26 years. As for sporadic AML, only 5% of patients present with bilateral tumors, but TSC is associated with bilateral AML in virtually all cases [7].

Sex distribution
Age distribution

Pathophysiology

Nowadays, AMLs are generally classified as PEComas, i.e., they are assumed to originate from degenerated perivascular epithelioid cells. At first glance, it may seem unlikely for AML to have a clonal origin, yet recent findings support that hypothesis and argue against the classical theory of AML being congenital malformations or hamartomatous polyclonal neoplasms [8]. Chromosomal aberrations are common, yet very heterogeneous if tumor specimens obtained from different patients are compared [9].

AML mainly consist of adipose tissue, smooth muscle cells, and vascular fragments. Depending on the prevailing tissue and the tumor's fat content as observed histopathologically, four subtypes of AML may be distinguished: lipomatous (≥70% fat), myomatous (≤10% fat), angiomatous and mixed [10]. An evaluation of smooth muscle cell morphology allows for an even more precise classification of AML, and these cells may appear spindle-shaped, be of the intermediate form, epithelioid or pleomorphic [11].

The afore-described subtypes differ with regards to their gene expression profiles, and presumably, chromosomal anomalies correlate with tissue composition, architectural features, and growth behaviour. While information regarding the prognostic value of an exact histopathological characterization is still scarce, epithelioid AML have been proposed to be re-classified as malignant neoplasms [12].

Prevention

No specific measures can be recommended to prevent AML. However, patients suffering from TSC may undergo regular screening to detect mesenchymal tumors during early stages. Then, therapy may be initiated before aneurysms develop within AML and the patient's risk of life-threatening hemorrhages due to aneurysm rupture can be diminished.

Summary

Angiomyolipoma (AML) is a benign mesenchymal tumor. It derives the name from its characteristic histopathological properties: mature adipose tissue, spindle-shaped smooth muscle cells and branched vessels prone to dilation and rupture. The most common subtype of AML is renal AML, and there are several hundred case reports concerning hepatic AML. Extrarenal, non-hepatic AML are extremely rare. While most cases are sporadic, it has been estimated that one in five cases of renal AML and one in ten cases of hepatic AML corresponds to manifest tuberous sclerosis (TSC). Moreover, renal AML are very common in TSC; hemorrhages due to rupture of aneurysms forming in AML are the leading cause of death in patients suffering from this genetic disorder [1]. Hepatic lesions, namely hepatic AML, adenoma, hemangioma and hepatic cysts are detected in about 30% of TSC patients [2]. Moreover, AML may be observed in patients diagnosed with lymphangioleiomyomatosis, neurofibromatosis type 1 and Von Hippel-Lindau disease [3].

The clinical presentation of AML patients varies largely and ranges from asymptomatic condition to abdominal pain to hemorrhagic shock. Most patients are indeed asymptomatic and here, AML is usually an accidental finding. Imaging techniques may reveal a space-occupying mass in renal, hepatic or other tissues, and may provide valuable information as to the properties of that mass. Nevertheless, only histopathological features are considered diagnostic of AML. Therapeutic strategies are adapted to the individual case and primarily depend on tumor size and the presence of aneurysms prone to rupture.

Patient Information

Angiomyolipoma (AML) is a benign neoplasm most commonly encountered in kidneys and liver. Its name is derived from its main components: branched vessels, smooth muscle cells and fat. Its etiology is only poorly understood, but considerable shares of AML patients suffer from tuberous sclerosis or lymphangioleiomyomatosis.

Women are affected significantly more often than men, and their median age at the time of diagnosis is 49 years. AML may be diagnosed incidentally, if images of the abdominal cavity are obtained for non-related reasons. Also, some patients manifest symptoms like lower back and flank pain (in case of renal AML), upper abdominal pain, early satiety and a feeling of fullness (due to hepatic AML). Tumors may interfere with organ function and patients may note blood in their urine. Rarely, sudden-onset abdominal pain and shock due to blood loss may prompt a suspicion of AML. The latter symptoms result from the rupture of vessels passing through the tumor.

Although life-threatening blood loss is a rare event in AML patients, it still poses a major threat. Consequently, treatment aims at eliminating this threat. This can be achieved by arterial embolization, i.e., by occlusion of the artery that supplies blood to the tumor. Another approach to AML treatment consists in the surgical removal of neoplastic tissue. Surgery is often curative, but tissue preservation may be better if a conservative approach and embolization are chosen. Preference of either therapy depends on the overall condition of the patient, on whether the lesion is symptomatic or not, on the size of the tumor and angiographic findings. Of note, current research is focused on drug therapy of AML, but to date, medication is not considered a first-line treatment option.

Self-assessment

References

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  2. Huang SC, Chuang HC, Chen TD, et al. Alterations of the mTOR pathway in hepatic angiomyolipoma with emphasis on the epithelioid variant and loss of heterogeneity of TSC1/TSC2. Histopathology. 2015; 66(5):695-705.
  3. Lowe LH, Isuani BH, Heller RM, et al. Pediatric renal masses: Wilms tumor and beyond. Radiographics. 2000; 20(6):1585-1603.
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  5. Kenerson H, Folpe AL, Takayama TK, Yeung RS. Activation of the mTOR pathway in sporadic angiomyolipomas and other perivascular epithelioid cell neoplasms. Hum Pathol. 2007; 38(9):1361-1371.
  6. Kristof AS. mTOR signaling in lymphangioleiomyomatosis. Lymphat Res Biol. 2010; 8(1):33-42.
  7. Seyam RM, Bissada NK, Kattan SA, et al. Changing trends in presentation, diagnosis and management of renal angiomyolipoma: comparison of sporadic and tuberous sclerosis complex-associated forms. Urology. 2008; 72(5):1077-1082.
  8. Paradis V, Laurendeau I, Vieillefond A, et al. Clonal analysis of renal sporadic angiomyolipomas. Hum Pathol. 1998; 29(10):1063-1067.
  9. Katter MM, Grignon DJ, Eble JN, et al. Chromosomal analysis of renal angiomyolipoma by comparative genomic hybridization: evidence for clonal origin. Hum Pathol. 1999; 30(3):295-299.
  10. Agaimy A, Vassos N, Croner RS, Strobel D, Lell M. Hepatic angiomyolipoma: a series of six cases with emphasis on pathological-radiological correlations and unusual variants diagnosed by core needle biopsy. Int J Clin Exp Pathol. 2012; 5(6):512-521.
  11. Nonomura A, Enomoto Y, Takeda M, Takano M, Morita K, Kasai T. Angiomyolipoma of the liver: a reappraisal of morphological features and delineation of new characteristic histological features from the clinicopathological findings of 55 tumours in 47 patients. Histopathology. 2012; 61(5):863-880.
  12. Varma S, Gupta S, Talwar J, Forte F, Dhar M. Renal epithelioid angiomyolipoma: a malignant disease. J Nephrol. 2011; 24(1):18-22.
  13. He W, Cheville JC, Sadow PM, et al. Epithelioid angiomyolipoma of the kidney: pathological features and clinical outcome in a series of consecutively resected tumors. Mod Pathol. 2013; 26(10):1355-1364.
  14. Northrup H, Krueger DA. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 Iinternational Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013; 49(4):243-254.
  15. Soulen MC, Faykus MH, Jr., Shlansky-Goldberg RD, Wein AJ, Cope C. Elective embolization for prevention of hemorrhage from renal angiomyolipomas. J Vasc Interv Radiol. 1994; 5(4):587-591
  16. Davis C, Boyett T, Caridi J. Renal artery embolization: application and success in patients with renal cell carcinoma and angiomyolipoma. Semin Intervent Radiol. 2007; 24(1):111-116.
  17. Pancholi V, Munjal K, Jain M, Munjal S, Agrawal R, Nandedkar S. Preoperative diagnosis of renal angiomyolipoma with fine needle aspiration cytology: a report of 3 cases. Acta Cytol. 2006; 50(4):466-468.
  18. Zeng JP, Dong JH, Zhang WZ, Wang J, Pang XP. Hepatic angiomyolipoma: a clinical experience in diagnosis and treatment. Dig Dis Sci. 2010; 55(11):3235-3240.
  19. Bissler JJ, McCormack FX, Young LR, et al. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med. 2008; 358(2):140-151.
  20. Kuusk T, Biancari F, Lane B, et al. Treatment of renal angiomyolipoma: pooled analysis of individual patient data. BMC Urol. 2015; 15:123.
  21. Faddegon S, So A. Treatment of angiomyolipoma at a tertiary care centre: the decision between surgery and angioembolization. Can Urol Assoc J. 2011; 5(6):E138-141.



Media References

  1. Angiomyolipome der Niere CT, CC BY-SA 3.0

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