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A 24-year-old lady presented with left flank pain of 3 months duration. She had stigmata of tuberous sclerosis complex in the form of angiofibromas on face, ash-leaf macules on back and right upper limb and shagreen patches over back. Computed tomography scan of the abdomen showed 6.5 cm × 5.0 cm × 4.4 cm lobulated intensely enhancing exophytic mass lesion in mid pole of left kidney with significant para-aortic lymphadenopathy with no evidence of fat in the mass. She underwent radical left nephrectomy with a provisional diagnosis of renal cell carcinoma. Histopathological examination showed multicenteric angiomyolipoma involving kidney and para-aortic lymph nodes. This case report underscores the need for further research to differentiate fat-poor angiomyolipoma and lymphadenopathy from renal cell carcinoma.
Renal angiomyolipoma (AML) is an uncommon benign tumor, which comprises of fat, abnormal blood vessels, and smooth muscle elements in varying proportions. Though it constitutes a small number (1–2%) of renal tumors in general population, 50–75% patients of tuberous sclerosis complex (TSC) develop renal AML. AML is classically diagnosed by identifying the intratumoral fat component as evident by negative attenuation on unenhanced Computed tomography (CT) scans. However, fat-poor AMLs defy diagnosis and raise the suspicion of renal cell carcinoma. This suspicion is further emboldened by the presence of enlarged regional lymph nodes and may result in radical nephrectomy. Diagnosis of AML after histopathological examination of the nephrectomy specimen and the lymph nodes coerces one to analyze retrospectively what could had been done to avoid this unnecessary surgery. Presently, there is lack of any conclusive diagnostic technique to solve this mystery. This report presents a case of fat-poor AML with para-aortic lymphadenopathy and entails an insight in various methods, which may be further refined to identify fat-poor AML so that a radical procedure can be avoided confidently.
A 24-year-old lady was receiving antiepileptic medication for the last 10 years. She had left flank pain for the last 3 months. An ultrasound of the abdomen revealed a left renal mass and she was referred to us for its evaluation. She had no bowel or urinary complaints. On general examination, there were angiofibromas on face, ash-leaf macules on back, and right upper limb and shagreen patches over back. Her abdomen was unremarkable. CT scan of the abdomen showed lobulated intensely enhancing exophytic mass lesion in mid pole of left kidney measuring 6.5 cm × 5 cm × 4.4 cm with para-aortic lymphadenopathy and no evidence of fat in the mass [Figure 1]. MRI of the abdomen revealed the same findings with no demonstration of fat in the mass [Figure 2]. MRI of brain showed multiple hyper-intense foci (tubers) in cortical/sub cortical location in bilateral cerebral parenchyma with streaky linear/radial hyper-intensities in cerebral white matters and subependymal nodules along lateral ventricles. A provisional diagnosis of TSC with left renal cell carcinoma (RCC) was made because of the absence of fat in the tumor and the presence of enlarged para-aortic lymph nodes. A left radical nephrectomy was performed in view of large size (>4 cm) and mid pole location of tumor, and substantial lymphadenopathy. Enlarged para-aortic lymph nodes (2 cm in size) were noted during the operation. The post operative period was uneventful. Histopathological examination of nephrectomy specimen showed multicenteric AML involving kidney and para-aortic lymph nodes [Figures [Figures33 and and44].
TSC, an autosomal dominant disorder results from inactivating mutations in either TSC1, located on chromosome 9q34, or TSC2, located on chromosome 16p13.3. The incidence of TSC at birth is estimated to be approximately 1 in 6000. Although many organs are susceptible, most patients exhibit dermatological, renal and neurological manifestations. Renal manifestations include AML (50–75%), benign cyst (17–35%), and renal cell carcinoma (1–2%). AMLs associated with TSC present at an earlier age than sporadic AMLs and tend to be larger, bilateral and do not have any predilection for sex. Classic AMLs are seen sporadically, most often in middle aged women and are usually unilateral.
With the widespread use of ultrasound, more AMLs are being diagnosed incidentally. On ultrasonography, a typical AML appears as a circumscribed, highly reflective mass, which is more echogenic relative to the renal parenchyma. The presence of posterior acoustic shadowing further distinguishes AML from renal cell carcinoma. These features, however, do not confirm the diagnosis. CT scan has been the most reliable modality for confirming the diagnosis of AML. Demonstration of even a small amount of fat within the renal tumor (–20 to –80 Hounsfield units) clinches the diagnosis of AML and virtually excludes renal cell carcinoma. However, one should be sure that the fat is intratumoral, and not the peri-renal fat that has been engulfed by an expanding renal cell carcinoma. A diagnosis of renal cell carcinoma is favored if there is evidence of calcification coexisting with fat. About 14% of AMLs have fat content low enough to be picked on radiographic imaging. One series of 129 AMLs have reported that 31.7% of AMLs had equivocal radiographic features. Prando A presented a series of 127 AML tumors and proposed a classification based on the radiological evidence of fat. He described four radiological patterns of fat distributions in AML ranging from predominantly fatty (pattern I) to without fat AML (Pattern IV). Pattern IV was seen in 6% tumors in this series which led to surgical removal of these tumors due to inability to distinguish them from renal cell carcinoma preoperatively. Our patient falls in pattern IV AML as no fat could be demonstrated radiologically in the tumor.
The natural history of renal AML has been largely unclear. These lesions tend to increase in size during adolescence and pregnancy suggesting the possibility of hormonal modulation in tumor growth. Reported complications of AML include spontaneous hemorrhage, end stage renal disease and malignant transformation.[7,8] Malignant transformation has been reported in epithelioid variety of AML where perivascular epithelioid cell has been identified as the fourth component.
More than 40 cases of lymph nodal angiomyolipoma associated with renal AML have been reported in the literature. Benign appearance of the tumor in the lymph nodes on histopathological examination and lack of evidence of distant spread or recurrence of the tumor on follow-up of these patients have suggested this phenomenon to be a part of multicenteric nature of the tumor rather than metastasis.
Managing AML is a challenging task considering difficulties in diagnosis and uncertainties in natural course of the disease. A rational approach has evolved based on tumor size, clinical course and symptomatology. Recommended options include observation, selective arterial embolization, or nephron preserving surgery. The risks of hemorrhage, tumor growth, and malignant transformation increase with tumor size. Asymptomatic AML of size less than <4 cm should be observed with ultrasonography every 1–3 years. Asymptomatic large (>4 cm) AMLs require sonographic evaluation every 6 monthly and increase in size will indicate need for intervention. Symptomatic small (<4 cm) AML may be observed for resolution of symptoms or intervention may be undertaken if symptoms fail to get relieved. Symptomatic and large (>4 cm) AML warrants treatment with either selective arterial embolization or nephron saving surgery. Recently, role of CT-guided radiofrequency ablation is also being explored as a minimally invasive modality for treatment of symptomatic AML especially in solitary kidney where maximal preservation of renal parenchyma is highly desired.
Dilemma in management starts when imaging fails to identify fat in AML. Presence of lymphadenopathy, as in our case, further confounds this issue as and raises the strong suspicion of renal cell carcinoma. This diagnostic dilemma ultimately forces the surgeon to undertake radical nephrectomy. Histopathological examination of nephrectomy specimen finally provides the diagnosis of multicenteric renal AML with lymph node involvement that leaves the surgeon perplexed because of inability to diagnose AML preoperatively. Various modalities are being investigated to solve this uncertainty of preoperative diagnosis of AML.
Fine needle aspiration cytology (FNAC) has been advocated to diagnose AML preoperatively. Various authors have concluded that preoperative diagnosis of AML can be made by image guided FNAC supplemented with immunochemical analysis of the smear with HMB-45.[12,13]
But FNAC has its own pitfalls. First, its accuracy to diagnose AML with certainty has been questioned. Moreover, FNAC cannot be considered to represent all the areas of the tumor. This becomes important in view of earlier case reports of renal cell carcinoma co-existing with AML.[15,16] Others reasons that have been cited to avoid FNAC are the risk of hemorrhage and the propensity of tumor seeding along the tract.
Intraoperative frozen section has also been investigated to diagnose AML so as to obviate the need for nephrectomy. In a study of 23 cases undiagnosed renal masses, intraoperative frozen section erroneously diagnosed two cases of AML as lymphoma and metastatic melanoma/sarcamatoid renal cell carcinoma. Algaba et al. cited a number of reasons for high false negativity of intraoperative frozen section including absence of feasible neoplasia (necrosis or fibrosis), cystic nature of tumor, inadequate sampling or representation of tumor, and the problems encountered when trying to preserve the typical cytoarchitecture of most of the carcinomas as frozen section. High false positivity of intraoperative frozen section may be attributed to the overvaluation of crushed tubules mimicking tumor, as well as the intrinsic limitations of the freezing method, that do not enable to precisely identify the size of the nucleus.
Both CT scan and MRI have been extensively studied to differentiate fat-poor AML from renal cell carcinoma. Kim JK et al., in their study 81 patients (19 fat poor AML and 62 RCC), concluded that biphasic helical CT may be useful in differentiating fat-poor AML from RCC, with homogeneous tumor enhancement and prolonged enhancement pattern being the most valuable CT findings. Pixel histogram analysis of unenhanced CT scan images fails to reliably distinguish fat-poor AML from renal cell carcinoma. Double-echo gradient-echo (GRE) chemical shift magnetic resonance (MR) imaging has also given encouraging results in differentiating fat-poor AML from renal cell carcinoma with a sensitivity and specificity of (a) 96% and 93%, respectively, with a signal intensity index of 25% and (b) 88% and 97%, respectively, with a tumor-to-spleen ratio of –32%.
We conclude there is need for search of new and effective criteria to differentiate fat-poor AML from RCC in the presence of lymphadenopathy.
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Conflict of Interest: None.