Final Diagnosis -- A 39-year old female with angiomyolipomsa

FINAL DIAGNOSIS:    ANGIOMYOLIPOMA WITH EPITHELIAL CYSTS (AMLEC).

DISCUSSION:

Angiomyolipomas (AMLs) are well-characterized triphasic tumors composed of varying amounts of vascular (thick-walled dysplastic or dysmorphic blood vessels), smooth muscle (spindled or epithelioid with clear cytoplasm) and mature adipose elements¹. AML usually occurs in the kidney, but can occasionally involve the liver and retroperitoneum. AML comprise 2.0-6.4% of all renal tumors, however they represent one of the most common benign renal lesions¹. AML can occur as an isolated renal lesion or as part of the tuberous sclerosis complex (TSC). Approximately 50% of patients with TSC develop AML, which tend to be bilateral and multifocal². The triphasic nature of AML has led many in the past to consider these lesions as hamartomatous. However, recent detection of clonal genomic alterations^3-5 and rare case reports of malignancy in AMLs^1,6-8 favor their classification as neoplastic lesions. AMLs share morphologic and immunohistological features with the perivascular epithelioid cell (PEC), and are considered to be members of the growing family of tumors derived from these distinctive cells, referred to as PEComas, and that includes clear cell ("sugar") tumors of the lung and pancreas, and lymphangioleiomyomatosis^9,10. Although the diagnosis of AML is usually straightforward, some cases showing predominance of any one of the AML components may mimic a number of lesions and lead to an erroneous diagnosis of malignancy, including liposarcoma (fat-predominant AML), leiomyoma (muscle-predominant AML), renal cell carcinoma (epithelioid AML), and vascular malformations (paucicellular, vascular-predominant AML)11. The evolution of AML is classically benign, but malignant transformation has been rarely reported in 12 cases to date^1,6-8.

AMLs are typically solid lesions both radiologically and grossly¹, without cystic or epithelial components. Although entrapped non-cystic renal tubules have been described in AML, presentation as a cystic mass has been reported recently in only 16 cases^11-13. This distinctive benign renal neoplasm has recently been recognized and seperately termed angiomyolipoma with epithelial cysts (AMLEC) by Fine and colleagues¹¹ or cystic angiomyolipoma by Davis and colleagues¹². These descriptive names for this entity are currently favored until its pathogenesis and relationships to other renal neoplasms are better understood. Therefore, AMLEC or cystic AML has to be considered in the differential diagnosis of adult cystic renal neoplasms, which includes cystic renal cell carcinomas, cystic nephroma (CN), and mixed epithelial and stromal tumor (MEST). The most distinctive immunohistochemical feature of AMLEC or cystic AML, absent in the above three tumors mentioned earlier is immunoreactivity with melanocytic markers (HMB45 and Melan-A)^11-13.

The renal tumor herein presented was histologically and immunophenotypically diagnostic of muscle-predominant AML containing prominent and grossly evident epithelial cysts. This phenotype is distinctly unusual, as AMLs are typically solid¹. Bilateral or multiple AMLs have been considered presumptive evidence of, or diagnostic of, TSC². The case herein presented had no personal or family history of TSC. Of the 16 previously reported cases of AMLEC^11-13, only one was associated with TSC, suggesting that this rare variant of AML may not be related to TSC. Additionally, the female/male ratio is 10/6 for these 16 cases of AMLEC, indicating a slight female predominance for AMLEC. Therefore, unlike MEST which is considered estrogen hormone dependent because of its almost exclusive occurrence in females, AMLEC may be estrogen hormone independent. AMLs have been considered benign lesions and those found in the kidney are generally managed conservatively. Partial nephrectomy or angiographic embolization has been recommended for symptomatic lesions and lesions greater than 4-cm, and most asymptomatic lesions are followed with interval abdominal imaging¹⁴. However, 12 cases of metastatic AML have been reported^1,6-8. Though the asymptomatic cystic renal tumor in the case herein presented was less than 4-cm in greatest dimension, definitive surgical treatment was pursued because of the presence of a radiologically enhancing nodule in the cyst wall, which was worrisome for malignancy.

AMLEC are readily distinct from most adult cystic renal lesions. The chief differential diagnostic consideration for AMLEC or cystic AML is mixed epithelial and stromal tumor (MEST), previously classified as cystic hamartomas of the renal pelvis, adult mesoblastic nephroma, or renal pelvic or cortical hamartomas^11-13. Immunohistochemically, the stroma of both AMLEC and MEST labels for smooth muscle actin, desmin, ER, and PR^11-13. However, the most distinctive immunohistochemical feature of AMLEC or cystic AML, absent in all the differential diagnostic considerations mentioned above, is immunostaining with melanocytic markers (HMB45 and Melan-A)^11-13. The other important benign differential diagnostic consideration for AMLEC or cystic AML is cystic nephroma (CN). The main malignant differential diagnostic consideration for AMLEC or cystic AML is multilocular cystic renal cell carcinoma. Based on the results of immunohistochemical staining in the case herein presented, cystic and sarcomatous renal cell carcinoma (HMB45 negative), cystic nephroma (HMB45 negative), mixed epithelial and stromal tumor (HMB45 negative), leiomyosarcoma (HMB45 negative), and melanoma (HMB45 positive, S-100 protein positive) were excluded as differential diagnoses. The presence of HMB45 in PEC of AML has been widely recognized as a specific finding, however, that of c-kit (CD117) has not been as common^4,6,9. According to recent reports, c-kit is also expressed in renal oncocytoma (71%), chromophobic renal cell carcinoma (85%) and even in PEC in classic AML^15,16. The tumor herein presented was not immunoreactive for c-kit.

The histogenesis of AMLEC or cystic AML is unclear. However, the histogenesis of the mullerian-like stroma in AMLEC has been postulated to be due to the embryological proximity between the urinary and genital systems¹¹. These two systems share common origin from the urogenital ridge, and it has been postulated that disturbances during a critical period in development may lead to crossover of epithelium or mesenchymal elements between the two systems, predisposing to neoplasms that combine these features¹¹. The strong HMB-45 positivityof the "cambium-like" layer of compact subepithelial cells in AMLEC supports the concept that they are a variant of AML, although their morphology is distinctly different from the exterior muscle-predominant AML wall. The mullerian histomorphology and peculiar immunohistochemical profile (HMB45+, Melan-A+, ER+, PR+, and CD10+) of the compact subepithelial cells suggests both mullerian and melanocytic differentiation of PECs in AMLEC, a rare variant of AML^11-13. This observation of dual differentiation is not unprecedented in AML, since the smooth muscle cells of AMLs are known to have both melanocytic and muscular features^1,4,6,9. The minimal immunoreactivity for muscle markers in this subepithelial zone suggests that these cells have lost some of their muscular phenotype while developing a mullerian phenotype. Apart from the fact that the presence of epithelium is extremely uncommon in AML and has been reported previously in only 16 cases^11-13, the nature of the epitheliumwithin AMLEC is also controversial. Davis and colleagues¹² favored the view that the epithelial component of AMLEC represented true epithelial differentiation by the AML, whilst Fine and colleagues¹¹ favored the view that it mainly represented dilated entrapped native renal collecting duct epithelium. Both views are plausible.

In conclusion, AMLEC should be routinely included in the differential diagnostic considerations for adult cystic renal neoplasms, which includes cystic renal cell carcinomas, cystic nephroma (CN), and mixed epithelial and stromal tumor (MEST). Although, AMLEC may be confused with MEST, the most distinctive feature is the fact that AMLEC is immunoreactive to melanocytic markers (HMB45 and Melan-A)^11-13.

REFERENCES:

1. L'Hostis H, Deminiere C, Ferriere JM, Coindre JM: Renal angiomyolipoma: a clinicopathologic, immunohistochemical, and follow-up study of 46 cases. Am J Surg Pathol 1999, 23(9):1011-1020.
2. Neumann HP, Schwarzkopf G, Henske EP: Renal angiomyolipomas, cysts, and cancer in tuberous sclerosis complex. Semin Pediatr Neurol 1998, 5(4):269-275.
3. Green AJ, Sepp T, Yates JR: Clonality of tuberous sclerosis harmatomas shown by non-random X-chromosome inactivation. Hum Genet 1996, 97(2):240-243.
4. Martignoni G, Pea M, Bonetti F, Zamboni G, Carbonara C, Longa L, Zancanaro C, Maran M, Brisigotti M, Mariuzzi GM: Carcinomalike monotypic epithelioid angiomyolipoma in patients without evidence of tuberous sclerosis: a clinicopathologic and genetic study. Am J Surg Pathol 1998, 22(6):663-672.
5. Kattar MM, Grignon DJ, Eble JN, Hurley PM, Lewis PE, Sakr WE, Cher ML: Chromosomal analysis of renal angiomyolipoma by comparative genomic hybridization: evidence for clonal origin. Hum Pathol 1999, 30(3):295-299.
6. Cibas ES, Goss GA, Kulke MH, Demetri GD, Fletcher CD: Malignant epithelioid angiomyolipoma ('sarcoma ex angiomyolipoma') of the kidney: a case report and review of the literature. Am J Surg Pathol 2001, 25(1):121-126.
7. Martignoni G, Pea M, Rigaud G, Manfrin E, Colato C, Zamboni G, Scarpa A, Tardanico R, Roncalli M, Bonetti F: Renal angiomyolipoma with epithelioid sarcomatous transformation and metastases: demonstration of the same genetic defects in the primary and metastatic lesions. Am J Surg Pathol 2000, 24(6):889-894.
8. Park HK, Zhang S, Wong MK, Kim HL: Clinical presentation of epithelioid angiomyolipoma. Int J Urol 2007, 14(1):21-25.
9. Bonetti F, Pea M, Martignoni G, Doglioni C, Zamboni G, Capelli P, Rimondi P, Andrion A: Clear cell ("sugar") tumor of the lung is a lesion strictly related to angiomyolipoma- the concept of a family of lesions characterized by the presence of the perivascular epithelioid cells (PEC). Pathology 1994, 26(3):230-236.
10. Zamboni G, Pea M, Martignoni G, Zancanaro C, Faccioli G, Gilioli E, Pederzoli P, Bonetti F: Clear cell "sugar" tumor of the pancreas. A novel member of the family of lesions characterized by the presence of perivascular epithelioid cells. Am J Surg Pathol 1996, 20(6):722-730.
11. Fine SW, Reuter VE, Epstein JI, Argani P: Angiomyolipoma with epithelial cysts (AMLEC): a distinct cystic variant of angiomyolipoma. Am J Surg Pathol 2006, 30(5):593-599.
12. Davis CJ, Barton JH, Sesterhenn IA: Cystic angiomyolipoma of the kidney: a clinicopathologic description of 11 cases. Mod Pathol 2006, 19(5):669-674.
13. Armah HB, Ming Y, Rao UNM, Parwani AV: Angiomyolipoma with epithelial cysts (AMLEC): a rare but distinct variant of angiomyolipoma. Diagn Pathol 2007, 2:11.
14. Steiner MS, Goldman SM, Fishman EK, Marshall FF: The natural history of renal angiomyolipoma. J Urol 1993, 150(6):1782-1786.
15. Makhlouf HR, Remotti HE, Ishak KG: Expression of KIT (CD117) in angiomyolipoma. Am J Surg Pathol 2002, 26(4):493-497.
16. Petit A, Castillo M, Santos M, Mellado B, Alcover JB, Mallofre C: KIT expression in chromophobe renal cell carcinoma: comparative immunohistochemical analysis of KIT expression in different renal cell neoplasms. Am J Surg Pathol 2004, 28(5):676-678.

Contributed by Henry Armah, MD, and Anil Parwani, MD, PhD