Hemangioblastoma is an uncommon, benign neoplasm that mainly occurs in the CNS, especially in the cerebellum. EHs, also referred to as peripheral hemangioblastomas, are rare subsets of hemangioblastoma arising outside of CNS, but still within the nervous paraneuraxial structures, somatic tissues, and visceral organs. There have been about 200 cases of EH reported to date in the world literature, as part of VHL disease or in sporadic cases, and up to 140 cases were from nervous paraneuraxial structures (14). The sporadic primary hemangioblastomas of the kidney is an even rarer neoplasm. We have reviewed the English literature and found 25 cases of primary RH(Table 1) (2–17). Clinically, sporadic RH is found to be identical to other subtypes of EHs and the sporadic CNS hemangioblastoma, and has a benign outcome.
As detailed in Table 1, 25 patients with sporadic RH were adults and only one was a child (diagnosed with RH at age of 16 years)(5), with the median age at diagnosis of 47.5 years, ranging from 16 to 71 years. Fourteen patients were male and 12 patients were female, with male-to-female ratio of 1.17/1.0. In 15 of 26 cases, tumors were located in the right kidney, and the upper pole was the most common site of tumor. The average tumor size was 4.22 cm in the greatest dimension, ranging from 1.2 to 15 cm (5, 11). Overall, 60% of patients were asymptomatic, 24% had hematuria, 12% experienced lower back or abdominal pain, while only one patient presented with systemic symptoms, such as fever and weight loss (11). None of the patients included in this study had VHL disease (One RH case with possible VHL disease (13) was excluded from review.
Since this tumor is so rare, there were minimal descriptions of its characteristic radiological features. He et al. have described peripheral nodular enhancement in the corticomedullary phase, progressive centripetal enhancement in the nephrographic and delayed phases, and sometimes complete “filling in” in the delayed phase in 2 RH cases, which may be unique only to RH compared to other renal neoplasms (16).
All reported tumors were removed surgically. Almost all RH cases (25/26) showed unilateral, unifocal distribution, with the exception of one case (11) in which the patient had 3 lesions in the left kidney (right kidney uninvolved), and all lesions were confirmed as RH histologically. Macroscopically, RH displayed a solid, occasionally cystic cut surface (7). Microscopically, similarly to CNS hemangioblastoma, RH was composed of well-demarcated, large sheets of polygonal cells, with a prominent, arborizing vascular network. The tumor cells were varied in size with clear to eosinophilic cytoplasm, which commonly contained sharply delineated fine lipid vacuoles. The rhabdoid feature was rare, but was reported in one case (7). In majority of the cases, the tumor cells were bland looking (2), but some cases showed cells with mild to moderate nuclear pleomorphism (3). Mitotic figures were rare in the reported cases.
Immunohistochemically, as detailed in Table 2, almost all of the RH cases demonstrated diffuse positivity for alpha-inhibin (24/26), NSE (23/23), S100 protein (25/25), and vimentin(19/21), and negativity for neuroendocrine markers (synaptophysin, chromogranin A), melanocytic markers (HMB45, melan-A), endothelial markers (CD31, CD34), and mesothelial markers (calretinin, WT-1).
In 3/21 RH cases, tumor cells expressed focal, patchy positivity for AE1/AE3 (10, 16), including the present case. The majority of RH cases exhibited no immunoreaction for muscle, such as desmin (2–4), but two cases were noted to have focal expression of smooth muscle actin (2, 15). CD10 was reported positive in 7/16 cases (7, 8, 10, 14, 15). EMA was positive in 5/15 cases (4, 7, 8, 14, 15) and CAIX was positive in 3/4 cases (4, 8, 12).
Including the present case, the diffuse and strong nuclear positivity of PAX8 was observed in 8/14 cases (10–12, 14–16), and PAX2 was positive in 2 reported cases (8, 12). PAX8 and PAX2 are cell lineage specific transcription factors that play a crucial role in the organogenesis of the kidney (17). Both factors are expressed in normal kidneys as well as in many renal epithelial neoplasms such as renal cell carcinoma (RCC), although PAX8 is usually more sensitive. Zhao et al, has put forward a hypothesis suggesting that the immunoprofile of EH can vary with different sites of origin (10). With the findings of positivity for PAX8 and/or PAX2 in the above-mentioned 9 cases, we agree with the idea that RH is capable of expressing kidney-specific antigens.
RH is likely to be an underrecognized tumor of kidney due to its rarity. This indolent neoplasm can be mistaken for various malignancies, including clear cell RCC or epithelioid angiomyolipoma. Clear cell RCC share similar morphological characteristics with RH, such as a clear cytoplasm and prominent vascular network. The most useful feature to differentiate clear cell RCC from RH is the absence of fine cytoplasmic lipid vacuoles, which is predominantly present in RH. Immunohistochemically, clear cell RCC is usually positive for AE1/AE3, EMA, CAIX and CD10, but negative for alpha-inhibin, S100, and NSE. However, to add to the confusion, Montironi et al (18) have reported 2 cases of clear cell RCC with 60-70% of tumors showing hemangioblastoma-like features. In his reported cases, the tumor cells expressed alpha-inhibin and S100 in the hemangioblastoma-like part only (not in the clear cell RCC part), but PAX8, CD10, and RCC were positive in both components of the tumor. After carefully reviewing the histologic morphology in our present case, we have found ~10% of tumor cells showing clear cytoplasm, but all tumor cells stained consistently for S100, alpha-inhibin, NSE, Vimentin, and negative for CD10 and CAIX. These findings supported a diagnosis of RH. Another major mimicker of RH is epithelioid angiomyolipoma, which presents with a tumor that also possesses sheets of polygonal cells with an abundant cytoplasm and rich vascular network. The key feature to differentiate RH from epithelioid angiomyolipomas is that epithelioid angiomyolipomas usually show reticulated cytoplasm instead of a lipid containing vacuolated cytoplasm. Immunohistochemically, epithelioid angiomyolipomas are usually HMB45 positive, melan-Apositive, but alpha-inhibin negative.
Molecular analysis of sporadic RH has been reported in two studies (five patients) (12, 14). No VHL gene mutation, hypermethylation or loss of heterozygosity (LOH) of chromosome 3p were detected. We agree with the hypothesis put forward by Muscarella et al. that (1) the genetic changes may be localized to the intronic or regulatory regions of VHL gene; (2) the genetic anomaly may involve other genes, which interplay with VHL gene expression; (3) alternative tumor genetic mechanisms (14). To possibly answer these questions, we performed molecular analysis of our case using next generation sequencing including (xxxx genes). No significant gene mutations, including VHL gene and copy number changes were detected. Therefore, the tumor genetic mechanism of RH, at least in our case, remained unclear.