Sporadic Hemangioblastoma of the Kidney: A clinicopathologic study of 3 cases and review of the literature

Background: Hemangioblastoma is a benign tumor of unknown histogenesis that mainly occurs in the central nervous system (CNS) associated with von Hippel-Lindau (VHL) disease. Much attention has been paid to the renal hemangioblastoma, but there are still some challenges in the differential diagnosis. Case presentation: Here, we describe three cases of sporadic renal hemangioblastoma with no clinical features of VHL diseases. All the three patients (male: 2; female: 1) were 40-56 years old. In all cases, the tumors were surrounded by a thick brous capsule and well-demarcated from the surrounding renal parenchyma. Tumors were composed of sheets or nests of polygonal to short spindle tumor cells and a rich capillary network. In case 1 and case 3, the large polygonal tumor cells contained abundant pale or eosinophilic cytoplasm, and some of the cells possessed intracytoplasmic lipid vacuoles. In case 2, tumor cells were characterized by uniform size, mild, clear or lightly stained cytoplasm and typical "clear cell" appearance. In the views of immunohistochemistry, the polygonal stromal cells were strongly and diffusely positive for α-inhibin, NSE, S100 protein, and vimentin. CD10 and PAX8 were positive, while EMA and CK showed focally positive in case 3. CK8/18, HMB45, MelanA, CgA, Syn, SMA, Desmin and CD56 were all negative. CD34 and CD31 outlined the contours and distribution of vascular networks in tumors. Conclusions: Renal hemangioblastoma is rare and prone to be misdiagnosed. More attention should be paid to the morphological features and reasonable application of immunohistochemistry for the diagnosis of hemangioblastoma.


Background
Hemangioblastoma, a benign tumor of unknown histogenesis, mainly occurs in the central nervous system (CNS), such as cerebellum, brainstem and medulla oblongata. In a large number of cases, the pathogenesis of hemangioblastoma is associated with von Hippel-Lindau (VHL) disease that is an autosomal dominantly inherited neoplastic disorder with germline mutations in the VHL gene on chromosome 3p25. Whereas, in most of the other cases, the onset of hemangioblastoma is usually sporadic (1). It has been reported that hemangioblastoma may occur outside the CNS such as soft tissue, peripheral nerve, bone, skin, liver, lung, pancreas, kidney, retroperitoneum, bladder, adrenal gland, and gastrointestinal tract (2). Differential diagnosis of sporadic renal hemangioblastoma is a huge challenge in clinical settings as it is similar to other malignancies such as renal cell carcinoma (RCC). In this case report, we presented three cases of sporadic renal hemangioblastoma without clinical evidence of VHL disease. Meanwhile, a literature review was performed to further understand the clinicopathologic features and differential diagnosis of this rare renal tumor.

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The tumor samples were obtained from all cases after nephrectomy. Then the samples were xed in 10% buffered formalin and embedded in para n. The sections (4 µm) were stained with hematoxylin and eosin. The histological features of the tumor mass were evaluated by two experienced pathologists.
Immunohistochemistry stain was conducted with Ventana BenchMark XT automated IHC stainer (Roche, Basel, Switzerland). Sections treated with PBS served as negative control, and the positive control was using the speci c tissues according to the manufacturer's instructions. Antibody information was given in Table 1. A 40-year-old male showed a hyperechoic mass in the middle pole of the right kidney after ultrasonography. Color doppler ow indicated shifted peripheral vessels around the mass and abundant blood ow signals. CT examination showed a heterogeneous soft tissue mass in the middle later pole of the right kidney, which showed obvious inhomogeneous enhancement after intensity (Fig. 1A). On this basis, RCC was suspected. The patient had no familial history or clinical evidence of VHL disease. An encapsulated tumor (3 × 3 × 3 cm) was seen to protrude outward from the kidney after nephrectomy. The cut surface was in a color of grayish-red or grayish-brown. The tumor mass was solid and tough, with no necrosis or cystic degeneration (Fig. 1B). The patient was followed up for at least 9 years with no tumor recurrence or metastasis.

Case 2
A healthy 45-year-old female was admitted to the hospital after trauma. CT scan displayed a round mass in the middle pole of the right kidney, with a diameter of about 3 cm. The tumor showed a clear boundary.
CT scan showed equal and low confounding density, together with signi cant strengthening after enhancement (Fig. 1C). The clinical diagnosis was RCC and radical nephrectomy was carried out. For the macroscopic observation, there was a round tumor in the middle of the kidney (2 cm × 2 cm × 2 cm) and with complete capsule. The cut surface was in a grey-red or grey-brown color with a little grey-white at the center. The tumor was solid and tough, with no necrosis or cystic changes (Fig. 1D). She had no erythrocytosis, and no VHL-related tumors were detected. The patient was followed up for 6 years, and no tumor recurrence or metastasis was seen.

Case 3
A 56-year-old male was admitted to our hospital because of schizophrenia. CT scan indicated a round mass (8 cm) at the dorsal side of the right kidney. The lesion presented a clear boundary, which protruded to the extrarenal region. Meanwhile, low density necrosis was observed in it. There was a remarkable enhancement in arterial stage, but no enhancement was noticed in internal necrosis (Fig. 1E). Then the right kidney was removed by nephrectomy. A well circumscribed, soft gray-brown color tumor (8 cm × 7 cm × 5 cm) was observed in the middle of the kidney (Fig. 1F). The patient had no familial history or clinical evidence of VHL disease. The patient was still alive and was followed up for at least 5 years.

Microscopic features
In all cases, the tumors were surrounded by a thick brous capsule and well-demarcated from the surrounding renal parenchyma ( Fig. 2A). Tumors were composed of sheets or nests of polygonal to short spindle tumor cells and a rich capillary network. In case 1 and case 3, the large polygonal tumor cells contained abundant pale or eosinophilic cytoplasm, and some of the cells possessed intracytoplasmic lipid vacuoles. In case 1, there were diverse cell morphology, varying nuclear size and atypical of partial cells ( Fig. 2B and 2C). However, tumor cells were characterized by uniform size, mild, clear or lightly stained cytoplasm and typical "clear cell" appearance in case 2 (Fig. 2D). No mitosis and necrosis were found in all cases. Signi cant hyaline degeneration of stromal cells could be seen in case 3 as well as psammoma-like calci cation ( Fig. 2E and 2F). In all 3 cases, there were edema and hemosiderin deposition in the interstitium.
Ki67 showed a proliferative index of less than 3%.
Their clinical characteristics, along with three cases in current study, were summarized in Table 2.
Twenty-one of 24 cases in the literature as well as our 3 cases have completely clinical data. The tumors in 19 cases (70.3%) were located in the right kidney and most of the patients were male (17/26, 65.4%). Among the male cases, 14 (53.8%) were aged < 50 yrs (ranged 16-71, mean age 45. 19) and the tumor size was in a range of 1.2 cm-15 cm (mean size 4.2 cm). The sporadic renal hemangioblastomas was more likely to occur in the right kidney. It seemed that such disease was more prone to present in the young adults, but further patients are required in future to further con rm this phenomenon. There were no signi cant clinical symptoms, and occasional symptoms such as lumbar pain or hematuria were observed, in which only 1 case showed polycythemia. CT scan showed clear round or quasi-round lowdensity mass in the renal parenchyma, which presented uneven enhancement after enhanced scan. It would be easily misdiagnosed as clear cell RCC or angiomyolipoma. Interestingly, Michele et al found most of cases reported in the literature were from the Far East, and considered that there might be an unknown genetic feature common to members of a particular ethnic or racial group (2). Macroscopically, most tumors appear as well-de ned masses surrounded by a thick brous capsule, only 2 cases presented areas of poorly marginated growth or the tumor broke through the brous capsule (5,10). In contrast to CNS hemangioblastoma, renal tumors generally presented as a solid mass, occasionally with small focal cystic changes (6,14). The cut surface often show grayish white, grayish yellow, grayish brown or red-brown to gray-yellow color, foci hemorrhage and necrosis were observed incidentally (12).
Histologically, renal hemangioblastomas had been well demarcated from the surrounding renal parenchyma, and some cases showed brous pseudocapsule. Similar to CNS hemangioblastoma, renal hemangioblastoma was composed of large, polygonal vacuolated stromal cells and a rich capillary network. According to the abundance of stromal cells, tumors were divided into cellular and reticular subtypes. Tumor cells were mild, presenting round nuclei with ne chromatin, microvacuoles within cytoplasm and rich in lipids. Eosinophilic hyaline globules were found both within tumor cell cytoplasm and within the stroma in 2 cases (6,11). Atypical cells and cells with rhabdoid features presented in some cases, which may be mistaken for a malignant tumor (12,16). In addition, a few mitotic activity and focal necrosis were also been documented (10,12). Except classical rich capillary network, dilated thick-walled vessels which similar to the thick-walled veins in angiomyolipoma could be observed in renal hemangioblastoma and stromal edema, brotic, hyalinization are also common ndings. Focal calci cation of the brous stroma and psammoma body-like calci cations were described by some studies (8,11,14). In this study, tumor cells distributed in sheets or lobular, with abundant eosinophilic cytoplasm and partly had lipid vacuoles (case1 and case 3). In some areas, atypical cells could be seen in case 1. In case 2, the stromal cells were scattered in small nests among the vascular networks and showed a transparent cytoplasm. Signi cant hyaline degeneration of stromal cells could be seen in case 3, together with psammoma-like calci cation. Edema, hemosiderin deposition was observed in the interstitium in all 3 cases.
VHL disease is an autosomal dominant hereditary disorder leading to clear cell tumors in various organs, such as CNS hemangioblastoma, pancreatic microcystadenoma, pheochromocytoma, epididymal papillary cystadenoma, endolymphatic sac tumor of the inner ear, and renal clear cell carcinoma. VHL gene is located at the short arm of chromosome 3 (3p26-P25). Its inactivation will lead to VHL protein synthesis disorder, which plays a key role in the regulation of the hypoxia response pathway. About 25% of CNS hemangioblastomas are associated with VHL disease and 75% are sporadic. Renal hemangioblastoma were generally considered to be independent of VHL genetic mutations, as aberration VHL gene has been detected in none of the cases previously reported. However, Xu et al (8) reported that a tumor type showing VHL gene mutation and hypermethylation in exon 2. We consider that the relationship between renal hemangioblastoma and VHL gene remains uncertain and more studies are needed.
Renal hemangioblastoma is rare and is most likely to be misdiagnosed as clear cell RCC as it is characterized by a rich vascular network and epithelioid cells with clear or eosinophilic cytoplasm. In terms of organizational structure, sheet-like or compact architecture were common features of hemangioblastomas. In contrast, clear cell RCC is more likely to be characterized by tubular, alveolar, nests or papillary structures. In clinical settings, it might be a clue for the differential diagnosis of hemangioblastomas. Additionally, immunohistochemistry plays a key role in distinguishing clear cell RCC from hemangioblastoma. In the views of immunohistochemisty, NSE, S100 and α-inhibin were expressed in almost all hemangioblastomas, while there was no expression in clear cell RCC. Meanwhile, clear cell RCC is usually positive for AE1/AE3, PAX8, PAX2, CD10 and CA9.
However, there were two cases of clear cell RCC with hemangioblastoma-like features in the recent years (20,21). Meanwhile, some RCC markers were positive in hemangioblastoma as above-mentioned. Therefore, a panel of antibodies were required for differential diagnosis. Another major confused tumor is epithelioid angiomyolipoma (AML), which could be based on the presence of large thick-walled veins, spindle smooth muscle bundles and various proportion of mature adipose tissue. Immunohistochemically, AML showed positive staining for HMB45, and MelanA while showed a negative reaction for α-inhibin, NSE, S100 in contradistinction to hemangioblastoma. Other differential diagnosis included adrenocortical adenocarcinoma and paraganglioma, which could be distinguished by careful morphological observation and adequate immunohistochemistry.

Conclusion
Renal hemangioblastoma is a rare tumor with benign nature. We reported 3 cases with renal hemangioblastoma and reviewed the literatures. Clinically, it occurs in middle-aged and younger population. In the micromorphological views, it shared similarities with clear cell RCC and AML. Genetically, renal hemangioblastoma appeared to have no related to VHL gene defects, but VHL gene mutations were found in limited cases. Recognition of this tumor and careful immunohistochemistry investigation are keys to a correct pathological diagnosis.