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Applied Immunohistochemistry & Molecular Morphology:
doi: 10.1097/PAI.0b013e3181daad26
Case Reports

Soft-tissue Hemangioblastoma of the Retroperitoneum: A Case Study and Review of the Literature

Yoshida, Akihiko MD* †; Oda, Rie MD*; Shibahara, Junji MD, PhD; Fukayama, Masashi MD, PhD; Tsuda, Hitoshi MD, PhD*

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*Clinical Laboratory Division, National Cancer Center Hospital

Department of Pathology, University of Tokyo, Tokyo, Japan

Reprints: Akihiko Yoshida, MD, Clinical Laboratory Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo Japan (e-mail:

Received for publication January 10, 2010; accepted February 23, 2010

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A 71-year-old woman was found to have a solid retroperitoneal mass measuring 7×6 cm on a computed tomography scan. The tumor was not connected to the spinal cord or large nerves. It was resected and showed the typical histology of hemangioblastoma, that is, numerous capillaries and stromal cells with focal cytoplasmic vacuolization. Immunohistochemical study revealed that the tumor stromal cells were positive for S-100 protein, neuron-specific enolase, and inhibin-α, supporting the diagnosis. In addition, the tumor cells labeled for carbonic anhydrase IX and brachyury. The diffuse strong carbonic anhydrase IX expression suggested that soft-tissue hemangioblastoma may share with central nervous system hemangioblastoma the tumorigenic mechanism involving the von Hippel-Lindau gene product and hypoxia-inducible factor. The brachyury expression observed in this case, albeit focal and weak, may implicate embryonic hemangioblasts as a potential line of differentiation, as was proposed in central nervous system hemangioblastoma. The patient is well 4 years after the surgery without any recurrence. A review of the literature revealed that soft-tissue hemangioblastoma is typically a solid tumor found in older females and often involves the retroperitoneum/pelvis.

Capillary hemangioblastoma (HB) is an uncommon neoplasm of uncertain histogenesis.1,2 It can occur sporadically or in association with von Hippel-Lindau (VHL) disease, an autosomal dominant neoplastic syndrome. HB occurs most commonly in the cerebellum and less commonly at other sites in the central neuraxis such as the brain stem, spinal cord, nerve roots, retina, and supratentorial compartment.1,2 Isolated cases involving extraneural tissues such as the liver, lung, skin, adrenals, bladder, pancreas, maxillary bone, kidney, and nasal skin have also been documented.3 HB arising in soft tissues is rare, and less than 10 such cases have been reported.3–9 Herein, we describe a HB occurring in the retroperitoneal soft tissue of a patient without VHL, and we present a review of literature to better delineate the clinicopathologic characteristics of this type of tumor.

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A retroperitoneal mass was found in a 71-year-old woman during a radiologic work-up after recent surgery for papillary thyroid carcinoma. The patient's family history was significant for gastric cancer and colon cancer, but no VHL-related tumors were recorded. The patient herself also lacked the signs of VHL syndrome. On a computed tomography (CT) scan, the tumor measured 7×6 cm, was located in the paraspinal/retrocrural region, and surrounded laterally by the right kidney, anteromedially by the inferior vena cava, and posteromedially by the right borders of Th11-12 vertebral bodies (Fig. 1). The tumor did not involve the spinal canal. Contrast study showed a strong enhancement in the early phase with rapid wash-out in the late phase. Magnetic resonance imaging revealed that the tumor was T1-low T2-high with marked gadolinium enhancement. The radiologic differential diagnoses included paraganglioma and solitary fibrous tumor. Laboratory data were unremarkable. Needle biopsy was not attempted because of the hypervascularity of the lesion. After transarterial embolization, the patient underwent tumor resection 3 months after tumor presentation. The patient is well 4 years after the surgery and CT reveals no evidence of recurrence.

Figure 1
Figure 1
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The resected specimen was fixed in 10% buffered formalin, routinely processed, and stained with hematoxylin and eosin. Immunohistochemical analysis was done with antibodies to the followings: AE1/AE3 (AE1/3; 1:100; Dako, Glostrup, Denmark), epithelial membrane antigen (EMA) (E29; 1:100; Dako), vimentin (V9; 1:200; Dako), smooth muscle actin (SMA) (1A4; 1:100; Dako), desmin (D33; 1:100; Dako), calponin (CALP; 1:200; Dako), S-100 protein (polyclonal; 1:1000; Dako), HMB45 (HMB45; 1:10; Dako), glial fibrillary acidic protein (GFAP) (polyclonal; 1:1000; Dako), CD57 (HNK-1; 1:100; Becton Dickinson, San Jose, CA), neuron-specific enolase (NSE) (BBS/NC/V1-H14; 1:200; Dako), CD34 (MY10; 1:100; Becton Dickinson), synaptophysin (polyclonal; 1:500; Dako), chromogranin A (polyclonal; 1:500; Dako), inhibin-α (R1; 1:100; AbD Serotec, Oxford, UK ), carbonic anhydrase IX (CA IX) (polyclonal; 1:1000; Novus Biologicals, Littleton, CO), brachyury (polyclonal; 1:500; Santa Cruz Biotechnology, Santa Cruz, CA), and Ki-67 (MIB-1; 1:100; Dako).

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Pathologic Findings

The resected specimen showed a 7.2×6.0×5.5 cm well-circumscribed nonencapsulated dull yellow rubbery mass adjacent to the psoas muscle (Fig. 2). The tumor was solid, without a large cystic component. No grossly visible peripheral nerves were associated with the tumor. The microscopic findings were typical of HB and indistinguishable from those of cases involving the central nervous system (CNS). Under low magnification, the tumor seemed lobulated because of the large branching “hemangiopericytomatous” vasculature (Fig. 3A). A rich capillary meshwork was observed between such vessels, along with intervening epithelioid stromal cells (Fig. 3B). The stromal cells had a lightly eosinophilic or multivacuolated cytoplasm (Fig. 3B, inset) and hyperchromatic, often irregularly contoured, nuclei. No mitotic figures were observed. The tumor interstices showed focal hyalinization and microscopic cystification. No necrosis was seen. Extramedullary hematopoiesis was not identified. Even a careful search did not reveal microscopic nerve bundles associated with the tumor. The resection margin was negative. Immunohistochemical analysis revealed that the tumor stromal cells labeled for vimentin, S-100 (Fig. 4), NSE, inhibin-α (focal), CD57, CA IX (strong diffuse membranous, Fig. 4), and brachyury (focal weak, Fig. 4), whereas they were negative for AE1/AE3, EMA, SMA, desmin, calponin, HMB45, GFAP, CD34, synaptophysin, and chromogranin A. Ki-67 decorated less than 1% of the tumor cells.

Figure 2
Figure 2
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Figure 3
Figure 3
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Figure 4
Figure 4
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HB is an uncommon neoplasm often manifesting as a cystic mass at sites in the central neuraxis such as the cerebellum. This tumor rarely occurs outside the CNS, and only a small number of such cases were the participants of earlier reports. Our literature review uncovered only 9 cases, including the present one, of HBs arising in soft tissues (Table 1),3–9 and these cases help delineate the clinicopathologic characteristics of this rare entity. First, as Patton et al8 rightly pointed out, soft-tissue HBs occur more often in females than males. If the case of HB occurring in a VHL patient is excluded, we find that 6 of 8 (75%) patients were female. Second, these tumors affect older individuals8 (mean: 59.5 y old), as compared with CNS HBs whose peak incidence is observed in individuals in their fourth decade.2 Third, although CNS HBs typically manifest as cystic lesions with solid mural nodules,2 soft-tissue HBs tend to lack this gross cystic quality.8 Fourth, the retroperitoneum/pelvis seems a common site for soft-tissue HBs; this tendency is even more highlighted when one considers the HB cases occurring in viscera within this anatomic space, such as in the adrenals, kidney, bladder, and pancreas.3 Fifth, these tumors are not always associated with peripheral neural structures, and over half the cases did not show the involvement of identifiable nerves. Sixth, clinical follow-ups, available for 7 cases, indicate that soft-tissue HBs are benign tumors, as recognized by the World Health Organization for cases with CNS involvement.1 Last, most soft-tissue HBs seem to occur sporadically, although genetic studies were admittedly incomplete in most cases.

Table 1
Table 1
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Mutational inactivation of the VHL gene, mapped at 3p25-26, is responsible for the genetic susceptibility of VHL patients to HB.1 The VHL gene mutation is also commonly found in sporadic HBs, suggesting its central role in tumorigenesis.1 Mutated VHL has been suggested to initiate neoplastic growth through the disruption of the VHL-HIF pathway.1,2 In the normoxic state, the intact VHL gene product (pVHL) helps in rapid degradation of the α-subunit of hypoxia-inducible factor (HIF). Under hypoxic conditions, HIF is stabilized with the subsequent induction of hypoxia-regulated genes, including those encoding for the vascular endothelial growth factor, erythropoietin, and CA IX.1,10,11 If pVHL does not function correctly, HIF is constitutively stabilized even in the presence of oxygen, thereby leading to the constant expression of the above mentioned HIF-responsive genes. Hence, in tumors associated with VHL disease, in which pVHL is deficient, the hypoxia-regulated genes, CA IX for instance, are expressed in a strong diffuse manner, regardless of the oxygen level. Thus, in VHL patients, conventional renal cell carcinoma, HB, pancreatic serous cystadenoma, and epididymal cystadenoma express CA IX in a strong diffuse manner on tumor membranes.10–12 In addition, some such tumors characteristic of VHL have activated HIF13 even in nonsyndromic cases, represented by consistent diffuse CA IX immunolabeling in CNS HBs. This finding indicates that the tumorigenic mechanism is the same in syndromic and sporadic cases. The strong diffuse CA IX positivity of the soft-tissue HB in this study, along with the vascular endothelial growth factor overexpression reported in another case,8 further suggests that the development of soft-tissue HB too has the same pathogenetic mechanism of VHL-HIF disruption.

The histogenesis of HB has been a subject of controversy. The suggested origin of tumor stromal cells includes glial, endothelial, arachnoid, neuroendocrine, fibrohistiocytic, and neuroectodermal cells.1 Recent studies have also postulated that an embryonic progenitor cell with hemangioblastic differentiation may be a cytologic equivalent of tumor stromal cells.1 Stromal cells were reported to express proteins such as brachyury that characterize embryonic hemangioblasts with the potential to differentiate into endothelial and hematopoietic lineages.1 Tirabosco et al14 lent support to the above hypothesis by reporting that all 14 CNS HBs were immunohistochemically positive for brachyury. The brachyury expression observed in this tumor, albeit weak and focal, may suggest that soft-tissue HBs also express the line of differentiation toward hemangioblastic progenitor cells.

The diagnosis of soft-tissue HB can be challenging, and this tumor may be histologically confused with a solitary fibrous tumor,3,5 paraganglioma,3 metastatic renal cell carcinoma,5,7,8 and lipogenic tumor.3,7,8 Diffuse S-100 labeling may also make benign or malignant peripheral nerve sheath tumor a serious diagnostic consideration. However, the difficulty in diagnosis mainly stems from the fact that the occurrence of this “brain tumor” is unexpected in soft tissue. If properly included in the differential diagnoses, we believe that HB shows sufficiently characteristic histology and immunoprofile to allow correct interpretation.

In summary, we report a case of soft-tissue HB arising in the retroperitoneum and not associated with neural structures. Our literature review delineated the typical characteristics of soft-tissue HB, that is, it is a solid tumor mainly seen in older females and commonly involving the retroperitoneum/pelvis. Immunohistochemical observation of CA IX suggested that soft-tissue HBs have the same pathogenetic mechanism of VHL-HIF disruption as CNS HBs. The brachyury expression seen in the present tumor may implicate embryonic hemangioblasts as a potential line of differentiation, as was proposed in CNS HBs.

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1. Plate KH, Vortmeyer AO, Zagzag D, et al. Von Hippel-Lindau disease and haemangioblastoma. In: Louis DN, Ohgaki H, Wiestler OD, et al, eds. WHO Classification of Tumours of the Central Nervous System. 4th ed. Lyon: IARC; 2007:215–217.

2. Yachnis AT. Capillary hemangioblastoma. In: McLendon RE, Rosenblum MK, Bigner DD, eds. Russell and Rubinstein's Pathology of Tumors of the Nervous System. 7th ed. London: Hodder Arnold; 2006:489–507.

3. Nonaka D, Rodriguez J, Rosai J. Extraneural hemangioblastoma: a report of 5 cases. Am J Surg Pathol. 2007;31:1545–1551.

4. Brodkey JA, Buchignani JA, O'Brien TF. Hemangioblastoma of the radial nerve: case report. Neurosurgery. 1995;36:198–200; discussion 200–201.

5. Fanburg-Smith JC, Gyure KA, Michal M, et al. Retroperitoneal peripheral hemangioblastoma: a case report and review of the literature. Ann Diagn Pathol. 2000;4:81–87.

6. Giannini C, Scheithauer BW, Hellbusch LC, et al. Peripheral nerve hemangioblastoma. Mod Pathol. 1998;11:999–1004.

7. Michal M, Vanecek T, Sima R, et al. Primary capillary hemangioblastoma of peripheral soft tissues. Am J Surg Pathol. 2004;28:962–966.

8. Patton KT, Satcher RL Jr, Laskin WB. Capillary hemangioblastoma of soft tissue: report of a case and review of the literature. Hum Pathol. 2005;36:1135–1139.

9. Kline DG, Hudson AR. Nerve Injuries: Operative Results for Major Nerve Injuries, Entrapments, and Tumors. Philadelphia: W.B. Saunders; 1995.

10. Mandriota SJ, Turner KJ, Davies DR, et al. HIF activation identifies early lesions in VHL kidneys: evidence for site-specific tumor suppressor function in the nephron. Cancer Cell. 2002;1:459–468.

11. Perigny M, Hammel P, Corcos O, et al. Pancreatic endocrine microadenomatosis in patients with von Hippel-Lindau disease: characterization by VHL/HIF pathway proteins expression. Am J Surg Pathol. 2009;33:739–748.

12. Vortmeyer AO, Tran MG, Zeng W, et al. Evolution of VHL tumourigenesis in nerve root tissue. J Pathol. 2006;210:374–382.

13. Zagzag D, Zhong H, Scalzitti JM, et al. Expression of hypoxia-inducible factor 1alpha in brain tumors: association with angiogenesis, invasion, and progression. Cancer. 2000;88:2606–2618.

14. Tirabosco R, Mangham DC, Rosenberg AE, et al. Brachyury expression in extra-axial skeletal and soft tissue chordomas: a marker that distinguishes chordoma from mixed tumor/myoepithelioma/parachordoma in soft tissue. Am J Surg Pathol. 2008;32:572–580.

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soft-tissue tumors; hemangioblastoma; immunohistochemistry

© 2010 Lippincott Williams & Wilkins, Inc.


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