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Clinicopathological analysis of extraneural sporadic haemangioblastoma occurring in the tongue
  1. Yacun Chen1,
  2. Jie Chen1,2,
  3. Ye Jiang3 and
  4. Xiang Lin1,4
  1. 1School of Chinese Medicine, The University of Hong Kong, Hong Kong, China
  2. 2Department of Orthopedics, Shanghai Jiao Tong University School of Medicine, Shanghai, China
  3. 3Department of Pathology, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
  4. 4Department of Chinese Medicine, the University of Hong Kong-Shenzhen Hospital (HKU-SZH), Shenzhen, China
  1. Correspondence to Dr Xiang Lin; linxiang{at}


Haemangioblastoma is a morphologically distinctive tumour with uncertain histogenesis, typically occurring in the cerebellum, brain stem or spinal cord and less commonly in extraneural locations. Here, we present a case of haemangioblastoma occurring in the tongue, which is the first reported case in terms of the pathogenic site. The tumour was morphologically indistinguishable from central nervous system haemangioblastoma, that is, neoplastic stromal cells with cytoplasmic vacuolisation and abundant small vessels. Immunohistochemical studies revealed that the tumour cells were positive for S100, NSE, CD56, Syn, EMA, vimentin and α-inhibin, while negative for CK, SMA, factor Ⅷ, D2-40 and GFAP. Immunostainings for CD34 and CD31 outlined the rich and delicate vascular channels. Ki-67 expression was presented in approximately 3% of tumour cells. Primary haemangioblastoma has not been previously described at this site, and this case emphasises the need to consider haemangioblastoma in the differential diagnoses of neoplasms occurring in the tongue.

  • Pathology
  • Oral and maxillofacial surgery

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Haemangioblastoma is a benign hypervascular tumour seen concomitant with the inherited von Hippel-Lindau (VHL) disease in approximately 30% of the patients, and the remainder present in sporadic forms. Histologically, it is characterised by numerous small vessels and neoplastic stromal cells. The tumour can occur in any nervous system site, predominantly in the central nervous system (CNS), but rarely in the peripheral nervous system and extremely rare in extraneural sites.1 Although exceedingly rare, solid haemangioblastomas arising outside the CNS have been reported and increasingly recognised, involving peripheral nerves,2–4 retroperitoneum,5–7 skin,4 soft tissues such as popliteal fossa8 9 and bone,10 11 and visceral organs including kidney,12–14 liver,15 16 lung,15 17 stomach,18 pancreas,19 adrenals20 and bladder.19 However, no cases have been reported on the site of the tongue to date. We now present a case of primary extraneural haemangioblastoma occurring in the tongue base with immunohistochemical and pathological characterisation and analysis.

Case presentation

A Chinese man in his early 40s presented with symptoms of snoring and hoarseness for over 1 year and aggravated over the previous week. His physician found a faint red mass in the patient’s tongue base with an uneven surface in the process of routine physical examination. The tumour has no tenderness and adhesion, and the mobility is acceptable. Other general and elemental physical examinations were negative. He was born and lived in Guangdong, China. He had no relevant family history or personal medical history. Subsequently, the indirect laryngoscopy showed a mass in the left tongue base measuring approximately 1.5×1.0 cm.

Then, contrast-enhanced CT and MRI scans of the oropharynx and mandible showed an uneven oval mass measuring nearly 4.6×3.9 cm with a relatively clear boundary, being located in the body and left root of the tongue. CT and MRI enhancement scans also demonstrated an inhomogeneous contrast enhancement in the mass (figure 1). The chest CT and ECG had no additional abnormal findings.

Figure 1

CT: The lesion on the left side of the tongue (red arrow) demonstrates slightly low density on non-contrast CT scan (A) and significantly enhanced on arterial phase CT scan (B), which measures about 46×39 mm.

The tumour was subsequently conducted with a radical resection. The whole mass was completely sampled and routinely fixed in 10% neutral buffered formalin after surgery. The tissues were embedded in paraffin. A series of 4 μm thick sections were cut from each paraffin-embedded block and stained with H&E. Three professional pathologists evaluated the slides and gave their final diagnosis.


Pathological manifestations

The excised tissue specimen measured 5.5×4×3 cm in size with an uneven surface and locally presented nodular appearance. The cut surface of the mass was well circumscribed, partly cystic, slightly tough and grey-red in colour (figure 2).

Figure 2

Macroscopic features: the excised tissue specimen measured 5.5×4×3 cm in size with uneven surface and locally presented nodular appearance. The cut surface of the mass was well-circumscribed, partly cystic, slightly tough and grey-red in colour.

Microscopically, at low magnification, the tumour had a fibrous capsule and appeared as a well-demarcated nodule (figure 3A). Numerous thin-walled vessels that had variable sizes were prominent and stromal cells intervened in the rich capillary network (figure 3B,C). The stromal cells were oval to polygonal with various degrees of pleomorphism. The cytoplasm of these cells was eosinophilic to clear and many contained lipid vacuoles, which were the most characteristic and distinguishing morphological features of the tumour and could be seen in most regions (figure 3D,E). The nuclei of these stromal cells varied in size, with mild to moderate atypical and hyperchromatic features (figure 3F). Nucleolus could be found but mitotic figures were scarce (figure 3G). Focal intratumoural haemorrhage was observed (figure 3H). No tumour cells were found in the surgical margin of this specimen microscopically.

Figure 3

Histological features: (A) the tumour was surrounded by a thick fibrous capsule and had a clear boundary (HE×40). (B, C) The tumour was composed of numerous blood vessels which varied from small capillaries to medium-sized vessels and stromal cells (HE×100). (D, E) The stromal cells were oval to polygonal with eosinophilic or vacuolated cytoplasm, and locally contained lipid droplets but no hyaline globules (HE×100). (F) The nuclei of these stromal cells varied in size, with mild to moderate atypical and hyperchromatic features (HE×400). (G) Nucleolus could be found in the stromal cells but mitotic figures were scarce (HE×400). (H) focal intratumoural haemorrhage was seen (HE×200).

Immunohistochemical findings

Immunohistochemistry studies revealed that the tumour cells were positive for S100, NSE, CD56, Syn, EMA, vimentin and α-inhibin, while showed negative for cytokeratin, factor Ⅷ, EGFR, desmin, SMA, D2-40, PAX2, PAX8, CgA, HMB45, GFAP and CD163. Immunostainings for CD34 and CD31 outlined the rich and delicate vascular channels, but stromal cells showed no expression due to the lack of endothelial cell markers and endothelium-associated adhesion molecules. Approximately 3% of the tumour cells were reactive for Ki-67 labelling index, even in the cellular area with prominent cell pleomorphism (figure 4). The immunohistochemical findings and detailed information of the antibodies were summarised in table 1.

Table 1

Immunohistochemical findings and the detailed information of the antibodies

Figure 4

Immunohistochemical staining: tumour cells were positive for CD56 (A×200), NSE (B×200), S-100 protein (C×200), EMA (D×200), vimentin (E×200), Fli-1 (F×200). Ki-67 expression was approximately 3% of tumours (G×100). CD34 staining outlined the capillary network of the tumour vasculature (H×100).

Differential diagnosis

Histologically, haemangioblastoma consists of vast capillary blood vessels, so it is prone to be confused with vasculogenic diseases frequently, such as haemangioma, haemangioendothelioma and haemangiosarcoma. However, three main characteristics could facilitate the diagnosis: (1) lacking stromal cells, (2) clear or microvacuolated cytoplasm and (3) related immunohistochemistry markers.

In addition, the most distinguishing morphological feature of haemangioblastoma is plenty of lipid-containing vacuoles, appearing in the typical clear-cell morphology, which resembles metastatic clear cell renal carcinoma (ccRCC). Actually, patients with VHL-associated haemangioblastoma are prone to consolidate RCC, adding to the complexity of this differential diagnosis. Immunohistochemistry is useful for distinguishing haemangioblastoma from RCC. PAX2(+) or PAX8(+) combined with α-inhibin (−) enhances the diagnosis of metastatic ccRCC while the opposite profile supports the diagnosis of haemangioblastoma.21 Furthermore, ccRCC that presents tongue metastasis is fairly rare and the follow-up of this patient has no evidence or signs of lesions in any other sites.


First, the initial biopsy was conducted and was suggestively diagnosed with granulation tissue-type capillary haemangioma based on the histological morphology. One week later, a radical resection of the mass in the left tongue base and mouth floor was successfully completed. The tumour was highly vascularised and demarcated from the surrounding tissues with focal slight adhesion. After surgery, the patient had an uneventful recovery under general postoperative treatment for approximately 22 days.

Outcome and follow-up

There was less facial swelling and drainage, no abnormal speech function, no abnormal mouth opening and closing function, and no abnormal neck movement after the operation. During regular follow-ups at months 3, 6, 12, 24 and 36, no evidence of recurrence or other abnormalities was observed.


Haemangioblastoma is a benign slow-growing neoplasm that occurs both in inherited forms associated with VHL disease and more often as sporadic lesions. VHL disease is an inherited condition caused by genetic mutations of the VHL tumour suppressor gene on chromosome 3, being transmitted in an autosomal dominant mode.21 Patients with VHL are at increased risk of developing ccRCC, capillary haemangioblastoma of the CNS and retina, phaeochromocytoma, neuroendocrine and pancreatic tumours.22–24 Although haemangioblastomas have a characteristic association with VHL disease, a larger number of these tumours occur sporadically, typically in the cerebellum.22 Extraneural haemangioblastomas are exceptional and usually occur in patients with VHL disease. Simultaneously, as a solitary sporadic lesion, it is increasingly recognised in extraneural sites, for instance, kidney, liver, lung, skin, adrenals, bladder, pancreas, soft tissues, stomach, bone and other locations. Nevertheless, the location in the tongue has never been reported in English literature, thus adding a new pathogenic site in that extraneural haemangioblastoma may occur.

Epidemiologically, haemangioblastomas mainly occur in adults, with 1:1 male to female ratio and could be reported for all ages and have even been presented as congenital solid tumour lesions.25 Moreover, the average patient age of VHL-associated haemangioblastoma as recorded is nearly 20 years younger than that of sporadic tumour.1

Histologically, haemangioblastoma comprises abundant capillary blood vessels and stromal cells with cytoplasmic vacuolisation. As mentioned above, atypical stromal cells constitute the neoplastic cell type in haemangioblastoma and they are surrounded by numerous non-neoplastic cells, including endothelial cells, lymphocytes and pericytes. However, the exact origin of stromal cells remains uncertain and controversial. Various cell lineages have been proposed, such as glial cells,26 endothelial cells,27 arachnoid cells,28 embryonic choroid plexus cells29 and fibro histiocytic cells.30 Ponnaluri et al have illustrated that the tumourlet-like stromal cells have both the proangiogenic and stem cell markers, which occur in optic nerve haemangioblastomas and retinal haemangioblastomas. The finding above highly suggested that haemangioblastomas may derive from stem cells or embryonic development.31 Additionally, other recent studies have demonstrated the hypothesis that the morphology of the tumour is the result of reactive angiogenesis with paracrine signalling pathway caused by deficient VHL tumour suppressor protein HIF1A-expressing stromal cells.32 However, these theories are better presented only in VHL-associated haemangioblastoma other than sporadic lesions in extraneural locations. Therefore, further research should be done to explore the histogenetic principles and origin of the tumour mass.

As for the prognosis of this tumour, Cheng et al revealed that only 4 out of 23 (17.4%) patients with CNS haemangioblastoma presented local recurrence during the follow-up.33 Recurrence of extraneural sporadic haemangioblastomas has never been reported after a thorough search. Patients with solitary sporadic tumours have a better outcome than those in the setting of VHL disease because the latter condition is prone to merge multiple lesions.34 In our case, the patient is alive and in a healthy condition 3 years later without any haematological and image findings of recurrence or metastasis after the therapeutic strategy of the total tumour resection. And further regular follow-ups would be conducted to detect the local and distant recurrence, even if the biological behaviour is benign and the tumour mass is resected.

Learning points

  • Extraneural sporadic haemangioblastoma may occur in the tongue, which is a completely new pathogenic site proposed up to now.

  • Morphological manifestation and immunohistochemical analysis are pivotal in the differential diagnosis of haemangioblastoma with other vasculogenic diseases.

  • Haemangioblastoma without atypia histological features suggests a good prognosis.

  • Patients with solitary sporadic tumours have a better outcome than those in the setting of von Hippel-Lindau disease because the latter condition is prone to merge multiple lesions.

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  • YC and JC contributed equally.

  • Contributors YC contributed to the writing of the case report and discussion. JC contributed to the patient care. YJ contributed to the case diagnosis and provided pictures. XL edited and audited the writing of the case report. All authors accepted responsibility for the finished work and the conduct of the study and controlled the decision to publish.

  • Funding This work was supported by a grant from the Health and Medical Research Fund (No. 19201121). The funding organisation had no role in the study design; in the collection, analysis and interpretation of the data; in the writing of the report; and in the decision to submit the paper for publication.

  • Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.