Primary clear cell microcystic adenoma of the sinonasal cavity is rare. It has previously been described only as a VHL-associated tumour. Von Hippel-Lindau (VHL) syndrome is an inherited cancer syndrome characterised by an elevated risk of neoplasia including clear cell renal cell carcinoma (ccRCC), haemangioblastoma, and phaeochromocytoma. We describe the second reported case of a primary clear cell microcystic adenoma of the sinonasal cavity. The 39-year-old patient with VHL syndrome had previously undergone resection and ablation of ccRCC. He presented with epistaxis. Imaging demonstrated a mass in the ethmoid sinus. Initial clinical suspicion was of metastatic ccRCC. However, tumour morphology and immunoprofile were distinct from the previous ccRCC and supported a diagnosis of primary microcystic adenoma. Analysis of DNA extracted from sinonasal tumour tissue did not show loss of the wild-type allele at the
Von Hippel-Lindau (VHL) disease is a cancer syndrome characterised by an increased risk of multiple tumour types occurring across different organ systems. These include haemangioblastomas within the central nervous system and characteristic visceral lesions including clear cell renal cell carcinoma (ccRCC) and phaeochromocytoma [
Sinonasal tumours are rare [
A 39-year-old man with molecularly confirmed VHL disease presented with epistaxis in 2012. Molecular analysis had confirmed a germline
Two years later, in 2014, the patient developed symptoms of nasal obstruction. Sinonasal tumour recurrence was suspected. Imaging demonstrated limited progression in the nasal cavity. Excision biopsy was performed. Histology appeared consistent with the initial presenting sinonasal tumour. Excision appeared complete, with no evidence of residual tumour. Subsequently, symptoms recurred. Therapeutic excision was performed in 2015 and again in 2016. To date, the patient’s VHL disease remains stable with no evidence of new lesions or metastatic disease.
The patient remained under the management of specialist multidisciplinary (MDT) team which coordinated regular imaging surveillance and clinical review. The MDT recommended regular magnetic resonance imaging (MRI) surveillance with localised resection as applicable. More extensive surgery or adjuvant therapy was not felt to be indicated.
Slides of the sinonasal tumour resected in 2012 and the patient’s ccRCC resected in 2005 were collated to allow comparison. Immunohistochemical and special stains for CD10, RCC, CK7, CK20, epithelial marker AE1/3, vimentin, EMA, Ki67, ssms1, sma, alpha-inhibin, p63, thyroglobulin, NSE, s100, GFAP, and PAS were performed according to standard automated protocols (Dako, UK).
The sinonasal tumour demonstrated tubulocystic morphology with a brush border, glycogen-rich cells, and low grade nuclei without conspicuous mitoses (Figures
Haematoxylin and eosin (HE) stains of the sinonasal tumour (a) ×4 and (b) ×20 and renal tumour (c) ×4 and (d) ×20.
The sinonasal tumour was positive for CK7, epithelial marker AE1/3, vimentin, NSE, and EMA, with patchy CK20 staining, but negative for RCC and CD10. Secretions were PAS-positive and Ki67 demonstrated a low proliferation index. Immunohistochemistry revealed renal tumour positivity for RCC, CD10, and EMA and negativity for CK7 and CK20 (Figures
Immunohistochemical profile of the renal and sinonasal tumours.
Immunohistochemical marker | Clear cell RCC (2005) | Sinonasal tumour (2012) |
---|---|---|
CD10 | Positive | Negative |
RCC | Positive | Negative |
CK7 | Negative | Positive |
CK20 | Negative | Positive (patchy staining) |
EMA | Positive | Positive |
Ki67 | Low proliferation | |
Epithelial marker AE1/3 | Positive | |
Vimentin | Positive | |
ssms1 | Negative | |
sma | Negative | |
Alpha-inhibin | Negative | |
p63 | Negative | |
Thyroglobulin | Negative | |
NSE | Positive | |
S100 | Negative | |
GFAP | Negative | |
PAS | Luminal secretions positive |
Immunohistochemistry (IHC) of renal and sinonasal tumours, ×2. (a) Sinonasal tumour cells were negative for CD10. (b) Renal tumour cells were strongly positive for CD10. (c) Sinonasal tumour cells were negative for RCC; however, weak staining of luminal secretions was seen. (d) Renal tumour cells demonstrated strong positivity for RCC marker. (e) Sinonasal tumour cells demonstrated positivity for CK7. (f) The renal tumour was negative for CK7; however, in this image a proximal renal tubule was seen to exhibit CK7 positivity. (g) The sinonasal tumour exhibited patchy CK20 positivity. (h) The renal tumour was negative for CK20.
(a) Sinonasal tumour with luminal PAS-positive secretions, ×20. (b) Ki67 staining demonstrates a low mitotic index, ×10.
The patient was known to have a constitutional deletion of exon 1 of
Point mutation analysis of the three coding exons of
Analysis of tumour DNA demonstrated no causative mutations; however, the tumour was heterozygous for an intron 1 polymorphism (c.341-50G>A), reducing the likelihood of LOH.
Primary tumours of the nasal cavity are rare [
In the case we present here the initial clinical suspicion was of metastatic ccRCC. Histologically, the clear tumour cells, cystic morphology, and positive staining for AE1/3 [
In the previously reported case of a primary clear cell microcystic adenoma of the nasal sinus, Xu et al. describe microcystic tumour morphology, clear glycogen-rich cells without nuclear atypia, EMA and cytokeratin positivity, and negativity for CD10 [
Xu et al. demonstrated sinonasal microcystic adenoma
In the World Health Organisation (WHO) classification of head and neck tumours, adenomatous lesions of the sinonasal cavity are of salivary gland origin [
The sinonasal microcystic adenoma described by Xu et al. was surgically resected due to local progression. However, the clinical course of such tumours is unknown [
In conclusion, the association of primary microcystic adenoma of the sinonasal cavity with VHL disease is possible but not proven. Such lesions are rare and may provide a considerable diagnostic challenge. Importantly, these lesions are considered essentially benign. However, they may have potential for rapid growth and local recurrence. This suggests that in such cases regular surveillance is merited and that repeated surgical resection may be required.
Written informed patient consent was obtained regarding the publication of this case.
This case was presented as a poster presentation at Nottingham Pathology 2016, the 9th Joint Meeting of the British Division of the International Academy of Pathology and the Pathological Society of Great Britain & Ireland in June 2016. Therefore, a modified abstract of this case was published in the
The authors declare that there is no conflict of interests regarding the publication of this paper
The authors acknowledge the valuable contribution of Professor Stewart Fleming in the assessment of this case.