Synchronous Presentation of Rare Brain Tumors in Von Hippel–Lindau Syndrome

diagnostics

Case Report Synchronous Presentation of Rare Brain Tumors in Von Hippel–Lindau Syndrome

Mariachiara Lodi 1, Antonio Marrazzo 2, Antonella Cacchione 1, Marina Macchiaiolo 3, Antonino Romanzo 4, Luciano Mastronardi 5, Francesca Diomedi-Camassei 6 , Alessia Carboni 2, Andrea Carai 7 , Carlo Gandolfo 2, Lidia Monti 8, Angela Mastronuzzi 1 and Giovanna Stefania Colafati 2,*

1 Department of Paediatric Haematology/Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; [email protected] (M.L.); [email protected] (A.C.); [email protected] (A.M.) 2 Neuroradiology Unit, Department of Imaging, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; [email protected] (A.M.); [email protected] (A.C.); [email protected] (C.G.) 3 Rare Diseases and Medical Genetics Unit, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; [email protected] 4 Ophtalmology Unit, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; [email protected] 5 Department of Surgical Specialities, Division of Neurosurgery, San Filippo Neri Hospital/ASL, 1, 00135 Roma, Italy; [email protected] 6 Department of Laboratories, Pathology Unit, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; [email protected] 7 Neurosurgery Unit, Department of Neuroscience and Neurorehabilitation, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; [email protected] 8 Citation: Lodi, M.; Marrazzo, A.; Department of Radiology, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; [email protected] Cacchione, A.; Macchiaiolo, M.; * Correspondence: [email protected]; Tel.: +39-06-6859-4727 Romanzo, A.; Mastronardi, L.; Diomedi-Camassei, F.; Carboni, A.; Carai, A.; Gandolfo, C.; et al. Abstract: Von Hippel–Lindau (VHL) disease is a heritable cancer syndrome in which benign and Synchronous Presentation of Rare malignant tumors and/or cysts develop throughout the central nervous system (CNS) and vis- Brain Tumors in Von Hippel–Lindau ceral organs. The disease results from mutations in the VHL tumor suppressor gene located on Syndrome. Diagnostics 2021, 11, 1005. chromosome 3 (3p25-26). A majority of individuals (60–80%) with VHL disease will develop CNS https://doi.org/10.3390/diagnostics hemangioblastomas (HMG). Endolymphatic sac tumor (ELST) is an uncommon, locally aggressive 11061005 tumor located in the medial and posterior petrosal bone region. Its diagnosis is based on clinical, radiological, and pathological correlation, and it can occur in the setting of VHL in up to 10–15% of Academic Editor: Sung-Hye Park individuals. We describe a 17-year-old male who presented with a chief complaint of hearing loss. Brain and spine Magnetic Resonance Imaging documented the presence of an expansive lesion in Received: 31 March 2021 the left cerebellar hemisphere, compatible with HMG in association with a second cerebellopontine Accepted: 24 May 2021 lesion compatible with ELST. The peculiarity of the reported case is due to the simultaneous presence Published: 31 May 2021 of two typical characteristics of VHL, which led to performing comprehensive genetic testing, thus allowing for the diagnosis of VHL. Furthermore, ELST is rare before the fourth decade of life. Early Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in detection of these tumors plays a key role in the optimal management of this condition. published maps and institutional afﬁl- iations. Keywords: hemangioblastomas; endolymphatic sac tumor; MRI; Von Hippel–Lindau syndrome

1. Introduction Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. Von Hippel–Lindau syndrome (VHLs) is a rare, inherited disease with autosomal This article is an open access article dominant inheritance, caused by the mutation of the VHL gene, and in about 20% of distributed under the terms and cases the mutation occurs de novo. The incidence of VHLs is about 1/36,000 in the conditions of the Creative Commons general population and typically manifests in the second decade of life. In the CNS, Attribution (CC BY) license (https:// characteristic HMGs are seen in the retina, brain, and spine with additional ELST. Outside creativecommons.org/licenses/by/ of the CNS, VHL disease presents with tumors of the pacreas, kidneys, adrenals, and 4.0/).

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VHL disease presents with tumors of the pacreas, kidneys, adrenals, and reproductive organs. Therefore, it is essential that radiologists be familiar with their imaging appear- Diagnostics 2021, 11, 1005 ance [1–3]. 2 of 8

2. Case Report A 17-year-old male was referred to our hospital with history of left hearing loss as- reproductive organs. Therefore, it is essential that radiologists be familiar with their imaging sociated with visual loss and worsening headache for about a year. Clinical evaluation appearance [1–3]. showed severe left hearing loss and diplopia occurring with the gaze toward the lower quadrants.2. Case Report No additional neurological deficits were detected. No significant familial pathologicalA 17-year-old history malewas reported. was referred Audiomet to ourry hospital confirmed with a history severe ofleft left sensorineural hearing loss hypacusia.associated with visual loss and worsening headache for about a year. Clinical evaluation showedBrain severe and spine left hearingMagnetic loss Resonance and diplopia Imaging occurring (MRI) withdocumented the gaze the toward presence the lower of a left,quadrants. solid cystic No cerebellar additional mass neurological with inhomogeneous deficits were signal detected. intensity No significantand vivid contrast familial enhancementpathological of history the solid was component reported. (Figure Audiometry 1a–d). confirmed a severe left sensorineural hypacusia.Moreover, an additional left cerebellopontine angle (CPA) tumor was detected, ex- tendingBrain into and the spineinternal Magnetic auditory Resonance canal and Imaging incorporating (MRI) documentedthe ipsilateral the facial presence acoustic of a nervesleft, solid (Figure cystic 1a–d). cerebellar A brain mass CT with scan inhomogeneouswas also performed signal to intensityallow for and a more vivid in-depth contrast pre-operativeenhancement stud of they (Figure solid component 1e,f). (Figure1a–d).

Figure 1. Papillary cystadenoma of the endolymphatic sac and cerebellar hemangioblastoma (HMG) in VHL. (a,b): Axial Figure 1. Papillary cystadenoma of the endolymphatic sac and cerebellar hemangioblastoma (HMG) in VHL. (a,b): Axial T2-WI and FLAIR images; (c,d): axial and coronal post-contrast T1-WI images. A cystic mass (without signal suppression T2-WI and FLAIR images; (c,d): axial and coronal post-contrast T1-WI images. A cystic mass (without signal suppression on on FLAIR sequence) grows through the mastoid and temporal bones, disrupting bone structures (1, ELST). After Gado- liniumFLAIR injection, sequence) the grows mass through becomes the relatively mastoid more and temporal homogene bones,ous with disrupting blunt peripheral bone structures rim enhancement. (1, ELST). After HMG Gadolinium appears asinjection, cystic mass the (2) mass in the becomes cerebellar relatively hemisphere, more homogeneous showing isolated with and blunt peripheral peripheral enha rimncing enhancement. mural nodule HMG (3). ( appearse,f): Axial as andcystic coronal mass computerized (2) in the cerebellar tomography hemisphere, (CT) scans showing show isolated bone destruction and peripheral of the enhancing temporal pyramid, mural nodule more (3).evident (e,f): while Axial comparingand coronal healthy computerized contralateral. tomography Normal-appearing, (CT) scans show right-side boned destruction inner ear (star) of the and temporal endolymphatic pyramid, duct more (circle) evident are while no longercomparing recognizable healthy contralaterally contralateral. Normal-appearing,(respectively, arrowhead right-sided and thin inner arrow). ear (star) and endolymphatic duct (circle) are no longer recognizable contralaterally (respectively, arrowhead and thin arrow). Ophthalmologic evaluation showed the presence of retinal hemangioblastomas (Fig- ure 2d–f)Moreover, confirmed an additionalwith TC and left MRI cerebellopontine studies (Figure angle 2a–c). (CPA) tumor was detected, ex- tending into the internal auditory canal and incorporating the ipsilateral facial acoustic nerves (Figure1a–d). A brain CT scan was also performed to allow for a more in-depth pre-operative study (Figure1e,f). Ophthalmologic evaluation showed the presence of retinal hemangioblastomas (Figure2d–f) conﬁrmed with TC and MRI studies (Figure2a–c). Diagnostics 2021,, 11,, 1005x FOR PEER REVIEW 3 of 8 Diagnostics 2021, 11, x FOR PEER REVIEW 3 of 8

Figure 2. HMG of the retina. (a–c): Axial CT scan, T2-WI (volumetric sequence) and axial post- FigureFigure 2. 2. HMG HMG of of the the retina. retina. ( a(a––c):c): Axial Axial CT CT scan, scan, T2-WI T2-WI (volumetric (volumetric sequence) sequence) and and axial axial post- post- contrastcontrast T1-WI T1-WIT1-WI images. images.images. A A Afocal focal focal hyperdense hyperdense hyperdense and and and isointense isointense isointense (compared (compared (compared to to surrounding tosurrounding surrounding vitreous) vitreous) vitreous) peripheralperipheral nodule nodulenodule is is depicted depicted on on on the the the lateral lateral lateral portio portio portionnn of of the of the theleft left leftretina retina retina (arrow). (arrow). (arrow). A A blunt blunt A bluntcontrast contrast contrast en- en- hancementenhancementhancement is is typical istypical typical of of ofthis this this hypervascular hypervascular hypervascular tumor. tumor. tumor. ( d(d– (d–f):f–): fOphthalmoscopy.): Ophthalmoscopy. Ophthalmoscopy.

SurgicalSurgical resection resectionresection of of both both both lesions lesions lesions was was was advised advised advised and and and performed performed performed through through through a a left left a retrosig- retrosig- left ret- moidrosigmoidmoid craniotomy. craniotomy. craniotomy. Complete Complete Complete resection resection resection of of the the ofcerebellar cerebellar the cerebellar lesion lesion lesionand and subtotal subtotal and subtotal resection resection resection of of the the cerebello-pontineofcerebello-pontine the cerebello-pontine angle angle one angleone were were one achieved achieved were achieved with with no no with post-operative post-operative no post-operative complications complications complications (Figure (Figure 3a,b).(Figure3a,b). 3a,b).

FigureFigure 3. 3. Follow-up Follow-up MRI. MRI. Axial Axial T2w T2w ( a(a) )and and GdT1w GdT1w ( b(b) )images images show show complete complete surgical surgical resection resection Figure 3. Follow-up MRI. Axial T2w (a) and GdT1w (b) images show complete surgical resection of ofof the the left left cerebellar cerebellar tumor tumor and and partial partial resection resection of of the the ipsilateral ipsilateral cerebellum-pontine cerebellum-pontine angle angle mass mass the left cerebellar tumor and partial resection of the ipsilateral cerebellum-pontine angle mass with withwith residual residual cystic cystic appearance appearance ( a(a, ,arrows) arrows) and and lesional lesional contrast contrast enhancement enhancement after after gadolinium gadolinium injectionresidualinjection cystic( b(b, ,arrows). arrows). appearance (a, arrows) and lesional contrast enhancement after gadolinium injection (b, arrows). HistologyHistology of of the the cerebellar cerebellar le lesionsion revealed revealed a a highly highly vascular vascular tumor tumor consisting consisting of of lob- lob- Histology of the cerebellar lesion revealed a highly vascular tumor consisting of lob- ulesules and and sheets sheets of of epithelioid epithelioid cells. cells. Many Many vacuolated vacuolated clear clear cells, cells, focal focal nuclear nuclear atypia, atypia, and and ules and sheets of epithelioid cells. Many vacuolated clear cells, focal nuclear atypia, and occasionaloccasional mitoses mitoses were were present. present. Immunostains Immunostains for for S-100 S-100 and and NSE NSE were were positive. positive. Prolif- Prolif- occasional mitoses were present. Immunostains for S-100 and NSE were positive. Prolifera- erationeration index index (anti-Ki67) (anti-Ki67) resulted resulted in in about about 3%. 3%. A A diagnosis diagnosis of of cerebellar cerebellar hemangioblas- hemangioblas- tion index (anti-Ki67) resulted in about 3%. A diagnosis of cerebellar hemangioblastoma tomatoma (HMG) (HMG) was was formulated formulated (Figure (Figure 4a–d). 4a–d). Regard Regardinging the the CPA CPA lesion, lesion, it it consisted consisted of of exile exile (HMG) was formulated (Figure4a–d). Regarding the CPA lesion, it consisted of exile papillary fronds lined by cubic epithelium with minimal nuclear atypia. Cytokeratin im-

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papillary fronds lined by cubic epithelium with minimal nuclear atypia. Cytokeratin im- munostainmunostain waswas positive.positive. TheseThese ﬁndingsfindings werewere consistentconsistent withwith endolymphaticendolymphatic sacsac tumortumor (ELST)(ELST) (Figure(Figure4 e,f).4e,f).

Figure 4. HMG (a) highly vascular neoplasia formed by lobules and nets of epithelioid cells, many Figure 4. HMG (a) highly vascular neoplasia formed by lobules and nets of epithelioid cells, many with clear cytoplasm. Focal nuclear atypia is observed (40×). (b) Anti-endothelial marker CD31 with clear cytoplasm. Focal nuclear atypia is observed (40×). (b) Anti-endothelial marker CD31 revealed a rich intermingled vascularity. Note that neoplastic cells are negative for this vascular revealedmarker (40×). a rich (c intermingled) S100 immunostain vascularity. resulted Note as positive that neoplastic in the majority cells are of negative cells (63×). for ( thisd) Prolifera- vascular markertion rate (40 was×). about (c) S100 3% immunostain (40×). ELST resulted(e) thin papillary as positive fibrovascular in the majority core of cellscovered (63× by). (cuboidald) Proliferation epi- ratethelium was aboutlayer (20×). 3% (40 (f×) ).Positivity ELST (e )for thin cytoke papillaryratin fibrovascularimmunostain core(40×). covered by cuboidal epithelium layer (20×). (f) Positivity for cytokeratin immunostain (40×). HMG and ELST, in association with retinal angiomatosis, led to suspect a Von Hip- pel–LindauHMG and Syndrome ELST, in (VHL). association with retinal angiomatosis, led to suspect a Von Hippel– LindauIn Syndromeconsideration (VHL). of clinical, neuroradiological, and histological features, blood sample wasIn consideration collected from of clinical,the patient neuroradiological, and genetic tests and were histological carried features, out in our blood patient sample by wasMultiplex collected Ligation-dependent from the patient and probe genetic amplification tests were carried (MLPA). out inMLPA our patient analysis by Multiplexto detect Ligation-dependentlarge deletions in the probe VHL amplification gene was carried (MLPA). out MLPAusing the analysis SALSA to detectP016B largeVHL deletionsprobe kit in(MRC-Holland, the VHL gene Amsterdam, was carried outNetherlands). using the SALSAThe kit P016Bcontains VHL eight probe probes kit to (MRC-Holland, the VHL gene Amsterdam,(four in exon Netherlands). 1 and two in each The of kit exons contains 2 and eight 3). Briefly, probes to100 the ng VHL DNA gene was(four denaturated in exon at 1 and two in each of exons 2 and 3). Briefly, 100 ng DNA was denaturated at 98 ◦C for 5 min, 98 °C for 5 min, and the MLPA probe cocktail was added to a total volume of 8 μL and and the MLPA probe cocktail was added to a total volume of 8 µL and allowed to hybridize allowed to hybridize for 16 h at 60 °C. Following addition of Ligase-65 and ligation at 54 for 16 h at 60 ◦C. Following addition of Ligase-65 and ligation at 54 ◦C for 15 min, the ligase °C for 15 min, the ligase was inactivated at 98 °C for 5 min. PCR primers, dNTP, and was inactivated at 98 ◦C for 5 min. PCR primers, dNTP, and polymerase mix were then polymerase mix were then added and PCR was carried out for 33 cycles of (95 °C for 30 s, added and PCR was carried out for 33 cycles of (95 ◦C for 30 s, 60 ◦C for 30 s, and 75 ◦C for 60 °C for 30 s, and 75 °C for 60 s). Products were then analyzed using an ABI PRISM 3130x 60 s). Products were then analyzed using an ABI PRISM 3130x Genetic Analyzer (Applied Genetic Analyzer (Applied Biosystems, acquired from Thermo Fisher Scientific Corpora- Biosystems, acquired from Thermo Fisher Scientific Corporation, Waltham, MA, USA) tion, Waltham, MA, USA) with ROX-500-labeled internal size standard. Data were gener- with ROX-500-labeled internal size standard. Data were generated using GeneMapper ated using GeneMapper (GeneMapper Software Version 4.0, Applied Biosystems, ac- (GeneMapper Software Version 4.0, Applied Biosystems, acquired from Thermo Fisher quired from Thermo Fisher Scientific Corporation, Waltham, MA, USA. Scientific Corporation, Waltham, MA, USA.

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The MLPAMLPA test test confirmed confirmed the constitutionalthe constitutional VHL geneVHL mutation gene mutation c.394delC (p.Gln132c.394delC (p.Gln132Lysfs*27)Lysfs*27) (NM_000551.3); (NM_000551.3); thus, the thus, finding thedefines finding thedefines diagnosis the diagnosis of type Iof Von type Hippel– I Von Hippel–LindauLindau Syndrome. Syndrome. Diagnostic imaging was extended to thethe whole body. AbdominalAbdominal ultrasonographyultrasonography showed multiple multiple cysts, cysts, as as in in cystic cystic fibrosis ﬁbrosis (from (from 1 to 1 to20 20mm) mm) in the in the head head and and body body of the of pancreas.the pancreas. InIn the presencepresence ofof suspicion suspicion of of VHL VHL disease, disease, the the study study of theof the spinal spinal cord cord should should be per- be performedformed using using thin-layer thin-layer sequences sequences to look to look for involvement for involvement of the of spinal the spinal cord (cordFigure (Figure5a,b ). 5a,b).Radiological Radiological follow-up follow-up of these of lesions these shouldlesions be should frequent be infrequent view of in their view high of probabilitytheir high probabilityof growth. of growth.

Figure 5. 5. HMGHMG of of the the spinal spinal cord. cord. Ax Axialial post-contrast post-contrast T1-WI T1-WI (a) and (a) andsagittal sagittal T2-WI T2-WI images images (b). A (b ). peripheral, barely visible, hyperintense (b), and enhancing nodule (a) is depicted on the posterior A peripheral, barely visible, hyperintense (b), and enhancing nodule (a) is depicted on the posterior edge of the conus medullaris (arrows). edge of the conus medullaris (arrows).

One year later, due to evidence of progressionprogression of the residual ELST in absence of serviceable hearinghearing onon thethe left left side, side, a a complete complete resection resection was was obtained obtained by by a translabyrinthic a translabyrin- thicapproach, approach, completely completely sparing sparing facial facial nerve nerve function. function.

3. Discussion Discussion Von Hippel–Lindau syndrome (VHLs) is a rare, inheritedinherited disease with autosomalautosomal dominant inheritance, caused caused by the mutati mutationon of the VHL gene. The mutation causes a lossloss of of function function of the the VHL VHL tumor tumor suppressor gene, located at the level of the short arm of chromosome 3 (3p25.3), which normally favors the degradation of the hypoxia-inducible factor (HIF) byby thethe proteasomeproteasome in in the the presence presence of of normal normal oxygen oxygen levels. levels. The The lack lack of oxygen-of oxygen-dependentdependent degradation degradation of HIF of leadsHIF leads to the to translocation the translocation of this of factorthis factor at the at nuclear the nuclear level leveland the and subsequent the subsequent transcription transcription of angiogenic, of angiogenic, erythropoietic, erythropoietic, and growth and growth factors (VEGF,factors (VEGF,Glut1, PDGF, Glut1, and PDGF, TGF andα), whoseTGFα), activation whose activation determines determines tumor genesis tumor [genesis4]. Subjects [4]. Subjects affected affectedby VHLs, by due VHLs, to the due overproduction to the overproduction of angiogenic of andangiogenic erythropoietic and erythropoietic factors, may developfactors, mayvascular develop lesions vascular affecting lesions the centralaffecting nervous the central system nervous (CNS), system including (CNS), cerebellar, including spinal, cerebellar,brainstem, spinal, and brainstem, supratentorial and supratentorial hemangioblastomas. hemangioblastomas. In addition, In retinal addition, angiomas retinal andan- giomasendolymphatic and endolymphatic sac tumors are sac described. tumors are At described. the visceral At level,the visceral manifestations level, manifestations include liver includeand renal liver cysts, and clear renal cell cysts, renal clear cell cell carcinomas renal cell carcinomas (RCC), pheochromocytomas, (RCC), pheochromocytomas, pancreatic pancreaticneuroendocrine neuroendocrine tumors (pNET), tumors epididymal, (pNET), epididymal, and broad and ligament broad cystadenomasligament cystadeno- of the masuterus of [the5]. uterus [5]. Endolymphatic sacsac tumorstumors developdevelop in in 10–15% 10–15% of of VHL VHL cases cases and and represent represent a distinctive a distinc- tivelesion. lesion. The The mean mean age ofage onset of onset is lower is lower in VHL in VHL patients patients (31.3 (31.3 years) years) than than in non-VHL in non-VHL ones ones(52.5 (52.5 years) years) [6] and [6] theyand they may may be bilateral be bilatera in 30%l in 30% of cases of cases [7]. The[7]. The tumor tumor arises arises from from the theduct duct and and the endolymphaticthe endolymphatic sac, specializedsac, specialize structuresd structures of the of vestibular the vestibular aqueduct aqueduct included inin the thickness of the dura mater, and can be locally invasive and erode the adjacent cluded in the thickness of the dura mater, and can be locally invasive and erode the adja- structures such as the semicircular canals and cochlea. Clinical symptoms include hearing cent structures such as the semicircular canals and cochlea. Clinical symptoms include

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loss (84–100%), tinnitus (73–77%), vertigo (62–68%), and facial nerve palsy (8%). Hearing loss may be sudden (secondary to intralabyrinthine hemorrhage) or gradual (usually owing to endolymphatic hydrops) [7]. On CT, endolymphatic sac tumors may show a moth-eaten appearance in the petrous temporal bone related to the “scalloping” of the surrounding bone structures and erosive changes in the vestibular aqueduct, semicircular canals, and cochlea. Central calcific spiculation and posterior rim calcification are commonly seen. Enhanced images show an avidly enhancing tumor [8,9]. At MRI, these tumors may be T1 hyperintense (secondary to hemorrhagic and proteinaceous contents) and T2 hyperintense. Intense enhancement of the solid portions of the tumor is seen after administration of gadolinium. Accurate early diagnosis of endolymphatic sac tumors followed by prompt surgical resection are critical, as they can help prevent or reduce hearing loss and other audio-vestibular symptoms [10]. The mainstay of ELTS management is complete surgical resection, but when it is not feasible, adjuvant radiotherapy or radiosurgery may be indicated [11]. The CNS HMG is the prototype tumor of VHL and may occur in the cerebellum, brainstem, spinal cord, cauda equina, or supratentorial region. In VHL, CNS HMGs most commonly occur in the cerebellum (44–72%), followed by the spinal cord and brainstem [12,13]. HMGs constitute about 1.5% to 2.5% of all neoplasms arising intracranially and 7% to 12% of all posterior fossa neoplasms [14]. Patients with cerebellar HMG may develop gait ataxia, dysmetria, headaches, diplopia, vertigo, and emesis: In many patients, the symptoms may be caused by the cyst or syrinx associated with the tumor rather than the tumor itself. Historically, cerebellar HMGs have been classified into four subtypes: type 1 (5%) is a simple cyst without a macroscopic nodule; type 2 (60%) is a cyst associated with a mural nodule; type 3 (26%) is a solid tumor; and type 4 (9%) is a solid tumor with small internal cysts [7]. CNS HMGs are classified as World Health Organization (WHO) grade 1 tumors. Histologic analysis reveals a vascular capillary network lined with hy- perplastic endothelial cells, which are surrounded by pleomorphic vacuolated stromal cells with lipid-rich cytoplasm. Computed tomographic (CT) images show a well-defined homogeneous cyst with an isoattenuating mural nodule on nonenhanced images [15]. Contrast-enhanced CT images show an avidly enhancing mural nodule within the cyst (the so-called cyst with mural nodule appearance). MR imaging features mimic those at CT. The cystic component is T1 hypointense and T2 hyperintense and the mural nodule is T1 hypointense and T2 isointense or hyperintense. After intravenous injection of gadolinium, the nodules show evident enhancement while no enhancement is seen in the cyst wall. The differential diagnosis includes juvenile pilocytic astrocytoma, arachnoid cyst, and metastases. Surgical resection is performed for the symptomatic tumors, which are usually tumors with large associated cysts and/or peritumoral edema. Detection of retinal HGMs must lead to a complete workup to exclude or confirm the syndrome, especially if they are multiple and bilateral. In more than 80% of cases, retinal HMGs are peripheral and present on ophthalmoscopic examination as highly vascularized solid nodules, possibly associated with surrounding edema. On CT examination they are slightly hyperdense (Figure2a) compared to the surrounding vitreous and may be calcific [16] on MRI retinal HMGs are hyperintense in T2WI (Figure2b) and demonstrate a rich enhancement after Gadolinium injection (Figure2c) [ 17]. Retinal detachment, cataract, uveitis, macular edema can be can be associated with retinal HGMs due to exudative phenomena [2,16]. Frequently spinal cord lesions coexist with cerebellar ones, which is why it is essential to perform a complete study of the spinal cord as well [12,18]. At the spinal level, HMGs are often located in the cervical portion. Similar to the cerebellar HMGs from radiology and morphology point of view, they can be both intra- and extrame-dullary and tend to show the nodular part facing the posterior pial side [17]. HMGs can be associated with medullary edema or with hydrosyringomyelias due to compressive alteration of the CSF dynamics. The vascular nature, which may also be associated with the presence of intralesional arteriovenous shunts [15,19], can make Diagnostics 2021, 11, 1005 7 of 8

differential diagnosis difficult, especially with spinal vascular lesions (dural fistulas or arteriovenous malformations). The clinical diagnosis of VHLs according to Danish criteria contemplate: - family history for VHLs and diagnosis of retinal hemangioblastoma, CNS hemangioblastoma, PPGL, or RCC; - negative family history for VHLs, in the presence of ≥2 CNS or retinal lesions (hemangioblastomas) or ≥2 visceral lesions (RCC, PPGL, multiple pancreatic or renal cysts, pNET, tumor of the endolymphatic sac of the o- cystadenoma of the epididymis, or broad ligament of the uterus) or the concomitant presence of a hemangioblastoma and a visceral lesion [20]. The diagnosis of VHLs may be suspected clinically but confirmed by genetic analysis. The identification of a pathological variant of the VHL gene currently represents the diagnostic gold standard. Comprehensive genetic testing of the VHL gene is recommended for individuals with the presence of one or more characteristic lesions including hemangioblastomas of the brain, spine, or retina; endolymphatic sac tumors; epididymal cystadenomas; pheochromocytoma; multiple pancreatic cystadenomas; and clear cell RCC diagnosed at age 40 or younger. There is also a large variety of hereditary cancer panels, many of which include the VHL gene. Thus, individuals might be diagnosed with a pathogenic variant in VHL due to other combinations of tumor diagnoses and family history (e.g., those with a diagnosis of clear cell RCC over the age of 40 and a family history of kidney cancer). Early detection of these tumors plays a key role in the optimal management of this condition. Radiologists should be aware of the imaging features of VHLs. For asymptomatic patients, we suggest observation with serial imaging, unless tumor growth appears or symptoms develop, rather than immediate therapeutic intervention. This peculiar case had the aim to highlight the importance of having recognized two different rare tumors, allowing us to achieve the genetic diagnosis and to begin an adequate follow-up.

Funding: This research received no external funding. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Written informed consent has been obtained from the patient to publish this paper. Data Availability Statement: The data presented in this study are available on request from the corresponding author. Conﬂicts of Interest: The authors declare no conﬂict of interest.

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