Andruska, Neal

Brenneman, Randall

Daly, Mackenzie D

Hogan, Jacob

Orlowski, Hilary L P

Pipkorn, Patrik

Roy, Amit

English

Digital Commons@Becker

Washington University School of Medicine Digital Commons@Becker Open Access Publications 1-1-2022 A case of Gorham-Stout disease of the skull base treated with intensity modulated radiation therapy Amit Roy Neal Andruska Randall Brenneman Jacob Hogan Hilary L P Orlowski See next page for additional authors Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs Authors Amit Roy, Neal Andruska, Randall Brenneman, Jacob Hogan, Hilary L P Orlowski, Patrik Pipkorn, and Mackenzie D Daly Teaching CaseA Case of Gorham-Stout Disease of the Skull BaseTreated With Intensity Modulated RadiationTherapyAmit Roy, MD,a,* Neal Andruska, MD, PhD,a Randall Brenneman, MD, PhD,aJacob Hogan, BS,a Hilary L.P. Orlowski, MD,b Patrik Pipkorn, MD, MSCI,c andMackenzie D. Daly, MDdaDepartment of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri; bDepartment ofRadiology, Washington University School of Medicine, St. Louis, Missouri; cDepartment of Otolaryngology, WashingtonUniversity School of Medicine, St. Louis, Missouri; dDepartment of Radiation Oncology, University of Colorado School ofMedicine, Aurora, ColoradoReceived June 3, 2021; accepted September 10, 2021IntroductionGorham-Stout disease (GSD) is a rare, locally destruc-tive musculoskeletal disorder of unknown etiology. GSDaffecting the skull base is a particularly challenging diseaseentity. Skull-base GSD has a high propensity for causinglife-threatening complications such as cerebrospinal fluid(CSF) leaks, meningitis, and osteomyelitis. Additionally,skull-base GSD is often surgically unresectable. Althoughthe primary treatment modality for GSD is surgery, priorseries demonstrate that GSD is radiosensitive, and radia-tion therapy (RT) is indicated for refractory or symptom-atic cases not amenable to surgery. Older case series havedescribed the management of skull-base GSD with 2-dimensional or 3-dimensional RT techniques. Recenttechnological advances, such as intensity modulated RT(IMRT) and image guided RT, have allowed for the deliv-ery of highly conformal RT, potentially improving diseaseoutcomes and minimizing toxicity for head and neckcancer. Here we describe a case of GSD of the skull basesuccessfully treated with conformal IMRT, and a providea review of the pertinent literature.Patient CasePresentationA 27-year-old previously healthy woman initially pre-sented in May 2017 with several months of progressivetooth loss and a 5-day history of progressive left mandibu-lar swelling, trismus, and decreased oral intake afterminor trauma to her face. Maxillofacial computed tomog-raphy (CT) without contrast revealed a nondisplaced frac-ture of the left mandibular angle with hypoplasticappearance of the left mandibular body and ramus withsuperimposed areas of permeative destruction and ero-sion (Fig 1A). She then underwent left mandibulectomy,reconstruction of left mandibular defect with left fibularfascio-osseous free-flap, and placement of mandibularplate in June 2017. Final pathology revealed chronicinflammation, marrow fibrosis, and vascular malforma-tion consistent with GSD. Her postoperative course wasuncomplicated.She was seen for routine follow-up in January 2018, atwhich time she began to have pain in her left jaw regionSources of support: This research did not receive any specific grantfrom funding agencies in the public, commercial, or not-for-profitsectors.Disclosures: Dr Roy reports personal fees from Precisca, outside thesubmitted work. The remaining authors have no relevant conflicts ofinterest to disclose.*Corresponding author: Amit Roy, MD; E-mail: aroy@wustl.eduhttps://doi.org/10.1016/j.adro.2021.1008092452-1094/© 2021 The Authors. Published by Elsevier Inc. on behalf of American Society for Radiation Oncology. This is an open access article underthe CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Advances in Radiation Oncology (2022) 7, 100809and was noted to have progressive, near complete toothloss in the mandibular region. Maxillofacial CT withoutcontrast medium demonstrated progressive bone resorp-tion of her left mandible extending into her right mandi-ble (Fig 1B). She received 1 dose of intravenousbisphosphonate therapy (zoledronic acid, 5 mg) in April2018 and was recommended to take calcium 1200 mgdaily and vitamin D 50,000 IU per week. She then under-went total mandibulectomy and reconstruction with atotal mandibular prosthesis with right radial forearm free-flap in August 2018. Final pathology demonstrated atro-phic-appearing bone with focal vascular malformation,consistent with GSD. Her postoperative course was againuncomplicated.She was seen in routine follow-up in February 2020, atwhich time she felt a knot in her left cheek region. Maxil-lofacial CT without contrast demonstrated interval osteol-ysis involving the left sphenoid, lateral orbit, zygomaticarch, and squamosal temporal bones, consistent withGSD (Fig 1C-F). She was evaluated by a multidisciplinaryteam including otolaryngology, radiation oncology, andneurosurgery, and the patient elected to proceed withconventionally fractionated IMRT.Treatment planning and deliveryThe patient received a CT simulation without intrave-nous contrast lying supine with a custom thermoplasticimmobilization mask with head neutral and arm on arm.CT images were transferred to the RT planning system.Diagnostic CT from February 2020 was fused to the pri-mary image data set to assist with target delineation. Thetreating radiation oncologist contoured a clinical target vol-ume (CTV) with multidisciplinary input from the patient’sotolaryngologist and neuroradiologist (Fig 2 A-D), asreported in a previous study.1 The CTV was designed toencompass all areas of GSD. Planning target volume (PTV)was created using a margin of 3 mm from the CTV. PTVwas trimmed from skin to 3 mm to limit skin dose. Organsat risk were delineated including the optic nerves, optic chi-asm, brain stem, lacrimal glands, middle ears, corneas,esophagus, eyes, larynx, lens, lips, pharyngeal constrictors,spinal cord, and submandibular glands.An IMRT treatment plan was developed to deliver4200 cGy in 21 once daily fractions (Fig 3A-F and Fig 4).The dose was within the recommended range of 3600 to4500 cGy based on the German Society of RadiationOncology (DEGRO) guidelines.2 Institutional dose con-straints were used during planning as follows: spinal cordmaximum dose <40 Gy, spinal cord +5 mm maximumdose <45 Gy, optic nerve maximum dose <54 Gy, opticchiasm maximum dose <54 Gy, brain stem maximumdose <54 Gy, lacrimal gland mean dose <26 Gy, middleear mean dose <35 Gy, eye maximum dose <45 Gy, lar-ynx mean dose <25 Gy, parotid gland mean dose <20 Gy,submandibular gland mean dose <25 Gy, lips mean dose<20 Gy, esophagus mean dose <20 Gy, and pharyngealconstrictors mean dose <50 Gy. Maximum dose withinPTV was <120% prescription (Rx) dose, and minimumdose within PTV was ≥95% Rx dose. PTV coverage goalwas V95% Rx dose ≥95%.Fig 1 Axial diagnostic computed tomographic images of the maxillofacial bones without contrast reveal osseous changes indicative ofGorham-Stout disease (blue arrows) including osteolysis and bone resorption. May 2017 scan demonstrating changes in left mandible(A). January 2018 scan demonstrating progressive mandibular disease crossing midline to the right (B). February 2020 scan demonstrat-ing further disease progression with new osteolysis within the maxilla (C-D), left sphenoid, lateral orbital wall, zygomatic arch, andsquamosal temporal bone (E-F).Fig 2 Axial (A-C) and coronal (D) computed tomographic images of the head and skull base from simulation radiation therapy plan-ning study demonstrating clinical target volume in green and planning target volume in cyan.2 A. Roy et al Advances in Radiation Oncology: January−February 2022All treatments were performed using the Ethos system(Varian Medical Systems Inc). The patient received a dailycone beam CT before RT delivery to assist with set-up.During treatment the patient experienced expected sideeffects as per Common Terminology Criteria for AdverseEvents version 5.0, including grade 2 oral mucositis (man-aged with oral narcotic pain medications), grade 1 dys-phagia, grade 1 xerostomia, grade 1 skin erythema(managed with over-the-counter skin creams), and grade1 xerophthalmia (managed with over-the-counter eyelubricants). The patient did not require any treatmentbreaks. After completion of RT, the patient has had anexcellent clinical course without evidence of disease pro-gression or significant late morbidity. She does have mildgrade 2 lymphedema in the left facial region, attributed toa combination of surgical disruption of facial lymphaticsand RT. Maxillofacial CT without contrast performedapproximately 3, 9, and 12 months post-RT demonstratedstability of osteolysis (Fig 5A-F).Discussion and Literature ReviewGSD, or “vanishing bone disease,” is a rare, locallydestructive musculoskeletal disorder of unknown etiology.The first case was described in 1838.3 In 1955, Gorhamand Stout summarized the clinical and histopathologicfeatures in 2 cases.4 GSD typically affects younger adults(<40 years old) and does not have any predilection forrace, gender, or familial history.5,6 GSD can affect anyanatomic region but is more commonly found in theskull, ribs, shoulders, and pelvis.4,5,7,8 The symptoms arenonspecific and based on the musculoskeletal site affected.Symptoms can include pain or muscle weakness, andpatients often present with pathological fracture.5,9,10GSD is a diagnosis of exclusion, and workup is requiredto rule out infectious, neoplastic, or osseous disease pro-cesses. Although there are a combination of radiologicand histologic features that support the diagnosis ofGSD,4,11,12 the precise pathophysiological mechanism isnot well understood.6 Furthermore, the clinical course isunpredictable, as both spontaneous regression and rapidprogression have been reported.5,9There is no standard treatment approach for GSD. The2 primary forms of treatment are surgery and RT.7 Medi-cal therapy with osteoclast inhibiting drugs such asbisphosphonates or interferon (alfa-2b) therapy has alsobeen reported, although these are typically used in con-junction with surgery or RT. Surgical options includeresection of effected bone with reconstruction or amputa-tion.7 The DEGRO guidelines suggest RT is an effectivetherapy with local control of »80% and minimaltoxicity.2,7,13 The prognosis for GSD is generally good,though patients with GSD affecting areas such as the skullbase and spine can have increased morbidity and mortal-ity given the proximity to critical structures.14To the best of our knowledge, this is the first case ofskull-base GSD treated with conformal IMRT reported inthe literature. Skull-base GSD is particularly challengingand can be life-threatening secondary to CSF leaks, result-ing in recurrent meningitis, medullary compression, orcervical instability.15,16 In addition, skull-base GSD has aFig 3 Axial (A-C), coronal (D-E), and sagittal (F) views of the intensity modulated radiation therapy plan for the patient.Fig 4 Dose volume histogram of the intensity modulated radiation therapy plan for the patient.Advances in Radiation Oncology: January−February 2022 Gorham-Stout skull-base radiation therapy 3high propensity for causing local symptoms, as seen withour case, that significantly affect patient quality of life.Therefore, optimal management of skull-base GSD is cru-cial. Surgery can be considered for up-front managementbut can result in significant morbidity, including graftresorption, recurrent CSF leaks, and infections.15-17 Inpatients with particularly advanced disease, surgery maybe technically challenging due to the lack of bone sub-stance for fixation of autologous or alloplastic materials.Our patient’s GSD was refractory to 2 surgical proceduresand medical therapy, with RT used as a salvage therapyoption.Descriptions of RT for GSD have historically been forcases of progressive GSD resistant to surgical interven-tion, as with our patient. RT has also demonstrated effi-cacy as definitive first-line therapy. RT for skull-base GSDhas mostly been reported in single case reports (Table 1)using 2-dimensional or 3-dimensional RT techniques,with a total RT dose ranging from 20 to 45 Gy. A majorityof patients (10 of 13) described in the literature demon-strated no local progression after RT. Although data arelimited, there is a suggestion of dose-dependency withregard to control of GSD, with in-field progression occur-ring in 2 cases after total doses of 36 Gy and 35 Gy, andout-of-field progression in 1 case after 36 Gy, whereas nopatients who received >36 Gy had disease progression.These data inform the DEGRO guideline recommenda-tions (36 to 45 Gy).2Our case highlights the safety and early efficacy of con-formal IMRT for the treatment of skull-base GSD refrac-tory to surgery and medical management. Our patientwas treated with a total dose of 42 Gy, consistent with theDEGRO guidelines. Our patient tolerated her RT coursewell with minimal acute toxicity. In-field progression hasbeen reported as late as 46 months post-RT.7 Althoughlong-term disease control and late toxicity cannot be fullyassessed without longer follow-up, the patient is currently12 months post-RT without evidence of disease progres-sion or significant late morbidity. IMRT has demon-strated significant benefit in decreasing toxicity from RTfor head and neck cancer.18-20 Our patient is young, andfurther disease progression or development of treatment-related toxicity could have devastating consequences. Fur-thermore, radiation-induced sarcoma after managementof skull-base GSD has been reported, placing importanceon reducing the total treatment volume.21 Proton therapyhas emerged as another modality to deliver RT for skullbase tumors while minimizing integral dose to organs atrisk.22,23 Therefore, we recommend that conformal RTtechniques (IMRT or proton therapy) be considered forthe treatment of skull-base GSD refractory to surgical andmedical management.Fig 5 Follow-up axial diagnostic computed tomograms of the maxillofacial bones without contrast at 3 months (A-C) and 9 months(D-F) post completion of radiation therapy demonstrate stabilization of disease without new areas of osteolysis.4 A. Roy et al Advances in Radiation Oncology: January−February 2022References1. Roy A, Andruska N, Orlowski HLP, et al. The novel use of a com-mercially available video-conference platform to facilitate multidis-ciplinary target volume review and delineation for skull-baseradiation therapy during the coronavirus disease 2019 pandemic.Adv Radiat Oncol. 2021;6:100598.2. Seegenschmiedt MH, Micke O, Niewald M, et al. DEGRO guidelinesfor the radiotherapy of non-malignant disorders: Part III: Hyperpro-liferative disorders. Strahlenther Onkol. 2015;191:541–548.3. Jackson JBS. A boneless arm. Boston Med Surg J. 1838;18:368–369.4. Gorham L, Stout A. Massive osteolysis (acute spontaneous absorp-tion of bone, phantom bone, disappearing bone): Its relation tohemangiomatosis. J Bone Joint Surg Am. 1955;37:985–1004.5. Patel DV. Gorham’s disease or massive osteolysis. Clin Med Res.2005;3:65–74.6. Newland L, Kong K, Gallagher R, Turner J. Disappearing bones: Acase of Gorham−Stout disease. Pathology. 2008;40:420–423.7. Heyd R, Micke O, Surholt C, et al. Radiation therapy for Gor-ham-Stout syndrome: Results of a national patterns-of-carestudy and literature review. Int J Radiat Oncol Biol Phys.2011;81:e179–e185.8. Hu P, Yuan X, Hu X, Shen F, Wang J. Gorham-Stout syndrome inmainland China: A case series of 67 patients and review of the litera-ture. J Zhejiang Univ Sci B. 2013;14:729–735.9. Lobo-Mueller E, Amaral JG, Babyn PS, Wang Q, John P. Complexcombined vascular malformations and vascular malformation syn-dromes affecting the extremities in children. Semin MusculoskeletRadiol. 2009;13:255–276.10. M€oller G, Priemel M, Amling M, Werner M, Kuhlmey AS, DellingG. The Gorham-Stout syndrome (Gorham’s massive osteolysis). JBone Joint Surg Br. 1999;81:501–506.11. Torg JS, Steel HH. Sequential roentgenographic changes occurringin massive osteolysis. J Bone Joint Surg Am. 1969;51:1649–1655.12. Heffez L, Doku HC, Carter BL, Feeney JE. Perspectives on massiveosteolysis. Report of a case and review of the literature. Oral SurgOral Med Oral Pathol. 1983;55:331–343.13. Dunbar SF, Rosenberg A, Mankin H, Rosenthal D, Suit HD. Gor-ham’s massive osteolysis: The role of radiation therapy and a reviewof the literature. Int J Radiat Oncol Biol Phys. 1993;26:491–497.14. Fl€orchinger A, B€ottger E, Claaß-B€ottger F, Georgi M, Harms J.[Gorham-Stout syndrome of the spine. Case report and review ofthe literature.]. Rofo. 1998;168:68–76.15. Simon F, Luscan R, Khonsari RH, et al. Management of GorhamStout disease with skull-base defects: Case series of six children andliterature review. Int J Pediatr Otorhinolaryngol. 2019;124:152–156.16. Woodward HR, Chan DP, Lee J. Massive osteolysis of the cervicalspine. A case report of bone graft failure. Spine. 1981;6:545–549.17. Boyer P, Bourgeois P, Boyer O, Catonne Y, Saillant G. Massive Gor-ham-Stout syndrome of the pelvis.Clin Rheumatol. 2005;24:551–555.18. Lee N, Puri DR, Blanco AI, Chao KSC. Intensity-modulated radia-tion therapy in head and neck cancers: An update. Head Neck.2007;29:387–400.19. Wang X, Eisbruch A. IMRT for head and neck cancer: Reducingxerostomia and dysphagia. J Radiat Res. 2016;57(suppl):i69–i75.20. Gutiontov SI, Shin EJ, Lok B, Lee NY, Cabanillas R. Intensity-modu-lated radiation therapy (IMRT) for head and neck surgeons. HeadNeck. 2016;38(suppl):E2368–E2373.21. Rodriguez-Vazquez JR, Chandra SR, Albertson ME, Hansen NJ,Johnson CM. Radiation-induced sarcoma on 18F-FDG PET/CTafter treatment of Gorham-Stout disease of the maxilla. Clin NuclMed. 2019;44:e607–e608.22. Blanchard P, Gunn GB, Lin A, Foote RL, Lee NY, Frank SJ. Protontherapy for head and neck cancers. Semin Radiat Oncol. 2018;28:53–63.23. Combs SE, Laperriere N, Brada M. Clinical controversies: protonradiation therapy for brain and skull base tumors. Semin RadiatOncol. 2013;23:120–126.Table 1 Summary of published studies of radiation therapy for management of skull base Gorham-Stout diseaseAuthors Site(s)Dose(cGy)Dose perfraction (cGy)Follow-up(mo) ResultsKurczynski and Horwitz (1981)22 SB 2000 200 24 No progression, +BRHeffez et al (1983)12 SB 4500 180 12 No progression, +BRDunbar et al (1993)13 SBSB, CS4500440018020065118No progression/remodelingNo progression/remodelingSchiel and Prein (1993)23 SB 4000 200 77 No progressionFrankel et al (1997)24 SB 2340 180 12 Stabilization and sclerosisKhosrovi et al (1997)25 SB, CS 4000 200 24 No progression, +BRMawk et al (1997) SB, CS 4140 180 3 No progression, +BRGirn et al (2006) SB, CS 3500 175 12 In-field progressionHeyd et al (2011)7 SB, CSSB, CSSB, CSSB, CS3600360040003060200200200180244654111Out-of-field progressionIn-field progressionNo progressionNo progressionAbbreviations: BR = bone remineralization; CS = cervical spine; SB = skull base.Advances in Radiation Oncology: January−February 2022 Gorham-Stout skull-base radiation therapy 5

A case of Gorham-Stout disease of the skull base treated with intensity modulated radiation therapy

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A case of Gorham-Stout disease of the skull base treated with intensity modulated radiation therapy

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