Reossification of Gorham-Stout disease of the maxilla and the pterygoid process during medical treatment with sirolimus, zoledronic acid and vitamin D: a case report

Introduction

The Gorham-Stout disease (GSD) is a rare osteolytic condition of the progressive osseous resorption and proliferation of connective tissue with vascular and/or lymphatic prevalence which replaces the prior normal elements of the diseased bone(s). Up to now more than 350 documented cases were described in the literature (1,2). Currently there are no coordinated guidelines for management of GSD which could be tailored depending on the anatomic site, the extent of the resorption or the manifestation age. Descriptions of initial empirical efforts with different effect for management of variously located GSD were followed by recognition of GSD as a part of the heterogeneous group of complex lymphatic anomalies (CLA) (3). Certain entities that belong to this broad group of rare disorders had demonstrated good treatment responses and prognostically more favorable results with some comparatively new pharmaceutical approaches, including: the mammalian target of rapamycin (mTOR) inhibitors (everolimus, sirolimus), steroids, interferon, bisphosphonates, vincristine and MAPK/MEK inhibitors (tramenib) (4-7).

GSD usually presents sporadically in young and adult patients (8). The clinical signs often represent local pain with possible swelling, progressive secondary deformity, and pathologic fractures. For such locations as ribs and spine life-threatening complications include hylothorax and progressive neurological deficit (9).

Craniomaxillofacial (CMF) GSD represents around 25% of the known cases (10). CMF GSD usually gets diagnosed in a delayed stage (mean time between the onset of the disease and its definite diagnosis is 3.5 years) (11). This assumes that at the time of diagnosis a considerable fraction of patients presents with remission of the active osteolytic process, the other affected subjects receive a delay in treatment initiation. These individuals may undergo a series of unnecessary and unjustified invasive interventions. After the onset of fibrosis at the GSD-affected locations defects of the bone and deformity may require reconstructive surgery (12,13).

We present a case of the right maxilla GSD with an in-continuity progression to the base of the right pterygoid process (PP) and was successfully treated with a combination of zoledronic acid (ZA), vitamin D, and sirolimus. This protocol was reported as effective for the treatment of GSD though very limited data exist that supports favorable outcomes for the CMF GSD (5,6,14-16). We present this article in accordance with the CARE reporting checklist (available at https://fomm.amegroups.com/article/view/10.21037/fomm-23-80/rc).

Case presentation

A 40-year-old male was admitted in June 2019 with the following history. In June 2018 he received endodontic procedure of tooth 1.6 in a private rural facility. During that he experienced sharp stabbing pain in the ipsilateral midface which did not resolve neither after the manipulation, nor in the following week. It did not respond to analgetics. Tooth 1.6 was extracted. The adjacent teeth 1.4, 1.5, 1.7, 1.8 were also soon extracted due to progressing mobility at the same facility. In August 2018 he was admitted to the head neck oncology department of the local rural hospital. An extended biopsy was outreached in the right maxillary region (specifically at the alveolar crest, the sites of the removed teeth 1.4–1.6) without a definitive diagnosis.

At referral to the first authors’ center (June 2019) the leading sign was the high-intensity pain. The defect of the right maxillary alveolar crest, and marked restriction of mandibular movement were observed. The teeth 1.4–1.8 were absent. The midfacial soft tissues, the right palate and teeth 1.3, 1.2, 1.1 were numb. Teeth 1.3, 1.2—mild pathologic mobility. Soon after presentation he complained about the onset of the right-sided diplopia (a year since the first disease-related signs). Complete blood work, kidney, hepatic, thyroid and parathyroid function test all exhibited normal counts.

The pathologic material including the cross sections and the paraffin blocks which was obtained during the biopsy (August 2018, 2 months after GSD manifestation occurred) was reassessed. The replacement of the bone by fibrous tissue which contained significant amounts of vessels represented by thin-walled capillaries, as well as neo-lymphatics. Surrounding areas showed chronic inflammation with lymphocytes, plasma cells and hemosiderin-laden macrophages. Foci of hemorrhages were also encountered. Mitotic signs were inconspicuous. No cellular atypia which might indicate malignancy was noted. Small amounts of osteoclasts were dispersed at the periphery of the resorbed bone. Osteoblastic response was absent (Figure 1).

Figure 1 Replacement of the bone by dense fibrous tissue infiltrated with thin-walled blood vessels and lymphatic spaces (hematoxylin and eosin, ×40).

Orthopantomography was performed after the physical exam. Roots of the upper frontal teeth appeared to be surrounded by a semi-translucent woven shadow (Figure 2A). The resultant radiographic data after the 4-year surveillance period was collected and compared progressively (Figure 2B).

Figure 2 Orthopantomograms taken at the initial presentation (A) and 4 years (3 years of continuous medical treatment and 1 year of additional observation) later (B).

The computed tomography (CT)-scan revealed: the defect’s anterior limit of the defect was delineated by the remaining tooth 1.3 and its socket (Figure 3A). At the tooth 2.4 the only contralateral element of the alveolar anatomy—the palatal cortical plate was seen (Figure 3B). Distally, at the tooth 2.5 the striking resorption of the right maxillary walls, especially the anterolateral wall and the contour of the infraorbital canal (IOC) (Figure 3C). The soft tissue GSD extension surrounded and impregnated the medial aspect of the IOC. At the 1.3, 2.3 apexes except the thin portion of the remaining outer cortical plate a massive defect of all the maxillary walls was witnessed (Figure 3D). At the lower margin of the inferior nasal conchae the posterolateral and the posteromedial walls were near totally replaced by the soft tissue component of the lesion, while the anterolateral wall at this level demonstrated slight distortion of its contour. The resorption of the base of the right PP appeared as an in-continuity involvement. The projection of the right palatine canals was overshadowed by the soft-tissue extension (Figure 3E). At the upper midface the right anterolateral antral wall was significantly dissolved, demonstrating islands of the affected cortex and rimmed by a homogenous soft-tissue envelope (Figure 3F). The summary was: the lytic destruction of the right maxilla of unknown etiology. The in-hospital ophthalmologist reported that the partial replacement of the orbital maxilla by the soft angiomatous tissues resulted in the eyeball displacement and diplopia.

Figure 3 CT-scan at initial presentation. The defect’s anterior limit of the was the remaining tooth 1.3 (A). At the tooth 2.4 the only contralateral element of the alveolar anatomy—the palatal cortical plate was seen (B). Distally, at the tooth 2.5 the striking resorption of the right maxillary walls, especially the anterolateral wall and the IOC (C). At the 1.3, 2.3 apexes a massive defect of all the maxillary walls was witnessed (D). The posterolateral and the posteromedial walls were near totally replaced by the lesion. The resorption of the base of the right PP appeared as an in-continuity involvement (E). At the upper midface the right anterolateral antral wall was significantly dissolved, demonstrating islands of the affected cortex and rimmed by a homogenous soft-tissue envelope (F). CT, computed tomography; IOC, infraorbital canal; PP, pterygoid process.

Differential diagnosis for this case included various types of osteolytic disorders. At a multidisciplinary case-conference the pathological process was characterized as a complex CMF lysis of bone tissue with replacement by non-tumorous fibrous and vascular tissue. The diagnosis of “GSD of the right maxilla and the base of the PP” was established, with an implicit prognosis. Off-label sirolimus 2 mg per day (soon corrected to the 1 mg per day dose); ZA 4 mg every 4 weeks and vitamin D 5,000 IU once daily treatment protocol was employed. Initially the target sirolimus plasma concentration (TSPC) was aimed for 6 ng/mL, but several weeks after the beginning of the treatment the patient complained of nausea. The TSPC test showed 11.9 ng/mL so the dosage was reduced to 1 mg/day from 2 mg/day. The TSPC levels of 4.5–5.0 ng/mL were sustained during the rest of the treatment.

The follow-up included physical examination, ocular checkup, orthopantomography and regular CT-scans of the skull, the radiographic data during the 4-year surveillance period was collected and compared (Figures 2B,4). No further resorption was noted at 9 months after treatment initiation. The patient reported marked decrease of pain and gradual improvement of the diplopia. The restoration of the anterior antral wall and the contour of the base of the PP was traced from this stage (Figure 5A,5B). Trismus has resolved. The frontal upper teeth had regained their stability.

Figure 4 The follow-up of more than 4 years (3 years of medical treatment and 1 year of additional follow-up) CT demonstrates signs of the local fibrosis and scarring at the limits of the initial defect. The anterior and anterolateral units of the right antrum display the absence of resorptive bony changes (A-C). At these levels, where the extensive affection of the lower wall of the IOC was observed at referral normal structure and shape of the canal were witnessed. The right infraorbital foramen was positioned and measured relatively symmetrically (D-F). CT, computed tomography; IOC, infraorbital canal.

Figure 5 Three-dimensional CT reconstruction image showing the gradual restoration of the anterior antral wall during the follow-up. (A) Anterior antral wall defect at presentation. (B) Anterior antral wall defect 1 year post presentation (10 months of treatment). (C) Anterior antral wall 1.6 years post presentation. (D) Anterior antral wall 2.3 years post presentation. (E) Anterior antral wall 3.5 years post presentation. (F) Anterior antral wall 4.6 years post presentation. CT, computed tomography.

After 3 years of treatment the patient’s condition suggested the achievement of prominent remission: the associated pain was reduced to rare episodic transient numbness of the infraorbital tissues, the diplopia was eliminated and the osteolytic changes were limited to its original borders. According to the results of the continuous radiologic investigations signs of the local fibrosis and scarring were demonstrated at the limits of the initial defect, which as well advocated the termination of the facial osteolysis. It was agreed on the discontinuation of the medical treatment. The recent follow-up CT-scan was outreached in September 2023. In the coronal plane the remaining scarce fragments of the alveolar process are shown. The anterior and anterolateral units of the right antrum display near total restoration. At the levels, where the extensive affection of the lower wall of the IOC was observed at referral normal structure and shape of the canal were witnessed. The right infraorbital foramen was positioned and measured relatively symmetrically. Two locations demonstrated apparent changes: the anterior antral wall and the base of the PP (Figure 5).

The follow-up was prolonged for another 12 months (the full surveillance reached over 4 years). Throughout this period no signs of recurrence were observed. The dentition and mastication were restored with the partial removable denture.

The patient was grateful to our team for the results of the therapy. The treatment and the additional follow-up period were not associated with any significant adverse events (except of the early nausea). He reported the continuous improvements mainly consisting of the regaining stability and sensation of the alveolar process, the teeth and palate. He was able to return to his previous professional duties as an industrial truck driver.

All procedures performed in this study were in accordance with the ethical standards of the P.A. Hertsen Moscow Oncology Research Institutional research committee(s) and with the Helsinki Declaration (revision of 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

GSD of the humerus, pelvis, thorax, the shoulder girdle and mandible are most often and comprehensively described (2). The maxilla appears among the most rarely affected bones (12,13,17-19). Most cases of maxillofacial GSD are detected before 40 years of age, with a mean presenting age of 29.6 years (3,6,12,16,20-25). Our case incorporated an in-continuous resorption of the PP thus the process was termed as polyostotic GSD. Though involvement of PP as a part of a complex scull base osteolysis was reported before we did not meet any data on combined continuous affection of the maxilla and the PP (10).

Our patient was clinically and radiographically traced for more than 4 years and demonstrated the significant restoration of the bone that was destructed during the active resorptive GSD manifestation. The grounds for such remarkable reparative changes are unknown. A case of partial reossification of the GSD of the arm treated surgically by free osseous grafts was reported before. The introduction of bone grafts had led to limited formation of new bone (20). The limitation is dictated by the nature of the single case descriptions. No matter how useful the implicated medical treatment protocol exhibited itself in this observation of ours it should not be blindly reused (e.g., overprescribed) especially in children.

GSD along with Kaposi-form lymphangiomatosis, generalized lymphatic anomalies and central conducting lymphatic anomalies are classified as CLA (3). In GSD the growth of lymphatics and elevated osteoclastic activity result in bone resorption. Vascular endothelial growth factor (VEGF), especially VEGF-A, -C, -D functions to induce lymphangiogenesis, with activation of the phosphoinositidine-3-kinase (PI3K) which leads to signaling of mTOR—an important link in the cell cycle and is crucial in immune reactions. This sequence results in boosting of lymphatic vasculature proliferation and angiogenesis (14). Sirolimus (rapamune) has the capability to inhibit mTOR pathway therefore the drug has strong immunosuppressive and antiproliferative effect. Recently GSD was shown to be associated with KRAS mutations. However, no definite correlation was found between genetic mutations and clinical manifestations. New genomic sequencing studies may provide additional information about the etiology of the disease. ZA is the nitrogen-containing bisphosphonate, an agent which was successfully implemented for GSD management. ZA has antiangiogenic properties in addition to osteoclast inhibition, besides ZA inhibits the mTOR pathway (5,14,15,21,22). This condition assumes that combined prescription of ZA and sirolimus in lymphatic anomalies and GSD will produce a synergistic curative effect.

The high complexity of the CMF anatomy dictates region-specific changes of the GSD progression. In case of GSD of the jaws one of the leading symptoms—teeth mobility, frequently leads to occlusion distortions and subsequent exorbitant extractions after dental consult (26). Such unsupported and often extensive interventions lead to absence and disfigurements of the supporting alveolar bone, thus creating a surplus bone loss which may aggravate the perception of the severity of the osseous destruction. Pain as well may serve as the leading symptom and its onset is generally associated with the start of active clinical GSD manifestation (27,28). The complaints may include local or regional events of varying severity, frequency, and duration. As observed in our case, this pain was nearly constant and unresponsive to non-steroid anti-inflammatory analgetics.

CMF GSD is distributed variably: monostotic or polyostotic involvement; combined affection of both jaws (21.4 %) with additional engagement of other bones (zygomatic bone—16.9%, temporal bone—16.9% and scull base—15.7%). The lesions are nearly equally defused between those reaching and/or crossing the midline and those which are lateralized without prognostic value (10,12).

For maxillofacial and CMF GSD, a clinical radiologic and pathologic pattern may be outlined. For maxilla this includes pain, teeth mobility (history of extractions due mobility/displacement), enophthalmos and diplopia, possible self-limiting abruption, the unspecific pathologic findings accompanied by lytic radiographic pattern of the antral walls, with a surrounding soft tissue rim and a possibility for in-continuous extension to the adjacent bones (29,30).

GSD still lacks standard-of-care guidelines, ZA and sirolimus are used off-label (31,32). Children and subjects with rare disorders are subjected to the off-label drug prescription more often if compared to the rest of the population. For CLA sirolimus was used in the dosage-groups. The TSPC levels of 10.0–15.0 ng/mL—the “high dose”, 5.0–10.0 ng/mL—“the intermediate dose”, and the “low dose” of 2.0–5.0 ng/mL (33). In our case early side-effects provoked correction of the TSPC to the “low-dose” levels (2 mg/day was changed to 1 mg per/day). This change of the dosage did not seem to influence the effectiveness anyhow. Lengthy consumption of mTOR inhibitors is known to cause hyperlipidemia, increase of cholesterol, glucose intolerance and insulin resistance. The reported adverse effects include: elevated risk of infection (especially interstitial pneumonia) as well as venous thromboembolism, and risk of lymphoma or other malignancy secondary to immunosuppression (31-33). Long-term bisphosphonates use is associated with possible gastrointestinal complications (esophagitis, esophageal ulcers and esophageal bleeding) and osteonecrosis of the jaws (34). It is true for both of the utilized pharmaceuticals that despite their potential curative influence it remains unclear when to stop the therapy (especially keeping in mind that the major bone recovery was observed during the first year of treatment) and if the continuous therapy has ongoing benefit. The example of our case suggests that in the otherwise healthy adults such a medical treatment protocol may be employed with special care on sirolimus dosage.

Conclusions

Rationally, it is strongly recommended to provide patients with facial GSD (or CLA) long-term continuous clinical and radiographic follow-up even after established remission. Besides, when GSD is suspected the lesion should be additionally reviewed as a CLA and classified according to the Vascular Anomalies Classification (35). Special attention must be attracted to the sirolimus dosage as our case demonstrated that the “low dose” TSPC was clinically effective while reducing the side-effects. Further research of this treatment protocol (and its safe rates) is needed to establish the potential rate of restoration of the GSD lesions responsive to it.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://fomm.amegroups.com/article/view/10.21037/fomm-23-80/rc

Peer Review File: Available at https://fomm.amegroups.com/article/view/10.21037/fomm-23-80/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://fomm.amegroups.com/article/view/10.21037/fomm-23-80/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are sufficiently researched and dealt with. All procedures performed in this study were in accordance with the ethical standards of the P.A. Hertsen Moscow Oncology Research Institutional research committee(s) and with the Helsinki Declaration (revision of 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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