An 84-Year-Old Man with a History of Myeloma and Biphosphonate-Related Osteonecrosis of the Jaw Treated with Preoperative Vascular Embolization Before Partial Maxillectomy

Introduction

Myeloma is a malignant hematologic plasma cell tumor that proliferates within the bone marrow and is complicated by severe bone destruction. Myeloma cells proliferate by destroying bone tissue to make room for growth, and they produce factors involved in osteoclast activation [1]. Therefore, myeloma is treated using bisphosphonate preparations (BPs), which induce osteoclast apoptosis and inhibit bone resorption. Furthermore, BPs exert direct anticancer effects by inhibiting myeloma cell proliferation, enhancing apoptosis, or inhibiting angiogenesis [2].

BPs are used for treating myeloma and suppressing osteoporosis and bone metastasis of various cancers. Thus, the usefulness of BP therapy is increasing. However, osteonecrosis of the jaw may develop when patients who have been receiving BPs for an extended period undergo dental procedures such as tooth extraction [3]. This jaw-specific necrosis occurs in patients receiving bone resorption inhibitors, such as anti-nuclear factor kappa B ligand antibodies and anti-sclerostin antibodies other than BPs, and also in patients receiving angiogenesis inhibitors, such as tyrosine kinase inhibitors and anti-vascular endothelial growth factor human monoclonal antibody. Osteonecrosis of the jaw associated with BPs (the most common of these drugs) was first reported in 2003 as bisphosphonate-related osteonecrosis of the jaw (BRONJ). Initially, it was defined as an exposed bone in the craniofacial region in current or former BP users without a history of radiation therapy to the craniofacial region that did not heal within 8 weeks of confirmation by a medical professional [4]. Currently, it is known that BPs, anti-receptor activator of nuclear factor kappa B antibodies, and angiogenesis inhibitors can cause similar osteonecrosis of the jaw. The American Association of Oral and Maxillofacial Surgeons (AAOMS) issued a position paper defining such osteonecrosis of the jaw as medication-related osteonecrosis of the jaw (MRONJ), defined as palpable bone exposure in the maxillofacial region through an intraoral or extraoral fistula lasting > 8 weeks in patients without radiation therapy or metastatic disease to the jaw and who have received antiresorptive therapy alone or in combination with immunomodulatory or angiogenic agents [5].

The incidence of MRONJ associated with BP therapy is 0.02–0.05% in patients with osteoporosis [6] and 1.6–18.0% in patients with cancer [7].

MRONJ onset should be prevented. However, if it develops, the primary treatment goals are pain control and prevention of necrosis expansion and pathological fractures. MRONJ treatment is either conservative or surgical. Conservative treatment involves administering antimicrobial agents and rinsing with chlorhexidine or antimicrobial agents to improve oral hygiene.

Surgery is performed when the disease is refractory to conservative treatment and when necrosis progresses. Preoperative measures include rinsing the mouth to control local infection, smoking cessation, and managing underlying diseases such as diabetes mellitus. Jawbone resection should be performed with removal of a necrotic bone margin, leaving the healthy bone intact and the wound completely closed to prevent bone exposure on the resection surface. Notably, posterior maxilla re-section may result in bleeding from the artery or its branches located behind the pterygoid plate or within the pterygopalatine fossa. If an intraoperative arterial injury occurs, immediate hemostatic treatment is necessary. However, local hemostasis is often difficult. One option in such cases is emergency ligation of the external carotid artery on the central side.

Recent advances in diagnostic imaging techniques such as computed tomography (CT) and angiography (CTA) have enabled detailed visualization of vascular distribution, and therapeutic procedures are now performed using catheters and angiography [8]. Emergency hemostasis for bleeding from the maxillary artery or its branches can be performed with catheter-based vascular embolization, even after bleeding. However, the preparation for such hemostasis takes time. Similar to emergency litigation of the external carotid artery, the external carotid artery must be clamped until the catheter is ready for hemostasis, which is an urgent procedure. Preoperative catheter-based vascular embolization prevents intraoperative bleeding and the need for emergency procedures in patients undergoing the surgical treatment of head and neck tumors, temporomandibular joint replacement surgery, and extraction of cystic lesions near the maxillary artery branches [9–12].

This report describes the case of an 84-year-old man with a history of myeloma and BRONJ treated with preoperative vascular embolization before partial maxillectomy.

Case Report

An 84-year-old man presented to our department for evaluation of pain and bone exposure in his right maxilla. He had myeloma, atrial fibrillation, hypertension, diabetes mellitus, and rheumatoid arthritis as comorbidities. Myeloma had been diagnosed 7 years previously, and the current stage of the disease corresponded to Stage I of the International Staging System. He had been taking BPs for 4 years. After extracting a right maxillary molar for periodontitis treatment 3 years earlier, he experienced continued poor healing at the extraction site, with pain in the right maxilla and purulent discharge from the exposed bone.

The initial intraoral examination at the first visit showed bone exposure on the gingival surface of the right maxilla, with occasional drainage of pus from the region around the exposed bone. The patient had no history of cigarette smoking. He was taking antihypertensive medications, steroids, and anticoagulants, but he had discontinued the BP therapy. Panoramic radiography and CT revealed bone resorption and decomposing bone-like hard tissue in the right maxilla (Figure 1A–1D). His condition was consistent with the definition of MRONJ given in the AAOMS’ Position Paper, and right maxillary MRONJ was diagnosed; therefore, no biopsy was performed. We planned to treat the patient surgically, using partial right maxillectomy.

Preoperative CT images revealed necrotic bone in a portion of the posterior wall of the right maxillary sinus. This necrosis may have been caused by adhesion of surrounding inflammatory granulation tissue to the maxillary artery or its branches. In such cases, there is a risk of bleeding from the maxillary artery or its branches during surgical removal of the necrotic bone, and emergency hemostasis is extremely difficult to achieve. Therefore, we decided to perform embolization the day before surgery to prevent abnormal bleeding and ensure surgical safety. The embolization target was the peripheral maxillary artery beyond the middle meningeal artery bifurcation, and the direction of the artery was confirmed preoperatively by CTA (Figure 2A). A sheath was placed from the right inguinal region, a circumflex (CX) catheter (Simmons type, SY2; Terumo Interventional Systems, Tokyo, Japan) was placed in the right external carotid artery using a guidewire and angiography, and a microcatheter (Progreat λ™; Terumo Interventional Systems, Tokyo, Japan) was placed under fluoroscopy into the right posterior superior alveolar artery branch distal to the right maxillary artery. Contrast medium was then injected to confirm the peripheral vascularity of the maxillary artery (Figure 2B). Next, the artery was peripherally embolized from the middle meningeal artery branch using coils (VortX™ Diamond-18, 3×3.3 mm: 3 pieces; Boston Scientific, Marlborough, MA, USA) (C-STOPPER COIL™ 2.0×60 mm: 3 pieces and 2.0×30 mm: 1 piece; Piolax Medical Devices, Yokohama, Japan). The vessels were embolized from the middle meningeal artery bifurcation to the peripheral vessels. Confirmatory angiography showed that the distal portion of the right maxillary artery was visually obliterated (Figure 2C), and the embolization procedure was completed.

The day after embolization, a right partial maxillectomy was performed under general anesthesia to completely remove the necrotic bone with a margin of approximately 0.5 cm on CT images. The upper portion was resected to the floor level of the maxillary sinus, and the posterior portion was resected beyond the maxillary tubercle to the base of the pterygoid process (Figure 3A). After partial maxillary resection, the bone wound surface was covered as much as possible with the surrounding oral mucosa. Areas that were difficult to cover with mucosa were covered with polyglycolic acid sheets and coated with fibrin glue for complete coverage of the bone surface. In addition, gauze coated with bacitracin was loaded into the maxillary sinus opening. Finally, the buccal division, which had been performed to widen the operative field, was sutured closed with the patient in the supine position, and the surgery was terminated. The intraoperative blood loss volume was 155 mL.

No postoperative bleeding occurred, and the gauze that had been placed in the open sinus was removed 1 week after surgery. The micro-coil used for embolization remained in place (Figure 3B), and no embolization-associated complications, such as delayed healing due to decreased blood flow, were observed. Pathology examination of the resection was performed by the pathologist using hematoxylin-eosin staining (Figure 4). Based on the histopathological findings, the pathologist ruled out myeloma and diagnosed BRONJ. Postoperatively, the wound was successfully covered with surrounding mucosa with an open sinus (Figure 5A), and the patient’s ongoing pain resolved. The open sinus was closed using a maxillary denture (Figure 5B, 5C). The patient was clinically well for 3 years postoperatively with no recurrence of osteonecrosis of the jaw.

Discussion

This case report shows that preoperative vascular embolization is a useful way to prevent surgical risks such as abnormal bleeding from the maxillary artery when treating MRONJ extending to the posterior maxilla using surgery. It shows the target site to be embolized.

Patients with osteoporosis or bone metastases from cancer are often administered BPs and bone resorption inhibitors (eg, anti-nuclear factor kappa B ligand and anti-sclerostin antibodies) and angiogenesis inhibitors (eg, tyrosine kinase inhibitors and anti-vascular endothelial growth factor human monoclonal antibodies). Reportedly, osteonecrosis of the jaw occurs in patients receiving BP for myeloma following tooth extraction, as in the present case. This case also showed the characteristic features of BRONJ on CT, such as septation and irregular bone destruction, and did not show bone rarefaction, a feature of myeloma [13], but did exhibit osteonecrotic lesions associated with BPs. Thus, MRONJ, including BRONJ, is a refractory disease that occurs in patients who have previously used these agents [14]. Most cases are caused by invasive dental procedures such as tooth extractions. However, MRONJ can also be caused by severe periodontal disease or ill-fitting dentures in edentulous patients [15,16]. Treatment can be conservative (eg, cleaning and antibiotics) or surgical (eg, jaw osteotomy), although early considered effective when hemostasis is difficult [20,21], but it is invasive, with a high risk of subsequent nerve palsy and other sequelae. Furthermore, ligation of the external carotid artery is easily performed when the patient has cervical lymph node metastases from maxillary cancer, and cervical dissection is performed simultaneously. In cases such as ours, where basically no neck incision was planned, ligation of the external carotid artery is not a technique that any surgeon can quickly perform on an emergency basis. Moreover, even if accurate ligation is possible, the external carotid artery is relatively close to the central nervous system; thus, ligation-related injuries are likely to be severe. Notably, recent advances in interventional radiology (including elucidation of the vascular anatomy, development of diagnostic radiology equipment such as digital subtraction angiography, and the use of guidewires, catheters, and embolic material) have improved the safety and accuracy of endovascular embolization [8]. Endovascular embolization is an effective hemostatic treatment for bleeding that is difficult to control locally in patients with cancer [22,23]. In the present case, super-selective arterial embolization of the dominant artery at the resection site was performed preoperatively to reduce intraoperative bleeding after resection of necrotic bone that had extended posteriorly to the maxilla. We considered embolization of the posterior superior alveolar, infraorbital, and descending palatine arteries to prevent abnormal intraoperative bleeding. In such cases, the target artery should be embolized as peripherally as possible. However, a limitation of this technique is that the risk of vascular injury increases as the diameter of the popliteal artery branches decreases. Therefore, the middle meningeal artery branch, in which catheter insertion is relatively easy and less likely to cause serious complications, may be a useful embolization site. Nevertheless, the central part should be avoided as an embolization site because of severe vision loss, a complication due to retinal embolization of the ophthalmic artery, a branch of the middle meningeal artery [24,25].

In this case, no severe complications, such as ocular symptoms or facial paresthesias, occurred. Unlike emergency hemostatic surgery, embolization is an elective procedure performed under local anesthesia and is relatively safe. However, the vascular anatomy of the maxillofacial region is complex, and there is a risk of severe complications involving the cranial nerves. Therefore, it is essential to discuss the extent of resection, the actual vascular geometry, and the embolization site with the radiologist prior to surgery.

Conclusions

Preoperative embolization of the maxillary artery, which is more peripheral than the branch to the middle meningeal artery, minimizes the risk of abnormal bleeding during surgery surgical treatment has recently been recommended [17–19]. In the maxilla, resection may extend to the posterior wall of the maxillary sinus and the pterygoid plate behind the maxillary tubercle. In these cases, the maxillary artery and its branches are intermingled immediately posteriorly, and unexpected intraoperative arterial injury can make surgery difficult. In general, intraoperative bleeding is first treated by compression hemostasis, vessel ligation, and suturing. Of these interventions, ligation of the external carotid artery is sometimes applied because it is when surgical resection of MRONJ with erosions in the posterior maxillary molar and posterior wall of the maxillary sinus is performed.