Delayed postoperative bleeding associated with laryngopharyngeal necrosis following salvage endoscopic laryngopharyngeal surgery for recurrent adenoid cystic carcinoma of the tongue base after carbon ion radiotherapy: Case report

Abstract Carbon ion radiotherapy (CIRT) can deliver high-dose radiation to a tumor with minimum damage to normal tissue. Recently, transoral surgery (TOS) has become a treatment option for locoregional recurrence after radiotherapy for laryngopharyngeal carcinoma, aimed at preserving laryngeal function. A 67-year-old woman with crT2N0M0 adenoid cystic carcinoma of the tongue base, previously cured with CIRT, underwent salvage endoscopic laryngopharyngeal surgery at another hospital. One month after the surgery, she suffered massive pharyngeal bleeding and was transferred to our hospital for emergency hemostasis. We observed massive necrosis of the tongue base, extending to the epiglottic vallecula, and bleeding from the wound. Consequently, surgical debridement and cauterization were performed. Although wound healing took several months, laryngeal function was finally preserved. Careful postoperative observation is required when salvage TOS is performed in patients who previously underwent CIRT. The efficacy and safety of the procedure needs to be carefully evaluated in the future.


Introduction
Carbon ion radiotherapy (CIRT), using a carbon ion beam, can focus high-dose radiation on a tumor deep inside the body while minimizing the dose to normal tissue.The cell killing effect of CIRT differentiates it from conventional radiotherapy (RT) in that it is largely independent of radioresistant factors such as cell-cycle and hypoxia [1].In the head and neck region, CIRT is mainly applied to radioresistant tumors, such as malignant melanoma and adenoid cystic carcinoma (ACC), for which the therapeutic effectiveness has been reported [2].No clear treatment protocol for recurrent lesions after CIRT has been established, but reports relating to the usefulness of salvage surgery have been made [3,4].Additionally, some recent reports have shown that transoral surgery (TOS) is effective in preserving laryngeal function in patients with rT1/2 locoregional recurrence of laryngopharyngeal cancer after RT, although careful postoperative observation is necessary [5,6].We could not find any reports relating to salvage TOS after CIRT, but we assumed that similar or additional precautions are necessary.Here, we report a case in which a patient with a locoregional recurrence of ACC of the tongue base, previously cured with CIRT, underwent salvage endoscopic laryngopharyngeal surgery (ELPS) and suffered postoperative bleeding associated with laryngopharyngeal necrosis.

Case
A 60-year-old nonsmoker woman with unremarkable medical history was diagnosed with cT4aN0M0 ACC at the tongue base at another hospital, based on the 7th edition of International Union Against Cancer TNM classification.Although total glosso-laryngectomy Adenoid cystic carcinoma; carbon ion radiotherapy; laryngeal necrosis; pharyngeal necrosis; salvage transoral surgery was initially recommended to her, she declined and underwent CIRT of 57.6 Gy (relative biological effectiveness [RBE]) in 16 fractions and achieved a complete response.However, 7 years after CIRT, local recurrence was detected at the tongue base with a diagnosis of crT2N0M0 ACC.
The patient underwent salvage ELPS for laryngeal preservation by the previous physician.First, the lesion surrounding an abnormal mucosa on the left side of the base of the tongue was resected.An additional resection was performed after a lesion with deep induration on the right side was identified.After all lesions were removed, steroids were injected locally to prevent scar contracture.Intraoperative bleeding was minimal, and no cartilage was exposed during the procedure.Ligation of the artery through an external incision was not performed.She was discharged 6 days after the surgery.On 17 days after the surgery, her general condition was good and there was no sign of wound complications.However, one month after the surgery, she coughed up a large amount of blood and was brought to our hospital.Hypopharyngeal video endoscopy (EH-1990STK; PENTAX) revealed a massive blood coagulum, but not the bleeding points (Figure 1(A)).She underwent emergency hemostasis via transoral videolaryngoscopic surgery (Figure 1(B-E)) after tracheotomy.After massive blood coagulum was removed by using forceps and suction (Figure 1(B)), main bleeding point was identified on the left pharyngolaryngeal fold, probably originating from the superior laryngeal artery, and a perforation in the epiglottis was observed (Figure 1(C)).Necrotic tissue extended from the epiglottic vallecula to the tongue base and the left side of the hyoid bone was exposed (Figure 1(D)).After the main bleeding point was cauterized with a malleable suction coagulator, active bleeding stopped.In addition, several minor bleeding sources were cauterized, and debridement of necrotic tissue was performed.The operation time was 94 min, and the total blood loss was 300 mL.The blood coagulum and two necrotic tissues were submitted for histopathological examination.No malignant findings were noted, but a high degree of bacterial and fungal growth was observed.This case was diagnosed as laryngopharyngeal necrosis associated with salvage TOS.The clinical course and wound healing process are summarized in Figure 2 and Figure 3, respectively.Considering the   Although the wound gradually granulated (Figure 3(D)), the healing process was very slow and hyperbaric oxygen therapy (HBO; 2 atmospheres, 90 min, 24 sessions) was initiated on POD 89 to accelerate wound healing.On POD 139, the wound was almost completely epithelialized, and the perforation of the epiglottis had contracted and was no longer visible.VF revealed aspiration in the median cervical position (PAS: 8), but not in the left lateral flexion compensated position, so direct swallowing training using jelly was started on POD 146.After VF revealed no aspiration (PAS: 1) on POD 188 (Figure 4(B)), she started to eat a soft diet.On POD 230, the tracheal cannula was removed, and she started to eat a normal diet.A pinhole-sized tracheocutaneous fistula remained; therefore, she underwent a procedure for its closure under local anesthesia on POD 299.The PEG tube was removed on POD 327.Almost two years after hemostasis, she is still alive with no recurrence or deterioration of swallowing function.

Discussion
The course of this case suggests that careful postoperative observation is required when salvage TOS is performed in patients who previously underwent CIRT.In salvage cases, TOS is a less invasive organ preservation surgery compared to radical surgery such as total laryngectomy or total laryngopharyngectomy, but the risk of complications is relatively higher and wound healing takes longer than in primary cases, requiring careful postoperative observation [5,6].As a result of RT, wound healing processes are impaired by fibrosis and chronic ischemia of the tissue, and any surgical insult can increase the risk of infection, potentially leading to serious complications such as chondronecrosis [7,8].Considering the strong biological effects of CIRT [1], post-CIRT tissue may be extremely susceptible to invasive procedures and have a lower wound-healing capacity.In addition, the first reported laryngeal SCC case treated with CIRT resulted in laryngeal necrosis, and it is presumed that hollow organs reinforced by cartilage, such as the larynx and trachea, may be susceptible to CIRT because radiosensitive perichondrium, which supply blood to cartilage, are severely damaged by CIRT [9].When considering salvage TOS for post-CIRT cases, the above-mentioned toxicity of CIRT should be taken into account.
Treatment strategies for salvage TOS cases after conventional RT have been mentioned in previous literature [6,10], and this case was treated with reference to those reports.First, antibiotics were administered until adequate wound healing was achieved.Although no evidence is available regarding the type or duration of prophylactic administration of antibiotics, it has been recommended for salvage cases considering the vulnerability of the wound to infection [6].In addition, antifungal medication was initiated because histopathologic examination did not exclude the involvement of fungal infection.However, we could not find any reports of similar treatment in post-salvage TOS cases; therefore, the efficacy and appropriateness of this treatment is unclear.Second, considering that post-TOS hemorrhage can occur beyond 2-3 weeks postoperatively in salvage cases [11], the patient was discharged on POD 35 after the tendency toward epithelialization was confirmed.Initially, she was discharged 6 days after salvage ELPS without antibiotics prescription.Meanwhile, HBO was also administered on POD 89 to accelerate wound healing in this case.HBO has been reported to be effective in approximately 70% of cases of laryngeal necrosis (13/18) in which conservative treatments such as antibiotics, steroids, and humidification have been refractory, contributing to laryngeal preservation [12].In this case, the wound was gradually shrinking, but the healing process itself was very slow.Therefore, considering the low wound-healing capacity after CIRT, HBO was initiated.As for intraoperative procedures in this case, local steroid injections were administered within the resection area to prevent scar contracture during salvage TOS.However, the use of local steroid injection has previously been reported to be a potential risk for complications related to wound healing in cases with extensively exposed muscle layers and a history of irradiation [13].Therefore, the procedure should also be avoided in post-CIRT cases.
In the head and neck region, there are very few reports of salvage surgery of recurrent lesions after CIRT.In a report of salvage surgery with free flap reconstruction for recurrence of osteosarcoma in the skull base following CIRT, no postoperative complications were observed [3].However, to avoid postoperative wound complications, tumor resection was performed with wide margin including tissue severely damaged by CIRT.In another case, a patient with cervical metastasis of mucosal malignant melanoma following CIRT underwent salvage neck dissection without any postoperative complications, but it seemed that the radiation dose to the cervical area was relatively low compared with the dose to the hard palate where the primary tumor was detected [4].Meanwhile, some reports of salvage surgery after CIRT are available for malignant tumors in other fields.A study based on six cases of salvage surgery for recurrent lung cancer after CIRT showed that the procedure was safe without complications, but a combined resection of the tumor and normal tissue was required in five cases due to significant fibrosis and adhesions [14].In a report of salvage surgery for 15 cases with locally recurrent liver cancer or liver metastases after particle therapy, perioperative complications of Clavien-Dindo classification IIIa or higher was observed in four patients, and it was recommended that the resection line be set away from the highly irradiated area to reduce the risk of complications [15].From the standpoint of wound healing, resection of the irradiated area including the tumor is desirable, as reported above, but to achieve preservation of laryngeal function, the resection area must be minimized.Both curative treatment and preservation of laryngeal function can be achieved by salvage TOS in highly selected cases, so the efficacy and safety of the procedure needs to be carefully evaluated in the future.

Conclusion
Considering the possibility of delayed fatal hemorrhage, as in this case, careful postoperative observation is required when salvage TOS is performed in patients who previously underwent CIRT.In this case, laryngeal preservation was accomplished by using a treatment protocol for complications of salvage TOS after RT.The efficacy and safety of the procedure needs to be carefully evaluated in the future.

Informed consent
Authors confirm that consent was obtained from the patient for this study.

Figure 1 .
Figure 1.endoscopic images before hemostasis (A) and during hemostasis (B-D), and schema of the surgical field (e).(A) endoscopic observation revealed a huge coagulum extending from the tongue base to the hypopharynx.the larynx was not visible, and bleeding points were not identified.(B) After a blade (*) was placed over the tongue base, a huge blood coagulum was found and removed with forceps and suction.(c) Main bleeding point was identified on the left pharyngolaryngeal fold (arrow), and there was a perforation in the epiglottis (arrowhead), through which the arytenoids (*) were visible.(D) the area between the epiglottic vallecula and the tongue base was covered with necrotic tissue.the left side of the hyoid bone was exposed (arrowhead).(e) schema of the surgical field.the spread of necrotic tissue is enclosed by a dotted line.

Figure 2 .
Figure 2. clinical course of the case.the day on which the patient was transported to our hospital and hemostasis was performed was defined as day 0. eLps, endoscopic laryngopharyngeal surgery; peg, percutaneous endoscopic gastrostomy; HBO, hyperbaric oxygen therapy; cAM, clarithromycin; ceZ, cefazolin; AmB, amphotericin B; VF, videofluorography; pAs, penetration-aspiration scale; ist, indirect swallowing training; Dst, direct swallowing training; pOD, postoperative day.

Figure 3 .
Figure 3. endoscopic images after hemostasis.(A) Wound at postoperative day (pOD) 14. (B) On pOD 28, some granulation was seen (arrow).(c) On pOD 41, the wound gradually healed.(D) On pOD 83, the perforation of the epiglottis had contracted and was no longer visible.(e) On pOD 160, 2 weeks after direct swallowing training was started.

Figure 4 .
Figure 4. Videofluorography findings.(A) On pOD 10, contrast agent passed through the perforation in the epiglottis and flowed into the larynx (arrowhead: contrast agent, arrow: tip of the epiglottis).(B) On pOD 188, no aspiration was confirmed.