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Nasopharyngeal granulomatous mass after radiotherapy for nasopharyngeal carcinoma
Auris Nasus Larynx 43 (2016) 330–335 Contents lists available at ScienceDirect
Auris Nasus Larynx journal homepage: www.elsevier.com/locate/anl
Nasopharyngeal granulomatous mass after radiotherapy for nasopharyngeal carcinoma Lu Yang a,1, Houyong Li a,1, Huan Wang a, Huankang Zhang a, Shuyi Wang b, Allison N. Fry c, Wade W. Han c, Dehui Wang a,* a
Department of Otolaryngology-Head and Neck Surgery, Affiliated Eye, Ear, Nose and Throat Hospital, Fudan University, Shanghai, China Department of Pathology, Affiliated Eye, Ear, Nose and Throat Hospital, Fudan University, Shanghai, China c Florida Ear, Nose, Throat & Facial Plastic Surgery, Orlando, USA b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 2 February 2015 Accepted 16 October 2015 Available online 11 January 2016
Objective: To evaluate the diagnosis, management and nasal endoscopic surgical outcome of nasopharyngeal granulomatous mass in post-radiation nasopharyngeal carcinoma (NPC) patients. Materials and methods: A total of 23 cases of granulomatous mass after radiotherapy for NPC from 2008 to 2013 treated with nasal endoscopic surgery were retrospectively reviewed. Results: Radiotherapy dose (p = 0.036) and chemotherapy (p < 0.001) correlated with the latency period after the treatment against NPC. The symptoms of the 23 patients before the treatment were nonspecific including nasal obstruction, purulent discharge, headache, epistaxis, foreign body sensation and/or hearing impairment. 12 patients (52.2%) were misdiagnosed to be recurrence of NPC by imaging examination (CT/MRI). After the endoscopic surgery treatment, 18 patients were disease free while the other 5 patients had developed a recurrence. Four of those five recurrent patients were cured with the repeated treatment. Histologic findings of granulation tissue with fibrin and inflammatory cells were found in all of the patients. Conclusions: In situ granulomatous masses in post-radiation NPC patients are very prone to be misdiagnosed as recurrence of nasopharyngeal carcinoma. Chemotherapy is a significant independent factor affecting latency period (p = 0.029). The nasal endoscopic surgery is an effective therapy for post-radiation nasopharyngeal granuloma; surgery can not only alleviate symptoms, what is more important, but it also helps to confirm the diagnosis. ß 2016 Elsevier Ireland Ltd. All rights reserved.
Keywords: Nasopharyngeal granulomatous mass Nasopharyngeal carcinoma Radiotherapy Chemotherapy Endoscopic surgery
1. Introduction Nasopharyngeal carcinoma (NPC) is a common head and neck cancer in Southeast Asia. Considering its anatomic restrictions and sensitivity to radiation, radiotherapy has been
* Corresponding author at: Department of Otolaryngology, Eye, Ear, Nose and Throat Hospital, Shanghai Medical College, Fudan University, 83 Fenyang Road, Shanghai 200031, China. Tel.: +86 210 64 377 134 388; fax: +86 210 64 377 151. E-mail address: [email protected] (D. Wang). 1 These authors contributed equally to this article. http://dx.doi.org/10.1016/j.anl.2015.10.005 0385-8146/ß 2016 Elsevier Ireland Ltd. All rights reserved.
used as a first-line treatment in NPC for decades. However, during the therapy, normal tissue is inadvertently involved in the radiation field, especially within the nasopharynx, as it receives the full radiation dose. Vascular hyalinization, hypoxia, microcirculation disorder, and immunodepression caused by radiotherapy may lead to granulomatous masses with variable amounts of fibrin [1]. The severity of radiation damage after treatment is reported to be relative to radiation dose, as well as the use of chemotherapy [2]. Unlike xerostomia, cranial nerve neuropathy and otitis media, which are common complications of radiotherapy [3], the granulomatous mass in nasopharynx attracts limited attention since it was first
L. Yang et al. / Auris Nasus Larynx 43 (2016) 330–335
described in 1989 [4]. Although the symptomatology and imaging characteristics of nasopharyngeal granulomatous mass may mimic those of recurrent nasopharyngeal carcinoma, the treatment approaches are fundamentally different [5]. The objective of this study is to review nasopharyngeal granulomatous mass after radiotherapy against NPC and to assess the role of chemotherapy and its action during disease progression. 2. Materials and methods We performed a retrospective review of 23 patients treated with radiotherapy against NPC and who were diagnosed with nasopharyngeal granulomatous mass between 2008 and 2013. All patients were followed up more than 1 year. Those who had a recurrent tumor or a secondary primary tumor were excluded. Strategies of treatment against NPC were collected from department of radiotherapy in Affiliated Eye Ear Nose and Throat Hospital, Fudan University. Chemotherapy consisted of cisplatin or carboplatin combined with 5-fluorouracil. All data were analyzed with SPSS version 22.0. Statistically significant p-values were defined as <0.05. Spearman rank correlation was used to determine the relationship between radiotherapy dose and the latency period. Kaplan–Meier curves were used to perform the survival analysis. Radiotherapy dose and treatment against NPC were analyzed for their association with latency period using Cox proportional hazards regression models.
331
No preoperative treatment was taken before the surgery. Surgery was performed under hypotensive general anesthesia in all cases and second-generation cephalosporin was used for antimicrobial prophylaxis. The nasal cavities were packed prior to surgery with cotton pledges soaked with 1% tetracaine and 0.1% adrenaline for 10 min to achieve decongestion. The granuloma was visualized under the nasal endoscopy and the pedicle of granuloma was exposed to visualize an arterial pulse. After the achievement of hemostasis with diathermy, the granulation lesion was removed with a microdebrider. Necrotic tissue and sequestra were also excised and nasal packing was placed after the surgery. Transoral approach with microdebrider was used in 3 cases for the granuloma expanding into the oropharynx. Postoperative treatment included administration of antibiotics and nasal irrigation. 3. Result Among the 23 patients, 17 were male (73.9%) and 6 were female (26.1%). The mean age was 53.5 9.3 years (range 40– 72 years). The tumor histopathologies of patients were undifferentiated (52.6%) or poorly differentiated (47.4%) squamous cell carcinoma. The latency period between the completion of radiotherapy and the diagnosis of nasopharyngeal granulomatous mass ranged from 1 month to 27 years, with a mean latency period of 6.3 years. The total radiotherapy dosage data were only available for 19 patients and ranged from 64 to 132 Gy (mean 81.1 Gy). Among those 19 patients, 11 patients were treated with added chemotherapy (Table 1).
Table 1 Case summary. Case
Age (Y)
Gender
RT dose (Gy)
Treatment
Latency period (Y)
Osteonecrosis
Recurrence (after surgery)
1 2 3# 4* 5# 6# 7 8 9 10 11# 12 13 14 15 16 17 18 19 20 21 22 23
49 72 56 55 47 47 61 49 69 66 52 50 61 71 45 43 41 50 49 52 49 40 57
M M M M F M F M F F M M F M M M M M M M M M F
64 NA 64 + 66 66 62 + 66 64 + 68 74 72 NA 66 62 + 66 70 68 69 69 68 NA 64 70 NA 64 70 68
RT RT RT + CT RT RT + CT RT RT + CT RT RT RT + CT RT + CT RT + CT RT + CT RT RT + CT RT + CT RT RT + CT RT + CT RT RT RT RT
14 16 0.1 27 1.7 0.1 0.7 3 27 0.75 0.5 0.5 0.5 4.5 0.33 1.4 10 1.5 0.5 17 9 1 7
+ +
3 years – – 11/10/6 months 8 months 1.5 years – – – – – – – – – – 3 years – – – – – –
Mean
53.5
6.3
11
81.1
+
+ + + + + + +
+
NA, unavailable; RT, radiotherapy; CT, chemotherapy. Patient 4* had granuloma that recurred repeatedly with nasal obstruction and epistaxis, and osteonecrosis was found at the third reexamination. Patients 3#, 5#, 6# and 11# had been given a second radiotherapy for a recurrent NPC. Patients 11, 12, 13 and 15 had received induction chemotherapy with cisplatin and 5-fluorouracil and concurrent chemotherapy with cisplatin. Patients 3, 7, 10, 16, 18, and 19 had undergone concurrent chemotherapy with cisplatin.
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L. Yang et al. / Auris Nasus Larynx 43 (2016) 330–335
Fig. 1. Kaplan–Meier curves reveal that both radiotherapy dose (A) and treatment against NPC (B) significantly correlated with latency period with p = 0.036 and p = 0.000. RT = radiotherapy; CT = chemotherapy.
Five patients had received induction chemotherapy with cisplatin and 5-fluorouracil and concurrent chemotherapy with cisplatin, while other 6 patients had undergone concurrent chemotherapy with cisplatin. By Spearman rank correlation, radiotherapy dose had a negative correlation with latency period (r = 0.626, p = 0.004). By univariate analysis, radiotherapy dose (p = 0.036) and treatment against NPC (p < 0.001) significantly correlated with latency period (Fig. 1), but there was no difference between induction combined with concurrent chemotherapy and concurrent chemotherapy only (p = 0.694), nor the undifferentiated and poorly differentiated tumor histopathology (p = 0.859). Cox regression analysis showed chemotherapy to be a significant independent factor affecting latency period (p = 0.029). The presenting symptoms of the 23 patients are listed in Table 2, which including nasal obstruction (n = 13, 56.5%), purulent discharge (n = 12, 52.2%), headache (n = 8, 34.8%), epistaxis (n = 7, 30.4%), and hearing loss (n = 4, 17.4%).
Table 2 Distribution of symptoms. Symptoms
Number
%
Nasal obstruction Purulent discharge Headache Epistaxis Hearing loss Recurrence Osteonecrosis No recurrence Osteonecrosis
13 12 8 7 4 5 3 18 8
56.5 52.2 34.8 30.4 17.4 21.7 60 78.3 44.4
Endoscopic nasal examination revealed soft tissue hyperplasia with bleeding, necrosis, crusting and/or purulent exudates in nasopharynx. CT examination showed a mass of soft tissue in nasopharynx and contrast-enhanced CT showed no (n = 11, 47.8%) or medium (n = 12, 52.2%) enhancement (Fig. 2). Bony destruction and sclerosis of skull base were found in 11 patients,
Fig. 2. (A, B) CT scan of a 69-year-old female presenting with nasal obstruction and purulent discharge showed nonenhancing masses in nasopharyx and choana (arrow).
L. Yang et al. / Auris Nasus Larynx 43 (2016) 330–335
333
Fig. 3. A 50-year-old man had undergone radiation therapy with a total dose of 70 Gy for undifferentiated NPC. Six months after radiotherapy, he presented with nasal obstruction and headache. (A) Nasopharyngeal CT and (B) bone window prior to surgery revealed abscission of soft tissue, heterogeneously enhancing nasopharyngeal mass (arrow) and bone destruction (arrow).
among whom 3 patients had a recurrence of nasopharyngeal granuloma after initial surgical treatment (Fig. 3). MRI examination showed a lesion of intermediate intensity on T1WI and of intermediate or hyperintensity on T2WI (Fig. 4). Biopsies were performed in all patients before surgery, and there was no evidence of malignancy. Twelve patients (52.2%)
were misdiagnosed to be recurrence of NPC by contrastenhanced CT/MRI examination. Histology after surgery revealed a mass which was lined by benign squamous epithelium with inflammatory cell and fibrin (Fig. 5). Symptoms relief after surgery: patients reported significantly relief from nasal obstruction (n = 3, 23.1%), purulent
Fig. 4. MR image in a 41-year-old man with nasal obstruction and epistaxis showed isointensive on T1WI (A) and heterogeneously hyperintensive on T2WI (B). On T1WI image postcontrast the mass showed inhomogeneous enhancement (C, D).
334
L. Yang et al. / Auris Nasus Larynx 43 (2016) 330–335
achieve complete re-epithelialization, the necrosis and crusting did improve significantly. A recurrent granulomatous mass was detected in 5 patients in 8 months to 3 years after surgery. Those 4 patients who received the surgical treatment again were then disease free. Only one patient had lesion recurring repeatedly with nasal obstruction and epistaxis despite multiple treatments. However, surgery was found to be helpful to improve these symptoms. 4. Discussion
Fig. 5. Histology shows a mass that is lined by benign squamous epithelium with inflammatory cell (black arrow) and fibrin (white arrow).
discharge (n = 7, 58.3%), headache (n = 4, 50%), epistaxis (n = 6, 85.7%), and hearing loss (n = 1, 25%), and some relief with the rest of the patients. Followed-up reexamination showed fully recovered and completely re-epithelialized wound in 17 patients. While, those of the other 6 patients did not
Radiotherapy, the first-line treatment for NPC, has improved survival rate for decades. However, during the therapy, normal tissue is inadvertently radiated. The impairment of soft tissue is related to the radiotherapy dose, radiotherapy projection, and the concurrent use of chemotherapy [6]. Acute mucositis is a consistent clinically visible adverse effect during the radiotherapy, which starts at around the second to third week of treatment, and usually subsides several weeks after the conclusion of treatment [7]. However, some patients continue to develop granulomatous masses as a delayed post-radiation side effect. Although the radiation field has been redesigned to reduce the complications in other parts of the head and neck, the target volume routinely covers the nasopharynx.
Fig. 6. A 49-year-old man who received radiotherapy for undifferentiated NPC 3 years ago suffered from epistaxis for 3 months. (A–C) CT scan showed moderate enhancing masses in the right sphenoid sinus (arrow) and nasopharynx (arrow). (D) Bone destruction could be observed in the bone window (arrow).
L. Yang et al. / Auris Nasus Larynx 43 (2016) 330–335
Granulomatous mass is a benign, but slow invasive in local field inflammatory process. The lesion resembles a malignancy in both clinical manifestations and common imaging examinations, which may lead to improper diagnosis or management [8]. The incidence of post-radiation nasopharyngeal granulomatous masses is approximately 1% in King’s report [1]. The mechanisms of nasopharyngeal granuloma may occur from vascular hyalinization, microcirculation disorder, immunodepression, inflammation, and fibroblast formation. Besides, the damage of chemotherapy to vasculature and immunity may expedite this process [9,10]. During the surgery, we found consistently that there was a pulsated bleeding at the pedicle of granuloma arising from an arteriole and a surrounding organized capsule composed of thrombi and fibrous tissue. Considering this observation, we speculated that some granulomas were related to pseudoaneurysm caused by arterial hyalinization, fibrosis or necrosis. Patients with a low grade of granuloma may only present with purulent discharge and bleeding. Abscission of soft tissue with exposed bone caused by repeated hyperplasia and necrosis of granulation tissue may lead to osteonecrosis of skull base, and even to fatal bleeding [11]. To improve the patients’ quality of life and the rate of survival, clinics should routinely debride granulation tissue and necrotic bones, and prescribe prophylactic antibiotics. In our study, 47.8% of the patients were found to have osteonecrosis of skull base, compared with 8% in Alon’s study [12]. This difference may be related to the prominence of undifferentiated squamous carcinoma in China. Eleven of 23 patients suffered from osteonecrosis, 3 of whom had a recurrence of granuloma accounting for 60% of total recurrent patients (Table 2). There was no significant difference in the incidence of osteonecrosis between patients with or without recurrence (60% vs 44.4%) by Fisher’s exact test. However, osteonecrosis was found in one patient at the third recurrence, suggesting that osteonecrosis might be associated with the aggravation of granulomatous masses. More effort has to be made in identifying the relationship between osteonecrosis and the recurrence of granuloma. It can be difficult to distinguish granuloma from recurrent cancer by common imaging examinations alone, especially when companying with osteonecrosis [13]. In our study, the radiographic nasopharyngeal masses in 12 patients (52.2%) were misdiagnosed to be recurrence of cancer by contrast enhanced CT/MRI (Fig. 6). However, the biopsies were negative for malignancy and the pathological analysis after surgery showed granulation tissue and chronic mucositis. Those 12 cases reminded us that an over reliance on imaging examination could lead to misdiagnosis, and the importance of biopsy should be emphasized. Even if lesions are seated deeply, which may lead to a high risk of biopsy, oncologic therapy should not be given blindly. We advocated a treatment approach of endoscopic surgery for patients with symptoms to improve their quality of life. Meanwhile, endoscopic surgery provides more masses and incisal edges for histology. Some patients develop recurrent disease slowly after an initial surgical excision or radiation cure. Therefore, consistent nasal irrigation to keep nasal cavity clean, and routine evaluation of the
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activity of local soft tissue with endoscopy can help clinics to make a timely diagnosis to prevent major complications. 5. Conclusions Nasopharyngeal granulomatous mass is a rare complication after radiotherapy for NPC. However, it is difficult to distinguish from recurrent nasopharyngeal carcinoma. Comparing with radiotherapy alone, patients with added chemotherapy are disposed to bearing lesion. The nasal endoscopic surgery is an effective treatment for nasopharyngeal granuloma, which can alleviate symptoms. Conflicts of interest All authors report no conflicts of interest. Acknowledgment This project was supported by Shanghai Municipal Hospitals’ Rising and Leading Technology Program (No. SHDC12013121). References [1] King AD, Ahuja AT, Leung SF, Abrigo J, Wong JK, Poon WS, et al. MR imaging of nonmalignant polyps and masses of the nasopharynx and sphenoid sinus after radiotherapy for nasopharyngeal carcinoma. AJNR Am J Neuroradiol 2008;29:1209–14. [2] Sumitsawan Y, Chaiyasate S, Chitapanarux I, Anansuthiwara M, Roongrotwattanasiri K, Vaseenon V, et al. Late complications of radiotherapy for nasopharyngeal carcinoma. Auris Nasus Larynx 2009;36:205–9. [3] Lee CC, Ho CY. Post-treatment late complications of nasopharyngeal carcinoma. Eur Arch Otorhinolaryngol 2012;269:2401–9. [4] Yan JH, Li JX, Hu YH, Gu XZ. In situ benign growth after radical radiation therapy of head and neck cancers – report of eight patients. Radiother Oncol 1989;16:109–13. [5] King AD, Yuen EHY, Chan PN, Leung SF, Tse GMK, Kam MKM, et al. MR mimics of recurrent nasopharyngeal carcinoma. Eur J Radiol Extra 2005;55:23–7. [6] Vissink A, Burlage FR, Spijkervet FK, Jansma J, Coppes RP. Prevention and treatment of the consequences of head and neck radiotherapy. Crit Rev Oral Biol Med 2003;14:213–25. [7] Olmi P, Cellai E, Chiavacci A, Fallai C. Accelerated fractionation in advanced head and neck cancer: results and analysis of late sequelae. Radiother Oncol 1990;17:199–207. [8] Desai SV, Spinazzi EF, Fang CH, Huang G, Tomovic S, Liu JK, et al. Sinonasal and ventral skull base inflammatory pseudotumor: a systematic review. Laryngoscope 2015;125:813–21. [9] Hye Khan MA, Abdul Sattar M, Abdullah NA, Johns EJ. Cisplatininduced nephrotoxicity causes altered renal hemodynamics in Wistar Kyoto and spontaneously hypertensive rats: role of augmented renal alpha-adrenergic responsiveness. Exp Toxicol Pathol 2007;59:253–60. [10] Dasari S, Tchounwou PB. Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol 2014;740:364–78. [11] Zhang J, Wang Y, Chen W. Cause of epistaxis in patients irradiated for nasopharyngeal carcinoma. Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 2010;24:394–5. [12] Alon EE, Lipschitz N, Bedrin L, Gluck I, Talmi Y, Wolf M, et al. Delayed sino-nasal complications of radiotherapy for nasopharyngeal carcinoma. Otolaryngol Head Neck Surg 2014;151:354–8. [13] King AD, Ahuja AT, Yeung DK, Wong JK, Lee YY, Lam WW, et al. Delayed complications of radiotherapy treatment for nasopharyngeal carcinoma: imaging findings. Clin Radiol 2007;62:195–203.
Auris Nasus Larynx journal homepage: www.elsevier.com/locate/anl
Nasopharyngeal granulomatous mass after radiotherapy for nasopharyngeal carcinoma Lu Yang a,1, Houyong Li a,1, Huan Wang a, Huankang Zhang a, Shuyi Wang b, Allison N. Fry c, Wade W. Han c, Dehui Wang a,* a
Department of Otolaryngology-Head and Neck Surgery, Affiliated Eye, Ear, Nose and Throat Hospital, Fudan University, Shanghai, China Department of Pathology, Affiliated Eye, Ear, Nose and Throat Hospital, Fudan University, Shanghai, China c Florida Ear, Nose, Throat & Facial Plastic Surgery, Orlando, USA b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 2 February 2015 Accepted 16 October 2015 Available online 11 January 2016
Objective: To evaluate the diagnosis, management and nasal endoscopic surgical outcome of nasopharyngeal granulomatous mass in post-radiation nasopharyngeal carcinoma (NPC) patients. Materials and methods: A total of 23 cases of granulomatous mass after radiotherapy for NPC from 2008 to 2013 treated with nasal endoscopic surgery were retrospectively reviewed. Results: Radiotherapy dose (p = 0.036) and chemotherapy (p < 0.001) correlated with the latency period after the treatment against NPC. The symptoms of the 23 patients before the treatment were nonspecific including nasal obstruction, purulent discharge, headache, epistaxis, foreign body sensation and/or hearing impairment. 12 patients (52.2%) were misdiagnosed to be recurrence of NPC by imaging examination (CT/MRI). After the endoscopic surgery treatment, 18 patients were disease free while the other 5 patients had developed a recurrence. Four of those five recurrent patients were cured with the repeated treatment. Histologic findings of granulation tissue with fibrin and inflammatory cells were found in all of the patients. Conclusions: In situ granulomatous masses in post-radiation NPC patients are very prone to be misdiagnosed as recurrence of nasopharyngeal carcinoma. Chemotherapy is a significant independent factor affecting latency period (p = 0.029). The nasal endoscopic surgery is an effective therapy for post-radiation nasopharyngeal granuloma; surgery can not only alleviate symptoms, what is more important, but it also helps to confirm the diagnosis. ß 2016 Elsevier Ireland Ltd. All rights reserved.
Keywords: Nasopharyngeal granulomatous mass Nasopharyngeal carcinoma Radiotherapy Chemotherapy Endoscopic surgery
1. Introduction Nasopharyngeal carcinoma (NPC) is a common head and neck cancer in Southeast Asia. Considering its anatomic restrictions and sensitivity to radiation, radiotherapy has been
* Corresponding author at: Department of Otolaryngology, Eye, Ear, Nose and Throat Hospital, Shanghai Medical College, Fudan University, 83 Fenyang Road, Shanghai 200031, China. Tel.: +86 210 64 377 134 388; fax: +86 210 64 377 151. E-mail address: [email protected] (D. Wang). 1 These authors contributed equally to this article. http://dx.doi.org/10.1016/j.anl.2015.10.005 0385-8146/ß 2016 Elsevier Ireland Ltd. All rights reserved.
used as a first-line treatment in NPC for decades. However, during the therapy, normal tissue is inadvertently involved in the radiation field, especially within the nasopharynx, as it receives the full radiation dose. Vascular hyalinization, hypoxia, microcirculation disorder, and immunodepression caused by radiotherapy may lead to granulomatous masses with variable amounts of fibrin [1]. The severity of radiation damage after treatment is reported to be relative to radiation dose, as well as the use of chemotherapy [2]. Unlike xerostomia, cranial nerve neuropathy and otitis media, which are common complications of radiotherapy [3], the granulomatous mass in nasopharynx attracts limited attention since it was first
L. Yang et al. / Auris Nasus Larynx 43 (2016) 330–335
described in 1989 [4]. Although the symptomatology and imaging characteristics of nasopharyngeal granulomatous mass may mimic those of recurrent nasopharyngeal carcinoma, the treatment approaches are fundamentally different [5]. The objective of this study is to review nasopharyngeal granulomatous mass after radiotherapy against NPC and to assess the role of chemotherapy and its action during disease progression. 2. Materials and methods We performed a retrospective review of 23 patients treated with radiotherapy against NPC and who were diagnosed with nasopharyngeal granulomatous mass between 2008 and 2013. All patients were followed up more than 1 year. Those who had a recurrent tumor or a secondary primary tumor were excluded. Strategies of treatment against NPC were collected from department of radiotherapy in Affiliated Eye Ear Nose and Throat Hospital, Fudan University. Chemotherapy consisted of cisplatin or carboplatin combined with 5-fluorouracil. All data were analyzed with SPSS version 22.0. Statistically significant p-values were defined as <0.05. Spearman rank correlation was used to determine the relationship between radiotherapy dose and the latency period. Kaplan–Meier curves were used to perform the survival analysis. Radiotherapy dose and treatment against NPC were analyzed for their association with latency period using Cox proportional hazards regression models.
331
No preoperative treatment was taken before the surgery. Surgery was performed under hypotensive general anesthesia in all cases and second-generation cephalosporin was used for antimicrobial prophylaxis. The nasal cavities were packed prior to surgery with cotton pledges soaked with 1% tetracaine and 0.1% adrenaline for 10 min to achieve decongestion. The granuloma was visualized under the nasal endoscopy and the pedicle of granuloma was exposed to visualize an arterial pulse. After the achievement of hemostasis with diathermy, the granulation lesion was removed with a microdebrider. Necrotic tissue and sequestra were also excised and nasal packing was placed after the surgery. Transoral approach with microdebrider was used in 3 cases for the granuloma expanding into the oropharynx. Postoperative treatment included administration of antibiotics and nasal irrigation. 3. Result Among the 23 patients, 17 were male (73.9%) and 6 were female (26.1%). The mean age was 53.5 9.3 years (range 40– 72 years). The tumor histopathologies of patients were undifferentiated (52.6%) or poorly differentiated (47.4%) squamous cell carcinoma. The latency period between the completion of radiotherapy and the diagnosis of nasopharyngeal granulomatous mass ranged from 1 month to 27 years, with a mean latency period of 6.3 years. The total radiotherapy dosage data were only available for 19 patients and ranged from 64 to 132 Gy (mean 81.1 Gy). Among those 19 patients, 11 patients were treated with added chemotherapy (Table 1).
Table 1 Case summary. Case
Age (Y)
Gender
RT dose (Gy)
Treatment
Latency period (Y)
Osteonecrosis
Recurrence (after surgery)
1 2 3# 4* 5# 6# 7 8 9 10 11# 12 13 14 15 16 17 18 19 20 21 22 23
49 72 56 55 47 47 61 49 69 66 52 50 61 71 45 43 41 50 49 52 49 40 57
M M M M F M F M F F M M F M M M M M M M M M F
64 NA 64 + 66 66 62 + 66 64 + 68 74 72 NA 66 62 + 66 70 68 69 69 68 NA 64 70 NA 64 70 68
RT RT RT + CT RT RT + CT RT RT + CT RT RT RT + CT RT + CT RT + CT RT + CT RT RT + CT RT + CT RT RT + CT RT + CT RT RT RT RT
14 16 0.1 27 1.7 0.1 0.7 3 27 0.75 0.5 0.5 0.5 4.5 0.33 1.4 10 1.5 0.5 17 9 1 7
+ +
3 years – – 11/10/6 months 8 months 1.5 years – – – – – – – – – – 3 years – – – – – –
Mean
53.5
6.3
11
81.1
+
+ + + + + + +
+
NA, unavailable; RT, radiotherapy; CT, chemotherapy. Patient 4* had granuloma that recurred repeatedly with nasal obstruction and epistaxis, and osteonecrosis was found at the third reexamination. Patients 3#, 5#, 6# and 11# had been given a second radiotherapy for a recurrent NPC. Patients 11, 12, 13 and 15 had received induction chemotherapy with cisplatin and 5-fluorouracil and concurrent chemotherapy with cisplatin. Patients 3, 7, 10, 16, 18, and 19 had undergone concurrent chemotherapy with cisplatin.
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Fig. 1. Kaplan–Meier curves reveal that both radiotherapy dose (A) and treatment against NPC (B) significantly correlated with latency period with p = 0.036 and p = 0.000. RT = radiotherapy; CT = chemotherapy.
Five patients had received induction chemotherapy with cisplatin and 5-fluorouracil and concurrent chemotherapy with cisplatin, while other 6 patients had undergone concurrent chemotherapy with cisplatin. By Spearman rank correlation, radiotherapy dose had a negative correlation with latency period (r = 0.626, p = 0.004). By univariate analysis, radiotherapy dose (p = 0.036) and treatment against NPC (p < 0.001) significantly correlated with latency period (Fig. 1), but there was no difference between induction combined with concurrent chemotherapy and concurrent chemotherapy only (p = 0.694), nor the undifferentiated and poorly differentiated tumor histopathology (p = 0.859). Cox regression analysis showed chemotherapy to be a significant independent factor affecting latency period (p = 0.029). The presenting symptoms of the 23 patients are listed in Table 2, which including nasal obstruction (n = 13, 56.5%), purulent discharge (n = 12, 52.2%), headache (n = 8, 34.8%), epistaxis (n = 7, 30.4%), and hearing loss (n = 4, 17.4%).
Table 2 Distribution of symptoms. Symptoms
Number
%
Nasal obstruction Purulent discharge Headache Epistaxis Hearing loss Recurrence Osteonecrosis No recurrence Osteonecrosis
13 12 8 7 4 5 3 18 8
56.5 52.2 34.8 30.4 17.4 21.7 60 78.3 44.4
Endoscopic nasal examination revealed soft tissue hyperplasia with bleeding, necrosis, crusting and/or purulent exudates in nasopharynx. CT examination showed a mass of soft tissue in nasopharynx and contrast-enhanced CT showed no (n = 11, 47.8%) or medium (n = 12, 52.2%) enhancement (Fig. 2). Bony destruction and sclerosis of skull base were found in 11 patients,
Fig. 2. (A, B) CT scan of a 69-year-old female presenting with nasal obstruction and purulent discharge showed nonenhancing masses in nasopharyx and choana (arrow).
L. Yang et al. / Auris Nasus Larynx 43 (2016) 330–335
333
Fig. 3. A 50-year-old man had undergone radiation therapy with a total dose of 70 Gy for undifferentiated NPC. Six months after radiotherapy, he presented with nasal obstruction and headache. (A) Nasopharyngeal CT and (B) bone window prior to surgery revealed abscission of soft tissue, heterogeneously enhancing nasopharyngeal mass (arrow) and bone destruction (arrow).
among whom 3 patients had a recurrence of nasopharyngeal granuloma after initial surgical treatment (Fig. 3). MRI examination showed a lesion of intermediate intensity on T1WI and of intermediate or hyperintensity on T2WI (Fig. 4). Biopsies were performed in all patients before surgery, and there was no evidence of malignancy. Twelve patients (52.2%)
were misdiagnosed to be recurrence of NPC by contrastenhanced CT/MRI examination. Histology after surgery revealed a mass which was lined by benign squamous epithelium with inflammatory cell and fibrin (Fig. 5). Symptoms relief after surgery: patients reported significantly relief from nasal obstruction (n = 3, 23.1%), purulent
Fig. 4. MR image in a 41-year-old man with nasal obstruction and epistaxis showed isointensive on T1WI (A) and heterogeneously hyperintensive on T2WI (B). On T1WI image postcontrast the mass showed inhomogeneous enhancement (C, D).
334
L. Yang et al. / Auris Nasus Larynx 43 (2016) 330–335
achieve complete re-epithelialization, the necrosis and crusting did improve significantly. A recurrent granulomatous mass was detected in 5 patients in 8 months to 3 years after surgery. Those 4 patients who received the surgical treatment again were then disease free. Only one patient had lesion recurring repeatedly with nasal obstruction and epistaxis despite multiple treatments. However, surgery was found to be helpful to improve these symptoms. 4. Discussion
Fig. 5. Histology shows a mass that is lined by benign squamous epithelium with inflammatory cell (black arrow) and fibrin (white arrow).
discharge (n = 7, 58.3%), headache (n = 4, 50%), epistaxis (n = 6, 85.7%), and hearing loss (n = 1, 25%), and some relief with the rest of the patients. Followed-up reexamination showed fully recovered and completely re-epithelialized wound in 17 patients. While, those of the other 6 patients did not
Radiotherapy, the first-line treatment for NPC, has improved survival rate for decades. However, during the therapy, normal tissue is inadvertently radiated. The impairment of soft tissue is related to the radiotherapy dose, radiotherapy projection, and the concurrent use of chemotherapy [6]. Acute mucositis is a consistent clinically visible adverse effect during the radiotherapy, which starts at around the second to third week of treatment, and usually subsides several weeks after the conclusion of treatment [7]. However, some patients continue to develop granulomatous masses as a delayed post-radiation side effect. Although the radiation field has been redesigned to reduce the complications in other parts of the head and neck, the target volume routinely covers the nasopharynx.
Fig. 6. A 49-year-old man who received radiotherapy for undifferentiated NPC 3 years ago suffered from epistaxis for 3 months. (A–C) CT scan showed moderate enhancing masses in the right sphenoid sinus (arrow) and nasopharynx (arrow). (D) Bone destruction could be observed in the bone window (arrow).
L. Yang et al. / Auris Nasus Larynx 43 (2016) 330–335
Granulomatous mass is a benign, but slow invasive in local field inflammatory process. The lesion resembles a malignancy in both clinical manifestations and common imaging examinations, which may lead to improper diagnosis or management [8]. The incidence of post-radiation nasopharyngeal granulomatous masses is approximately 1% in King’s report [1]. The mechanisms of nasopharyngeal granuloma may occur from vascular hyalinization, microcirculation disorder, immunodepression, inflammation, and fibroblast formation. Besides, the damage of chemotherapy to vasculature and immunity may expedite this process [9,10]. During the surgery, we found consistently that there was a pulsated bleeding at the pedicle of granuloma arising from an arteriole and a surrounding organized capsule composed of thrombi and fibrous tissue. Considering this observation, we speculated that some granulomas were related to pseudoaneurysm caused by arterial hyalinization, fibrosis or necrosis. Patients with a low grade of granuloma may only present with purulent discharge and bleeding. Abscission of soft tissue with exposed bone caused by repeated hyperplasia and necrosis of granulation tissue may lead to osteonecrosis of skull base, and even to fatal bleeding [11]. To improve the patients’ quality of life and the rate of survival, clinics should routinely debride granulation tissue and necrotic bones, and prescribe prophylactic antibiotics. In our study, 47.8% of the patients were found to have osteonecrosis of skull base, compared with 8% in Alon’s study [12]. This difference may be related to the prominence of undifferentiated squamous carcinoma in China. Eleven of 23 patients suffered from osteonecrosis, 3 of whom had a recurrence of granuloma accounting for 60% of total recurrent patients (Table 2). There was no significant difference in the incidence of osteonecrosis between patients with or without recurrence (60% vs 44.4%) by Fisher’s exact test. However, osteonecrosis was found in one patient at the third recurrence, suggesting that osteonecrosis might be associated with the aggravation of granulomatous masses. More effort has to be made in identifying the relationship between osteonecrosis and the recurrence of granuloma. It can be difficult to distinguish granuloma from recurrent cancer by common imaging examinations alone, especially when companying with osteonecrosis [13]. In our study, the radiographic nasopharyngeal masses in 12 patients (52.2%) were misdiagnosed to be recurrence of cancer by contrast enhanced CT/MRI (Fig. 6). However, the biopsies were negative for malignancy and the pathological analysis after surgery showed granulation tissue and chronic mucositis. Those 12 cases reminded us that an over reliance on imaging examination could lead to misdiagnosis, and the importance of biopsy should be emphasized. Even if lesions are seated deeply, which may lead to a high risk of biopsy, oncologic therapy should not be given blindly. We advocated a treatment approach of endoscopic surgery for patients with symptoms to improve their quality of life. Meanwhile, endoscopic surgery provides more masses and incisal edges for histology. Some patients develop recurrent disease slowly after an initial surgical excision or radiation cure. Therefore, consistent nasal irrigation to keep nasal cavity clean, and routine evaluation of the
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activity of local soft tissue with endoscopy can help clinics to make a timely diagnosis to prevent major complications. 5. Conclusions Nasopharyngeal granulomatous mass is a rare complication after radiotherapy for NPC. However, it is difficult to distinguish from recurrent nasopharyngeal carcinoma. Comparing with radiotherapy alone, patients with added chemotherapy are disposed to bearing lesion. The nasal endoscopic surgery is an effective treatment for nasopharyngeal granuloma, which can alleviate symptoms. Conflicts of interest All authors report no conflicts of interest. Acknowledgment This project was supported by Shanghai Municipal Hospitals’ Rising and Leading Technology Program (No. SHDC12013121). References [1] King AD, Ahuja AT, Leung SF, Abrigo J, Wong JK, Poon WS, et al. MR imaging of nonmalignant polyps and masses of the nasopharynx and sphenoid sinus after radiotherapy for nasopharyngeal carcinoma. AJNR Am J Neuroradiol 2008;29:1209–14. [2] Sumitsawan Y, Chaiyasate S, Chitapanarux I, Anansuthiwara M, Roongrotwattanasiri K, Vaseenon V, et al. Late complications of radiotherapy for nasopharyngeal carcinoma. Auris Nasus Larynx 2009;36:205–9. [3] Lee CC, Ho CY. Post-treatment late complications of nasopharyngeal carcinoma. Eur Arch Otorhinolaryngol 2012;269:2401–9. [4] Yan JH, Li JX, Hu YH, Gu XZ. In situ benign growth after radical radiation therapy of head and neck cancers – report of eight patients. Radiother Oncol 1989;16:109–13. [5] King AD, Yuen EHY, Chan PN, Leung SF, Tse GMK, Kam MKM, et al. MR mimics of recurrent nasopharyngeal carcinoma. Eur J Radiol Extra 2005;55:23–7. [6] Vissink A, Burlage FR, Spijkervet FK, Jansma J, Coppes RP. Prevention and treatment of the consequences of head and neck radiotherapy. Crit Rev Oral Biol Med 2003;14:213–25. [7] Olmi P, Cellai E, Chiavacci A, Fallai C. Accelerated fractionation in advanced head and neck cancer: results and analysis of late sequelae. Radiother Oncol 1990;17:199–207. [8] Desai SV, Spinazzi EF, Fang CH, Huang G, Tomovic S, Liu JK, et al. Sinonasal and ventral skull base inflammatory pseudotumor: a systematic review. Laryngoscope 2015;125:813–21. [9] Hye Khan MA, Abdul Sattar M, Abdullah NA, Johns EJ. Cisplatininduced nephrotoxicity causes altered renal hemodynamics in Wistar Kyoto and spontaneously hypertensive rats: role of augmented renal alpha-adrenergic responsiveness. Exp Toxicol Pathol 2007;59:253–60. [10] Dasari S, Tchounwou PB. Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol 2014;740:364–78. [11] Zhang J, Wang Y, Chen W. Cause of epistaxis in patients irradiated for nasopharyngeal carcinoma. Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 2010;24:394–5. [12] Alon EE, Lipschitz N, Bedrin L, Gluck I, Talmi Y, Wolf M, et al. Delayed sino-nasal complications of radiotherapy for nasopharyngeal carcinoma. Otolaryngol Head Neck Surg 2014;151:354–8. [13] King AD, Ahuja AT, Yeung DK, Wong JK, Lee YY, Lam WW, et al. Delayed complications of radiotherapy treatment for nasopharyngeal carcinoma: imaging findings. Clin Radiol 2007;62:195–203.