Yan Wang, MD1,2, Shunjiu Cui, MD1, Cheng Li, MD1, and Bing Zhou, MD1
Ear, Nose & Throat Journal2023, Vol. 102(6) 397–401© The Author(s) 2021Article reuse guidelines:sagepub.com/journals-permissionsDOI: 10.1177/0145561321991344journals.sagepub.com/home/ear
AbstractSinonasal inverted papilloma (SIP) is a benign tumor originating from the nasal cavity and paranasal sinuses. Sinonasal inverted papilloma is characterized by local infiltration, high recurrence, and malignant transformation, and its associated dysplasia ranges from mild, moderate, severe, carcinoma in situ (CIS) to invasive squamous cell carcinoma. Sinonasal inverted papilloma with carcinoma in situ (IPwCIS) is the highest degree of dysplasia, which is a stage of malignant transformation of IP. Surgical excision and proper adjuvant therapy can help reduce recurrence rates and suppress further deterioration. In this study, we present a patient with IPwCIS who developed 3 recurrences with a multifocal attachment pattern in less than 18 months. We report the clinical manifestations, development, and treatment process in detail. We also performed a literature review to analyze the characteristics of the disease. Despite comprehensive treatment methods, tumor recurrence and further deterioration of IPwCIS persist.
Keywordsinverted papilloma with carcinoma in situ, treatment, recurrence, multifocal attachments, Ki-67
Sinonasal inverted papilloma (SIP) is a kind of benign epithelial tumor that occurs in the nasal cavity or the paranasal sinuses and accounts for 0.5% to 4.0% of all nasal tumors.1 Sinonasal inverted papilloma can cause significant health concern due to its high recurrence rates, focal aggressive growth, and malignant transformation. Endoscopic surgery remains the primary treatment method for tumor excision.2 A recent meta-analysis of the effectiveness of endoscopic surgery reported recurrence rates of 3% to 33%, with an average rate of 13.8%.3 Kim et al4 reported that 5% to 15% of SIP could progress into squamous cell carcinoma (SCC) throughout the course of the disease. Although incomplete resection of primary tumor is a potential risk factor for SIP recurrence and malignant transformation, the mechanism and etiology of SIP recurrence remain unclear.
In this study, we present a case of SIP with carcinoma in situ (IPwCIS) that recurred 3 times in a multifocal attachment pattern within 18 months. In this case, the recurrences and malignant transformation could not be delayed by radical resection of primary tumors, resection of bony attachment, negative tumor resection margins assessed by intraoperative frozen pathology, and the adding of postoperative adjuvant radiotherapy. This is a rare case and we have not found a similar report in the previous literature.
A 68-year-old female presented at a local hospital in July 2017 with a diagnosis of sinonasal lesions. The patient underwent transnasal endoscopic surgery to remove the sinonasal lesions. Histopathological examination reported an inverted papilloma (IP) with grade III dysplasia and carcinoma in situ (CIS). A rhinologist at the local hospital suggested the patient to take radiotherapy, but she rejected the treatment. Two months after discharge, the patient developed bloody nasal discharge and presented to the local hospital again. Follow-up examinations showed that the tumor recurred. The patient did not receive any treatment in the local hospital and was presented to our hospital in October 2017. Sinus computed tomography (CT; Figure 1A) and magnetic resonance imaging (MRI; Figure 1B) showed soft tissue density in the right nasal cavity and the posterior ethmoid sinus. After detailed preoperative evaluation, the patient underwent a transnasal endoscopic sinonasal tumor resection, ethmoidectomy, and maxillary sinusotomy. The tumor attachments were on the posterior ethmoidal roof and superior turbinate, and bones on the attachments were polished using a diamond burr. Postoperative histopathological examination reported an IP with moderate to severe dysplasia, focal CIS, and focal infiltration (Figure 1C). The Ki-67 index was moderate expression (about 40%; Figure 1D). Postoperative radiotherapy was recommended again, but the patient declined to follow the suggestion due to the concerns of damage to the right eye.
Five months after discharge, the patient complained of bloody nasal discharge again. Sinus CT and MRI were performed and showed recurrent lesions in the right posterior ethmoid sinus and recessus sphenoethmoidalis. The patient underwent a third transnasal endoscopic surgery in April 2018, including sphenoidectomy, resection of primary tumors in the nasal cavity and a skip solitary lesion in the pharyngeal recess. At that time, tumors had infiltrated into the sphenoid sinus ostium and the pharyngeal recess, resulting in obstructive inflammation in the sphenoid sinus. Intraoperative frozen section assessment of the peripheral mucosa indicated no tumor involvement. Histopathological examination showed tumors infiltrated into the right sphenoid sinus ostium, and tumor in the pharyngeal recess was IP with severe dysplasia and focal CIS. Finally, the patient received postoperative radiotherapy.
Six months after the radiotherapy, the patient complained of bloody nasal discharge once again. Sinus CT (Figure 2A) and MRI (Figure 2B and C) were performed and several suspected recurrent lesions were detected. During the fourth endoscopic surgery, we found that mucosa of the right inferior turbinate (IT), the nasal floor, the middle nasal meatus, and the ethmoid sinus were infiltrated by tumors (Figure 2D-F); mucosa of the sphenoid sinus was abnormal, and the maxillary sinus ostium showed edema. According to the SIP staging system, the patient was staged as T4.1 Likewise, the histopathological examination was IP with severe dysplasia and focal CIS, which presented in the sphenoid sinus, the nasal floor, and the maxillary sinus ostium; the histopathological examination of lesions in the ethmoidal roof and the IT showed IP with nonkeratinizing SCC (Figure 2G) with moderate Ki-67 expression (about 50%; Figure 2H), and the lamina propria of the mucosa was infiltrated by the tumors. The expression of P16 was as negative as last surgery (Figure 2I). The second adjuvant radiotherapy was performed postoperatively.
Sinonasal inverted papilloma is characterized by inverted squamous epithelial growth in the underlying connective tissue stroma with an intact basement membrane. The recurrence rates of SIP reported in previous literature vary between different treatment methods, including endoscopic, external, and combined approaches. A recent meta-analysis showed that the recurrence rate of endoscopic approach was significantly lower than that of open approach for surgical resection of SIP.5 Studies by Minni et al6 showed that SIP recurrence could be affected by several risk factors, such as surgical approaches, incomplete surgical resection, tumor anatomic location, tumor staging, and malignant degree. A retrospective review by Tong et al7 noted that SIP with multifocal attachment had a higher prevalence in secondary cases as compared with primary cases (53.7% vs 44.9%), which plays a significant role in tumor recurrence. The malignant transformation of SIP may occur synchronously with the first resection, or it may happen metachronously as the disease progresses. A meta-analysis by Mirza et al8 containing 63 case series and more than 2000 patients reported the incidence rates of synchronous cancer and asynchronous SCC were 7.1% and 3.6%, respectively; approximately 11% of the recurrent SIPs subsequently developed asynchronous SCC. Yasumatsu et al9 retrospectively reviewed the clinical features of 95 patients who were diagnosed with SIP or SCC associated with SIP; their results revealed that epistaxis may be the specific symptom for SCC associated with SIP and a proportion of T4 patients had a highly aggressive disease that correlated with survival outcomes. They noted that a more aggressive surgical approach combined with postoperative adjuvant therapy may improve the survival outcomes of patients with T4-stage SIP.9 In the current study, imaging examinations of the patient showed that the lesions were confined to the right nasal cavity and the paranasal sinus without obvious bone involvement. Thus, transnasal endoscopic surgery was performed, and negative surgical margins were achieved.
Histopathological examinations indicate that epithelial dysplasia is the earliest form of a precancerous lesion, which ranges from mild, moderate, and severe to CIS. Carcinoma in situ is the highest grade of dysplasia and may progress into an invasive SCC. A recent study reported the incidence of sinonasal IPwCIS was 17.2%, and IPwCIS usually occurred with multifocal attachment, thus resulting in a higher recurrence rate. The reported rate of IPwCIS progressing to invasion SCC was 2.7%.10
Other studies have reported that Ki-67 overexpression was associated with IP recurrence11 and malignant transformation.12 Inverted papilloma with carcinoma in situ was the primary histopathology presented after all 4 surgeries in this case. The immunohistochemical analysis of lesions from last 3 surgeries demonstrated that the proliferation Ki-67 index was high (40%-50%), while the P16 was mostly negative. Infection of the human papilloma virus (HPV) is a crucial risk factor for the development of head and neck cancers. Previous literature has shown that high P16 expression is induced by HPV16/18 infection.13 Altavilla et al14 noted that P16 was highly expressed in HPV-positive SIP, and Cheung et al15 showed that P16 was highly expressed in 2 cases of HPV-positive IPwCIS. However, P16 was detected negative in the case presented here, indicating that HPV infection may not be an underlying etiology of the frequent recurrence with multifocal attachment in this case. On the other hand, the tumor attachment became multifocal from initial surgery to the last one (see Figure 2D-F), the factor of tumor implantation cannot be ruled out because of mucosal abrasion during surgery on the basis of histopathological overexpression of Ki-67. Therefore, we suggest that the frequent recurrence may be related to the aberrant Ki-67 expression.
Adjuvant radiotherapy may be beneficial for improving the treatment outcomes of IPwCIS with frequent recurrence or unresectable lesions.10 According to the therapeutic principles of SIP, the bony attachment of tumor was polished using diamond burr dill in the second surgery, the bone of the attachment was removed in the third surgery, and multiple mucosal margins did not show tumor involvement. Postoperative radiotherapy was performed subsequently. However, 6 months after the radiotherapy, tumors recurred again and appeared in multiple new sites, and there was no evidence of tumor metastasis. Only adjuvant radiotherapy was applied in this situation. The patient is currently undergoing a close follow-up, and the efficacy of radiotherapy will be further discussed.
The etiology of frequent recurrence with multifocal attachment of SIP remains unclear. Based on the case presented here, we speculate that several clinicopathological factors including elder patients, history of multiple transnasal endoscopic surgeries, multifocal attachment, T4 stage, high Ki-67 expression, and potential tumor implantation may be risk factors for frequent recurrence of SIP. However, the cause of tumor infiltration into the pharyngeal recess, IT, and nasal floor is unclear. Generally, radical resection of tumor and postoperative adjuvant radiotherapy are beneficial for reducing recurrence rates. For patients with IPwCIS, a more aggressive surgical approach and adjuvant postoperative chemotherapy appear to be necessary in addition to routine radiotherapy, and long-term or lifelong follow-up is warranted.
This prospective study was approved by the Ethics Committee of our center (approval number: TRECKY2018-022).
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by grants from the Beijing Municipal Administration of Hospitals’ Ascent Plan (DFL20150202); the Clinical Medicine Development of Special Funding Support in Beijing Tongren Hospital, Capital Medical University (No. trzdyxzy201702); the National Natural Science Foundation of China (No.81770977); and the Beijing Municipal Science & Technology Commission (No. Z181100001718103).
Yan Wang https://orcid.org/0000-0002-3107-4614
1 Department of Otolaryngology—Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of China
2 Department of Otolaryngology—Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, Shandong Province, People’s Republic of China
Received: November 19, 2020; revised: January 05, 2021; accepted: January 11, 2021
Corresponding Author:Bing Zhou, MD, Department of Otolaryngology—Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, No. 1 Dongjiaominxiang, Dongcheng District, Beijing 100730, People’s Republic of China.Email: entzhou@263.net
