Sinonasal Inverted Papilloma: A Narrative Review

Abstract

Inverted papilloma (IP) is a relatively rare sinonasal benign lesion, peculiar in its etiology, clinical presentation and treatment. Its resemblance to other sinonasal pathologies and varied approaches, makes it an interesting disease. Recently there have been several advances in the management of IP. This article aims to summarize the contemporary developments thus enabling the readers to understand the years of research behind IP. To integrate the available literature on IP and study the current scenario in its management. A comprehensive literature review was done on Google Scholar and PubMed database using the following key words: “inverted papilloma”, “Schneiderian”, “sinonasal”, “medial maxillectomy”. Articles published in English were used. Articles published till May 2020 were reviewed. Years of research have aimed to gain more information regarding the epidemiology, histopathology, staging systems and surgical management of IP. To briefly summarize the research so far, it is safe to say that there exists an association between Human Papilloma Virus and IP. The Krouse staging system is the most commonly used. The treatment itself has changed from a conservative approach to a more aggressive excision with or without external approach and with or without chemoradiotherapy. In IP, whether or not associated with SCC, complete surgical removal of the tumour is advocated as the treatment of choice. With the advancements in endoscopic technique, surgeons have been using it to their advantage for the surgical evaluation and cure of IP, depending upon the stage. Endoscopic treatment is preferred, whereas for lesions less accessible endoscopically, or in those with peripheral extension, open surgery is indicated. Every patient requires counselling before discharge and thorough examination during the follow-up to detect any evidence of recurrence.

Introduction

IP was first described by Ward, 150 years ago as a follicular tumour [1]. In 1938, Ringertz recognized the endophytic growth pattern and introduced the term “inverted papilloma” [1]. It was Hyams who, in 1971 proposed that they be subclassified into three types, inverted, fungiform and cylindrical [2].

In 1991, the World Health Organization (WHO) classified the sinonasal papilloma into 3 distinct histopathological subtypes: exophytic, inverted, and oncocytic [3]. Stammberger was the first to report the endoscopic treatment of IP in the year 1981 [1].

It was named as Schneiderian papilloma in honour of C. Victor Schneider, who in the 1660 s identified the origin of the nasal mucosa from ectoderm [4].

Of the three types, IP and exophytic papillomas are the most commonly diagnosed subtypes, each accounting for almost 50%, and oncocytic are the rarest, comprising only 3–5% [3].

Epidemiology

IP accounts for 0.5–4% of all the nasal tumours [3, 4]. The annual incidence is approximately 0.6–1.5 cases per 100,000 per year [5]. Most commonly it affects patients in their 5th–6th decades with a male to female ratio of 2–3:1 [6, 7]. They occur over a wide age group but in general are not common in children [8].

The three variants are defined by location, gross/endoscopic appearance and histologic features [8]. However, the clinical features and biologic behaviour are similar [8]. Symptoms vary and are dependent on location [8].

The exact aetiology till today remains unclear [9]. Many have associated the occurrence of IP with chronic inflammation, Human Papilloma Virus (HPV) infection, Epstein-Barr virus (EBV), smoking, occupational, environmental exposures, cell cycle related proteins and angiogenic factors [9, 10].

The presence of HPV DNA subtypes 6, 11, 16, and 18 has been found to be associated with a higher chance of recurrence and malignant transformation [11]. HPV serotypes 6 and 11 are less associated with IP [11]. HPV 16 and 18 were found to be related to the malignant transformation [12].

With regards to EBV, the recent available literature does not support a role for this virus in the aetiology of IP [6].

A history of smoking and advanced age increased the risk of recurrence and malignant transformation [13].

Histopathology

IP is derived from the sinonasal (SN) Schneiderian membrane [4] which is derived from both the neuroectoderm of the olfactory placode and the nasopharyngeal mucosa of endodermal origin [12]. Such a diverse origin probably explains the very different histological appearance of benign papilloma at its site [12]. This multipotent epithelial neoplasm can differentiate into respiratory, transitional, or squamous cell lines [10].

The histological feature that distinguishes IP from other mucosal lesions is the propensity of the neoplasm to invert, proliferating into the underlying stroma with an intact basement membrane [10].

Origin and Extent

Most commonly they arise from the lateral nasal wall, adjacent to the middle turbinate, posterior to the uncinate process [1, 9, 14]. Of the paranasal sinuses, the ethmoidal and maxillary sinuses are most frequently involved [15, 16]. The frontal sinus and, less commonly, sphenoidal sinuses can be involved, generally via direct extension from the ethmoidal sinus [16].

According to the study conducted by Budu et al. [11] the sinuses most commonly involved were the maxillary and ethmoid sinuses, affected simultaneously in 110 cases (67.90%). The ethmoid sinus alone was affected in 45 cases (27.77%). Singular frontal sinus and sphenoid sinus involvement was exceptional and accounted for only 7 cases in the study group, respectively 3 cases (1.85%) for the frontal sinus and 4 cases (2.46%) for the sphenoid sinus.

Exceptionally, IPs may arise in other sites [2] such as middle ear–mastoid, pharynx, nasopharynx, lacrimal sac, and possibly in the wall of a branchial cleft cyst [2]. It has been suggested that the ectopic migration of the Schneiderian membrane during embryogenesis could account for these aberrant papilloma in sites contiguous with the SN tract [2].

Clinical Features

IP resembles in its presenting complaints with that of SN polyps, chronic rhinosinusitis and SN carcinoma [1].

Most common symptoms of IP are unilateral nasal obstruction associated with rhinorrhoea, epistaxis and sometimes facial pain and hyposmia [9, 15, 17]. The poor specificity of these symptoms makes it difficult to distinguish IP from other injuries and delays diagnosis in many cases [18]. A classic triad of facial asymmetry, palpable/visible tumour in the oral cavity, and visible intranasal tumour occurs in 40–60% of patients with advanced stage of tumour [5].

Other symptoms are anosmia (loss of smell), epiphora (watering from eyes), numbness over the cheek, hypo-nasal speech and orbital symptoms like proptosis if the lamina papyracea is breached [1].

Diagnosis

The definitive diagnosis is determined by biopsy, although in some cases false negatives can appear because these lesions may coincide with benign polyps [18]. Preoperative biopsies are important to rule out a malignant inverted papilloma or malignant neoplasm [18].

Computed tomography (CT) remains the imaging modality of choice, despite certain disadvantages [19]. Bone remodelling is characteristic and can be found in 43% of cases, presenting as calcifications and swelling of the paranasal sinuses, with erosion and sclerotic changes in some cases [18]. Areas of focal hyperostosis on CT images correspond to the origin of tumour [20]. This is useful not only in suggesting the diagnosis, but also to aid the surgical planning, as the location of tumour origin determines the extent of surgery required [1].

According to a retrospective study by Yousuf and Wright et al. [21], osteitis was seen in 20/22 patients and was used to correctly predict the site of attachment in 18/20 times.

Magnetic Resonance Imaging (MRI) is now considered as the imaging of choice in the follow-up of post operated patients [22]. MRI has a characteristic streaky delineation with convoluted cerebriform patterns (CCP) on both T2 and contrast-enhanced T1 weighted images. MRI is able to distinguish tumour from inflammation but is unable to differentiate papilloma from malignant tumour and is thus advocated as a better tool for recurrent tumour [19, 23].

No studies were found which compared the specificity and sensitivity of MRI and CT in the accurate pre-operative identification of the extent of IP [19]. There is currently not enough evidence to suggest one sole modality as providing optimum imaging for IP [19].

Endoscopy reveals an irregular multinodular pale, fleshy polypoid mass of variable consistency and with a tendency to bleed on touch [1].

Staging Systems

It has been difficult to compare surgical approaches to these neoplasms, because of the absence of a uniformly applied staging system representing the extent of disease [24].

In 2000, Krouse elaborated on a simple, easily applied staging system was developed based on the extent of tumour involvement noted on endoscopic examination of the nasal cavity and CT scan evaluation [25] [26]. Although there is no accepted staging system for patients with IP, the one proposed by Krouse is most commonly followed (Table 1) [25].

Table 1.

Krouse staging system

Krouse staging system
Stage I disease is limited to the nasal cavity alone
Stage II disease is limited to the ethmoid sinuses and medial and superior portions of the maxillary sinuses
Stage III disease involves the lateral or inferior aspects of the maxillary sinuses or extension into the frontal or sphenoid sinuses
Stage IV disease involves any extra sinus involvement or all tumours with concurrent malignant association

The other less commonly proposed ones are Hans, Olkawa, Kamel and Cannady staging system [25].

According to a study conducted by Gras-Cabrerizo et al. [26] distribution of patients according to recurrence was better with Krouse and Cannady’s than with Han’s system.

Treatment

Surgical resection is the treatment of choice [1]. Aim of the surgery should always be the maximum/complete eradication of the disease in the first attempt itself [1]. One important principle to remember during the surgery is that along with the removal of the tumour, it is mandatory to remove the mucoperiosteum also from which the tumour is arising [1, 15, 23].

The commonly used open surgical approaches are medical maxillectomy(MM) and lateral rhinotomy(LR), midfacial degloving and Caldwell-Luc approach [26]. The aggressive LR and MM approach had been the gold standard treatment for many years [9].

If it involved the anteromedial wall of the maxillary sinus (alveolar recess), either a Caldwell-Luc procedure associated with the endoscopic approach or an EMM with the novelty of conserving the inferior turbinate was performed [26].

If IP originated from the frontal sinus involving the lateral and superior walls, an endoscopic Modified Lothrop procedure (EMLP) may be selected combined with an external approach (osteoplastic frontal flap or sub ciliary incision) [26–28].

Midfacial degloving was first described by Casson in 1974 in the management of extensive lesions of the SN tract [9, 29].

The location of the tumour, extent of involvement, and extension outside the nose and sinuses are primary factors involved in determining whether the tumour would be resectable through an endoscopic approach [25].

Endoscopic sinus surgery, in particular EMM, is currently the gold standard for treatment of maxillary sinus papilloma [24]. Pedicle oriented endoscopic surgery principles can be applied in select cases where the tumour pedicle is located on the anterior wall, called modified EMM [24]. In this technique the head of the inferior turbinate and the nasolacrimal duct are preserved that allows for good visualization of the maxillary sinus, good oncological control and a reduction in the rate of complications [24].

The advantages of endoscopic excision are superior visualization, preservation of the normal SN physiological function and achievement of muco-ciliary clearance patterns, absence of external scars, minimal morbidity and low recurrence rates [9].

Endoscopic resection is contraindicated in IP with massive skull base erosion, intradural/intra orbital extension, abundant scar tissue from prior surgery, and/or in certain cases of associated squamous cell carcinoma (SCC) [11].

According to Budu et al. [11] recurrence after endoscopic surgery was found to be 16.04%. The endonasal endoscopic approach used alone or in combination with the external access proved to be efficient and bear lower tumour recurrence rates when compared to the external approach alone in cases classified as Krouse stage T2 and T3 [23].

Post operatively patients should be followed up by endoscopy every 3 months for the first 2 years [17]. After this period, patients can be followed up biannually for up to 5 years [17]. MRI and/or biopsies should performed when a recurrence is suspected [17].

Surgically unresectable masses and masses that have undergone malignant transformation should be subjected to irradiation [1]. Radiotherapy techniques and dose fractionation schedules are essentially the same as those used for carcinomas of the nasal cavity and paranasal sinuses [1].

The complications after surgery can be classified according to the Clavien–Dindo Classification of Surgical Complications (Table 2) [17].

Table 2.

The Clavien–Dindo classification of surgical complications

Summary of Clavien–Dindo classification of surgical complications
Grade I: Any deviation from normal post-operative care without the need for treatment or interventions
Grade II: Requiring pharmacological treatment or blood transfusion
Grade III: Requiring surgical, endoscopic or radiological interventionGrade III: Requiring surgical, endoscopic or radiological intervention
Grade IV: Life-threatening complication requiring IC/ICU management
Grade V: Death of a patient

Recurrence

The risk factors for recurrence are still unclear [25]. Correlation with morphology shows that significant dysplasia within the lesions is associated with a higher risk of recurrence and even progression to carcinoma [30]. Recurrences during the first year should be considered as residual tumours due to incomplete resections [18].

Authors are trying to find an association between the Krouse system and recurrence rates [31]. Recurrences according to Krouse’s system were found to be 0% in T1 stage, 16% (5/31) in T2 stage, 25% (9/35) in T3 stage, and 60% (3/5) in T4 stage [26].

The major cause for recurrence of the disease, or rather failure to cure it, is the incomplete resection of the tumour or insufficient cleanliness of the surgical margin and in tumours located in sites with difficult access [15, 32].

According to the study conducted by Li et al., [32], patients with advanced stage of IP who underwent single endoscopic surgery presented a higher recurrence rate. According to their study in 57 patients with IP based within the sphenoid sinus, it revealed that the attachment site of SIP over the optic nerve and carotid artery correlated with a 14.6% rate of recurrence [32].

Malignant Transformation

Malignant transformation can occur as keratinizing and non-keratinizing SCC (by far the most common, seen in ~ 10% of cases) and other less frequent histology such as mucoepidermoid carcinoma, verrucous carcinoma, and adenocarcinoma [20].

The occurrence of SCC/IP is so rare, that there is relatively little information on its natural history and treatment outcomes, and that too only in some meta-analysis with a small number of cases [14].

HPV family 6/11 and 16/18 has been observed in IP associated with severe dysplasia and SCC and HPV infection may be an early step in the process of malignant transformation [33].

Patients with HPV-positive SCCs of the head and neck, have superior outcome, attributed to enhanced radiation and chemo-sensitivity due to an intact apoptotic mechanism in response to radiation and chemotherapy [7].

The association between IP and malignancy can be metachronous or synchronous [34]. The reported incidence of metachronous or synchronous malignancies with IP varies from 2 to 27%; the median rate being 9% [25].

At present, there are no classification systems for SCC/IP and the American Joint Committee for Cancer (AJCC) staging system is most commonly used nowadays [14]. For the patients who had surgery for IP, the AJCC system may not be accurate, as the assigned stage was based on preoperative CT or MRI data and the operative records [14].

Recently, authors suggested that the focal loss of a CCP might be indicatory for IPs concomitant with malignancy [9].

The various surgical approaches used to deal with SCC/IP are LR, extended LR, subtotal maxillectomy, radical maxillectomy and craniofacial resection [14]. Surgery combined with cervical node dissection is done in patients with metastasis [14]. Combined therapy of surgery with radiation was also given with dose levels comparable to those used for invasive SCC (~ dose of 66–70 Gy) [7, 14].

After radical excision of the primary tumours, repair and constructive procedures were performed mostly with a pectoralis major musculocutaneous flap [14]. Others included a submental flap, free forearm flap, or free rectus abdominis myocutaneous flap [14].

According to Liang et al. [14], the 5-year survival rates at stages I–II, III, and IV were 64.2%, 59.7%, and 19.0%, respectively. Furthermore, patients with SCC/IP in stages III–IV, had a higher 5-year survival rate in those treated with combination therapy of surgery and radiation rather than those treated with surgery only [14].

Scope

The immunohistochemistry and biological markers involved in the transformation of IP to SCC remains unknown. Thus, it is important to explore the molecular mechanisms underlying the malignant transformation of IPs, which could help identify biomarkers for improved diagnosis of SN tumours and better targeted therapy. Furthermore, the identification of biomarkers will help to screen the patients in their initial visits and make it easy to identify patients who are at risk of malignant transformation.

Conclusion

IP is a pathology of varied biological behaviour. Its characteristic property of local erosion and destruction, difficulty in finding a specific site of origin, high risk of recurrence and lastly the malignant association makes this benign pathology a challenging entity for complete cure.

Although the exact aetiology still requires a definitive affirmation, there is sufficient evidence to cite the role of HPV DNA in the recurrence and malignant transformation within the papilloma.

CT remains the imaging modality of choice for IP and MRI imaging being the imaging of choice in the follow-up of post operated patients. Nasal endoscopy with biopsy remains gold standard for diagnosis. Krouse staging system is the most accepted staging system currently that allows us to stage and estimate the risk of recurrence.

Surgery for the complete eradication of the primary tumour remains the mainstay treatment option. Adjuvant radiation therapy with or without chemotherapy is reserved only for patients with multiple recurrences, inoperable tumours or those associated with malignancy.

With refinements in endoscopic techniques, the endoscopic stratagem has been found to be appropriate not only for the diagnosis and follow up, but also the treatment of limited and recurrent inverted papilloma. It is safe to say that the endoscopic removal of the inverted papilloma can be performed in stages I, II and in most cases of stage III after a detailed study of its origin and extent via radiological assessment.

The modified EMM technique can be used when IP arises from the anterior wall of the maxillary sinus.

The classical open techniques, such as lateral rhinotomy or midfacial degloving with medial maxillectomy, are rarely used nowadays for the initial stages of papilloma. For the more extensive primary tumours and the aggressive recurrent tumours, open surgical approaches can be used.

Lastly coming to the malignant association of IP, it has been found to take an average of approximately 2–5 years, wherein patients are lost to follow-up and the transformation usually reaches an advanced-stage before it is diagnosed. This calls for strict awareness amongst all the patients of a possibility of malignant transformation with recurrence despite surgery and the need for meticulous follow-up to avoid missing out the onset of a malignancy/recurrence.

Compliance with Ethical Standards

Conflict of interest

The authors declare no conflict of interests.