The nasal neoplastic disease entity known as inverting papilloma (IP), also called inverted papilloma, has long been a topic of intense debate because of its recurrent, destructive, and malignant potential. Traditionally, these tumors are approached externally to ensure adequate margins of resection. Intranasal approaches have been fraught with recurrences because these tumors are usually bulky, creating a difficult exposure. However, otolaryngologists have been gradually extending the indications for minimally invasive intranasal operations, including endoscopic techniques. Does endoscopic sinus surgery have the potential to lower the high recurrence rate associated with the intranasal approach to that of external techniques, on a consistent basis? This chapter presents the controversy surrounding the management of IP.

In 1854, Ward1 first described a nasal papilloma. Billroth reported on a recurring nasal papilloma 1 year later, which he called villi-form cancer; many others began to look at this peculiar entity that appeared to invert,^1–6 as examined microscopically. In his landmark paper in 1971, Hyams¹ clarified the confusion regarding the characteristic growth behavior of IP by demonstrating the prognostic significance of certain histologic features. Hyams showed that increased mitotic activity, hypercellularity, pleomorphism, and atypia are associated with more aggressive and recurrent tumors. Furthermore, these histologic findings are associated with an increased tendency toward synchronous and metachronous carcinoma. When surface keratinization and dyskeratosis are found, there is increased suspicion for squamous cell carcinoma.¹

Incidence

IP typically occurs within a peak age range of 50 to 70 years, although it has been found in children as young as 8 years old.⁷ It has a male preponderance, as shown in one large series, in which 83% of patients were men. IP is typically unilateral, but it may be bilateral in less than 10% of cases.⁸ The etiology of IP is unknown; nonetheless, both human papillomavirus (HPV) and Epstein-Barr virus (EBV) have been demonstrated in IP specimens.^{9, 10} Squamous cell carcinoma occurs in association with IP in less than 2 to 56% of cases, although no study with more than 50 cases had a greater than 30% incidence of carcinoma, and most had less than 15%.^{8, 11–17}

Malignancy is often associated with aggressive growth, including intracranial, orbital, or mastoid invasion.^18–20 Moreover, Cummings and Goodman⁴ noted a few cases in which transitional cell carcinomas were reclassified as IP. Clearly, the marked atypia found in aggressive IP can be misleading with regard to the true incidence of carcinoma, with a falsely higher incidence reported in the cases. In addition, most institutions that report these cases are tertiary care referral centers; thus, unusual cases are selected out, whereas less aggressive cases may never get into the literature.²¹ Lastly, histologic detection of a synchronous cancer during IP excision was reported at 4 to 11% in directed studies.^{16, 22} It may be even less common to find metachronous carcinoma.²¹ Nonetheless, long-term follow-up in one study demonstrated a 16% (8/51) incidence, with cancer detected as late as 13 years after the diagnosis of IP.¹⁶ Myers et al.²³ demonstrated a gradation in atypia from papilloma to malignancy in 4 of 6 synchronous carcinomas. This observation would support the theory that IP can undergo malignant transformation.²³ Several molecular genetics studies have shown a convincing association between tumor pathogenesis and either HPV or p53 tumor suppressor gene interaction, or both.^24–27

Site of Origin

The middle turbinate and medial maxilllary sinus wall are the most common sites of origin of IP.⁸ A single focus is the most likely source of the tumor. Multicentricity was documented in only 7 of 149 cases by Hyams¹ and in 10 of 29 cases by Norris.³ These findings would support the conclusion that incomplete excision is the cause of recurrence, and not delayed development of IP at another site. As for the paranasal sinuses, the ethmoid and maxillary sinuses are the major sinuses involved. Only 1% of cases involve the frontal sinuses. In rare cases, the tumor can be isolated to the sphenoid sinus.²⁸ Paranasal sinus involvement has been linked to an increased recurrence rate.²⁹

However, this adverse association has been demonstrated in recent small studies to be surmountable with endoscopic sinus surgery. Furthermore, the sinuses tend to become involved secondary to nasal cavity tumors. Suh et al.¹² showed that in 49 of 57 cases both the nasal cavity and paranasal sinuses were involved; in only 2 of 59 cases was the sinus involved exclusively.

Histology

IP occurs when the Schneiderian membrane of the nose and paranasal sinuses inverts into the stroma in a pattern of endophytic growth.30, 31 Microcysts are often trapped within the epithelium. The Schneiderian membrane is composed of ciliated pseudostratified columnar epithelium. It starts 1 to 2 cm posterior to the nares at the mucocutaneous junction and is found in the nasal cavity and paranasal sinuses. The membrane is of ectodermal origin, unlike the nasopharyngeal mucosa, which is endodermal, but similar in appearance. Fungiform (usually from the nasal septum) and cylindrical cell papillomas are histologic variants of Schneiderian papillomas, managed similarly to IP.³² The data reported by Hyams¹ showed recurrence in roughly one-half of patients with IP, regardless of the type.

Evaluation and Diagnosis

The most frequent presenting symptoms of IP are nasal obstruction (64 to 78%), followed by headache, epistaxis, facial pain, periorbital swelling, purulent rhinorrhea, chronic sinusitis, allergy, hyposmia, visual changes, and meningitis. Some patients are even asymptomatic. These signs and symptoms make IP difficult to distinguish from inflammatory disease.^{11, 30, 33, 34} Office endoscopic examination and computed tomographic (CT) imaging of the nose and paranasal sinuses are the gold standards of evaluation.⁸ In contrast to the more translucent bilateral inflammatory polyps, IP is usually unilateral (although in rare cases it is bilateral), vascular, and bulky. However, IP often arises along with nasal polyps, making the diagnosis difficult. The surgeon should always submit operative specimens according to their site of origin, rather than as a combined specimen. IP can display bone invasion on a CT scan, even to the extent that skull base erosion occurs; this finding requires craniofacial resection despite no evidence of cancer.^{7, 15, 35} As a whole, intracranial invasion is rare, found in only 5 of 1468 cases reviewed.¹⁸ Snyder and Perzin⁵ demonstrated bone erosion in 5 of 34 nonmalignant IP cases. However, in patients with cancer, bone erosion occurred in all cases. By contrast, 3 cases of malignancy in Rothfield’s study showed no erosion.³⁶ IP can also cause sinusitis, which can lead to radiographic bony sclerosis. If a lesion suspicious for IP is seen on examination and is accessible, office biopsy can be performed. If the differentiation between inflammatory disease and tumor cannot be made on CT scan, this distinction can often be made by T₂

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