Disclaimer: The information contained within the Grand Rounds Archive is intended for use by doctors and other health care professionals. These documents were prepared by resident physicians for presentation and discussion at a conference held at Baylor College of Medicine in Houston, Texas. No guarantees are made with respect to accuracy or timeliness of this material. This material should not be used as a basis for treatment decisions, and is not a substitute for professional consultation and/or peer-reviewed medical literature. Inverted Papilloma Today we are talking about inverted papilloma. We will be starting with a case report and a little later discussing what it is, its history, epidemiology, clinical history, pathophysiology, and then finally, management. So, we will start with a case report. G.H. is a 49-year-old male who presents with a six month history of left nasal mass and left nasal congestion. He reported occasional epistaxis and purulent rhinorrhea, denied any visual changes or headache. Past medical history is significant only for hypertension for which he takes amlodipine and hydrochlorothiazide Social history includes a 29-pack-year tobacco history and occasional alcohol use. Physical exam was only remarkable for an extensive left nasal mass extending to the right posterior nasal cavity. Labs on this patient were unremarkable. The first biopsy obtained showed squamous mucosa, parakeratosis, and acanthosis. A second biopsy was obtained in clinic, and this revealed atypical squamous proliferation. A CT scan was obtained, and this revealed a large left nasal mass with bony erosion of the nasal bones and upper portion of the maxilla. The mass extends up into the cribriform plate, upper nasopharynx, left ethmoid air cells, and into the left maxillary sinus. This patient underwent an endoscopic resection, a left maxillary antrostomy, and a left Caldwell-Luc. Final surgical pathology revealed inverted papilloma. Through the years many different names have been attributed to this lesion. Most are both inaccurate and misleading. Currently, inverted papilloma is the most favored title. It is a benign neoplasm from the sinonasal tracts, also called the schneiderian mucosa. It is characterized by an increase in the thickness of the overlying epithelium with extensive invasion into the underlying stroma. It has a long history dating over 150 years. In 1854, it was first described and named schneiderian papillomas in honor of C. Victor Schneider, who in the 1600s identified nasal mucosa origin from ectoderm. In 1938, Ringert coins the term “inverted papilloma,” based on its histological findings of inversion of the epithelium into underlying connective tissue. In 1971, Hyams, who is viewed at right, subclassified sinonasal papillomas into three types — cylindrical, fundiform and finally inverted papillomas. In 1987, Resler discovers the initial association with human papilloma viruses. Inverted papillomas are relatively uncommon tumors of the nasal cavity compromising approximately 0.5% to 4% of all primary nasal tumors. Its incidence ranges from 0.75 to 1.5 cases per 100,000 per year. They occur approximately 15 th as often as inflammatory polyps. Age ranges widely from 6 to 89 years, and most are usually diagnosed in the 5 th to 7 th decade. Average age of diagnosis is 53 years. There is a male predominance 3:1, and it affects primarily Caucasians. Symptoms are nonspecific often mimicking sinusitis. The most common is unilateral nasal obstruction seen in over 60% of patients. Nasal discharge, headache, facial pressure and pain, epistaxis, and anosmia may also be seen. Signs may include a polypoidal mass filling the nasal cavity extending from the vestibule to the nasopharynx. The nasal septum is often bowed to the contralateral side due to slow expansile growth. Proptosis and facial swelling seen in this patient at left can develop sometimes, due to this expansile lesion. It derives from the sinonasal mucosa, also known as the schneiderian membrane, as previously mentioned, which is the lining membrane of the nasal cavity and sinuses. This mucosa originates from the ectodermal germinal layer, which surrounds and migrates with the olfactory placodes in the nasal cavity. This occurs at the fourth week of embryonic life, thus creating a transitional zone between the respiratory epithelium of the nasopharynx, which is endodermally derived, and keratinizing squamous epithelium of the nasal vestibule. Sinonasal papillomas are characterized by being in general unilateral, although bilateral papillomas occur infrequently. Second, they have a destructive capacity with an ability to extend on into adjacent areas by spreading along a mucosa. Third, they have a tendency to recur, and they will recur even if completely excised. Finally, they have the potential for malignant degeneration. Histologically, as Hyams described, there are three types. The first is fundiform, compromising 50 percent of sinonasal papillomas. They are also known as exophytic. The second is cylindrical, compromising 3 percent of all sinonasal papillomas, also called oncocytic. And finally, inverted papillomas, compromising the remaining percentage. Fundiform papillomas arise primarily in the nasal septum. They are papillary, exophytic, verrucoid lesions, which can be seen at right. Histologically, they consist of papillary fronds of thick epithelium, predominantly squamous and, less frequently, respiratory. Surface keratinization is uncommon. Cylindrical papillomas have a clinical behavior similar to inverted papillomas. They arise primarily in the left lateral nasal wall. Histologically, they appear as multilayer papillary epithelium proliferation with eosinophilic to granulous cytoplasm whose outer surface may or may not be covered with cilium. Finally, inverted papillomas arise most commonly in the lateral nasal wall. They often extend into the maxillary sinus and ethmoid air cells. The next most common places of origin include both the maxillary sinus and ethmoid air cells. They less frequently involve the nasal septum, frontal, and sphenoid sinuses. They also may occur bilaterally, and they may be multicentric with multiple foci of origin. Histologically, inverted papillomas exhibit a hyperplastic epithelium with extension invasion into the underlying stroma. The epithelial cell type is variable, from a keratinized squamous epithelium to a ciliated columnar respiratory epithelium. A transitional type is also possible—intermediate between these two types and combinations of the two may both be present in the same lesion. The epithelium component is notable for cells that are regular in shape, nuclei that are uniform, and orderly cellular maturation from the basal layers to the top layers with occasional mitopic features present in the basal layers. The stromal component is characterized by a myxomatous to fibrous tissue. It has chronic inflammatory cells and variable vascularity. The etiology of inverted papilloma is still unknown, but a number of nonspecific causes, as seen in the slide to the right, have been implicated. It is most often considered a true epithelial neoplasm as its intense proliferation of epithelium is its dominant histologic feature. Finally, a viral etiology has also been suggested. The support for viral etiology includes its multifocal origin and its high rate of recurrence, as well as the fact that it has been found to be responsible for other papillomas in other areas of the body. Human papilloma virus is most often associated with inverted papilloma. HPV DNA has been identified in 32 percent of inverted papillomas by in situ heparinization and PCR. Among inverted papillomas associated with carcinomas, HPV is present in 58 percent. Type 16 is the most prevalent in inverted papillomas, comprising about 31% of all inverted papillomas that are associated with HPV. Malignant degeneration occurs in approximately 10 percent. Marked increase in cellularity, absence of cellular maturity, and loss of nuclear polarity are among the changes seen. When malignancy is present, it is thought to be due to malignant transformation of inverted papilloma, not the presence of two separate primary tumors. While research is still being done on this topic, a mutation of the P-53 leading to P-53 overexpression is hypothesized to be important to transformation. There are no predisposing factors to the development of malignancy. There is no correlation with the factor of alcohol use, unlike most other head and neck malignancies. There are no histologic features that can predict the development of malignancy, and there is no correlation evident between the number of recurrences or the interval to recurrence and the development of malignancy. Malignancies associated with inverted papilloma demonstrate aggressive growth, bilateral extension, and orbital/intracranial extension. Regional or distant metastases include spread to cervical and facial lymph nodes. Squamous cell carcinoma is the most common malignant neoplasm associated with inverted papilloma. Adenocarcinoma and small cell carcinoma are rare. The picture at right shows an adenocarcinoma with an inverted papilloma. Malignancies can be associated with inverted papillomas in three different ways. First, they can be synchronous where carcinoma and inverted papilloma exist within the same lesion. The picture at right shows a synchronous squamous cell carcinoma. The second is metachronous where a carcinoma appears where inverted papilloma has been previously removed. In the third, there are areas of inverted papilloma within a squamous cell carcinoma. The incidence of associated malignancy has been estimated to be approximately 10 percent. Lawson and Allen in 2003 reported that 7 percent of patients have associated malignancy, 7 with synchronous carcinoma and 4 with metachronous carcinoma. These develop three to eight years after initial diagnosis. In their literature review of 26 series published between 1970 and 2001, consisting of over 1400 patients, 8.9% were found to have associated malignancy, 67% with synchronous, and 32% with metachronous Finally, to management. Key to diagnosis is a detailed history, of course. Patients may have a history of unilateral symptoms or history of multiple surgical procedures for nasal polyps. Second, a thorough physical exam where a unilateral mass may be seen or endoscopic exam may reveal multiple polypoid masses with multiple digitations located laterally to the middle turbinate. Three, biopsy is key. Given the similar appearance and possible presence of concurrent polyps, histologic examination is critical. Multiple biopsies may be necessary, as seen in our case, due to inadequate sampling or sampling of concurrent polyp or inflammatory tissue or error in diagnosis. Finally, radiographic evaluation is critical. CT scan is considered to be the study of choice. The most common CT profile is a unilateral mass with a lobulant surface occupying the middle meatus and extending into one or more of the adjacent sinuses. Opacification, mucosal thickening, of the paranasal sinuses may be seen, as well as bony thinning remodeling or erosion caused by inverted papilloma growth. Disadvantages of the CT scan are primarily due to its difficulty to differentiate inspissated mucus, polyps, or mucoperiostial thickening from inverted papilloma. MRI may also be used in the diagnosis of inverted papilloma. It is superior to CT scan for distinguishing papillomas from underlying inflammation and provides better delineation of lesions in contrast to surrounding soft tissue. In T1 weighted images, inverted papillomas are isointense and homogenous. They are slightly hyperintense to muscle. The picture shows a 45-year-old male with history of inverted papilloma. T1 weighted coronal image shows intermediate signal density with relatively nondescript architecture, involving the right maxillary antrum, nasal cavity, and ethmoid sinus. On T2 weighted images, seen at right, inverted papillomas have intermediate signal density, while inflammatory polyps and inspissated material in the sinuses secondary to obstruction by papilloma are hyperintense. This picture shows the same patient, where high intensity secretions in the lateral part of the antrum are hyperintense, while the remaining portion of the inverted papilloma appears to be a convoluted cerebriform pattern and quite isointense. The medical management is limited. Historically, radiotherapy was used in the management of inverted papillomas. Inverted papillomas have not shown to be radiosensitive. With radiotherapy in recent times, it has been used in patients with synchronous squamous cell carcinoma. Currently, medical management is used as an adjunct to specific complications, such as sinusitis. Surgical management is the mainstay of treatment of inverted papilloma. Selection of the surgical procedure is based on its extent, location, and the presence of concurrent malignancy. Three procedures that have been used to treat inverted papillomas are lateral rhinotomy and medial maxillectomy. Currently, the gold standard for the treatment of inverted papilloma is midfacial degloving and endoscopic sinus surgery. Lateral rhinotomy medial maxillectomy is particularly useful for inverted papillomas that are perilacrimal, nasofrontal, supraorbital, ethmoidal, or in the orbit. A curvilinear incision beginning just below the medial aspect of the eyebrow is made inferiorly half-way between the medial canthus and the nasion. The incision is extended inferiorly along the lateral aspect of the nose around the ala. The incision includes a full thickness skin down to periosteum. The periosteum is then elevated as far lateral as the lateral aspect of the maxillary antrum, as far superior as the orbital rim exposing and preserving the infraorbital nerve, and along the nasal bone in the ascending process of the maxilla. The periorbit is then undermined off the lamina papyracea, dislocating the lacrimal sac out of the lacrimal fossa and transacting the lacrimal duct as far distal as possible. The periorbit is then further undermined off the medial floor of the orbit. The anterior and posterior ethmoid artery is identified. These are the most constant landmarks for the frontoethmoid suture line. Staying below the suture line is critical to avoid entrance into the anterior cranial fossa. An opening is made through the anterior wall of the maxillary antrum, and the entire front wall of the maxillary antrum is removed up to the orbital rim. Then osteotomies are made, first along the floor of the nose through the bone between the antrum and the nasal cavity; second, through the frontoethmoid suture line below the level of the anterior ethmoid artery; and finally, along the medial floor of the orbit to the posterior wall of the antrum. The lateral nasal wall is then removed by cutting through the middle inferior turbinate attachments and then all mucosa is removed from the maxillary antrum. Then the sphenoid sinus is opened and its mucosa also removed. Dacryocystorhinostomy is then performed to avoid epiphora, a common postoperative complication of this procedure. It can be accomplished in two ways—either by catheterization of the lacrimal duct using an indwelling silicone or incising the lacrimal sac along it long axis and then suturing the edges in place to adjacent tissues. The main advantages of this approach include a radical excision, access to all lateral sinuses, the skull base, nasopharynx, and orbit. Disadvantages include, obviously, a surgical scar, possible CSF leak, epiphora, injury to orbit, and mucocele formation. Midfacial degloving is particularly useful for inverted papillomas that are bilateral nasal in origin. Four types of incisions are required in this approach. The first is bilateral intercartilaginous incisions, bilateral septocolumellar incisions, a complete transfixion incision, and then a gingivobuccal incision, which you see at bottom. This is made from one maxillary tubercule to another. The soft tissue is then incised around the piriform aperture and nasal floor is undermined as high as the orbital rims. These incisions facilitate the exposure of a piriform aperture in the lateral nasal wall. A medial maxillectomy is then performed as previously described, and this can be combined with the frontal sinus osteoplastic flap for access to the frontal sinus. Its main advantages are that there is no external scar, invisibility, and bilateral access. Its disadvantages include insufficient access to more distant areas, such as vestibular, orbital, ethmoid cells; and complications include vestibular stenosis, oral antral fistula, epistaxis, and nasal congestion. Endoscopic sinus surgery is particularly useful for inverted papillomas in the lateral nasal and nasal cavity, middle meatus, maxillary sinus, and the anterior and posterior ethmoid cells. The procedure largely consists of tumor debulking through a microdebridder until the origin is identified, and then lesions are usually excised en bloc from the identified tumor attachment sites with a wide cup of normal mucosa. Frozen sections are obtained, negative margins confirmed, and bone may be removed from underlying sites of attachment. The contraindications to a purely endoscopic resection of inverted papillomas include the concomitant presence of squamous cell carcinoma, massive skull base erosion, intradural or intraorbital extension, and extensive involvement of the frontal sinus. Although traditionally endoscopic surgery is used more for small lesions, bulky lesions have made endoscopic surgery difficult. Recently, however, a new technique has been described for treatment of massive tumors with attachments within the maxillary sinus. It is called SSES (Sequential Segmental Endoscopic sinus Surgery). Basically, this involves sequential excision of larger tumors into massive segments, four segments usually. First, the nasal cavity; second, the middle meatus, including portions of the ostiomeatal complex; third, the maxillary sinus ostium and antrum along with the maxillary sinus medial wall if an endoscopic medial maxillectomy is performed; and then the frontal or sphenoid sinus. The following are the usual advantages and disadvantages of endoscopic surgery. It is a less invasive procedure and you have a multiangle visualization and absence of facial scarring. In terms of disadvantages - orbit injury, CSF leak, and periorbital ecchymosis. Another disadvantage commonly cited is the inability to obtain an en bloc resection. It is especially difficult for these larger tumors that fill the entire nasal cavity. However, as just previously described, this is increasingly circumvented by the ability to first debulk the tumor and then perform excision in segments. The main controversy in the treatment of inverted papilloma lies in the final advantage and disadvantage: seemingly contradictions, comparable versus greater recurrence rate. This inherent contradiction is reflected in the debate that still exists regarding whether less extensive procedures result in incomplete excision of the inverted papilloma and, thus, more recurrence. To look at this more closely, we must first examine the reason for the rate of recurrences as well as the evolution and treatment of inverted papillomas. First to recurrences. Recurrence is truly due to interaction of multiple factors, as can be seen in the slide above. The most important factor in determining the rate of recurrence is the method of removal, which determines the completeness of resection. Most recurrences represent residual disease. These recur early and appear at the primary site. Fifty to 70 percent of patients have had prior surgery and numerous reported series. The reported recurrence rate for inverted papilloma ranges from 8% to 16%, while recurrence rates for endoscopic surgery range from 9% to 61%. This wide range in recurrence is in large part responsible for the ongoing dilemma regarding the surgical approach. This dilemma first started in the 70s to 80s when first studies on endonasal removal of inverted papillomas reported higher recurrence rates, from 48% to 78%. These include simple excisions intranasally via polypectomy or turbinectomy. They were often performed without microscopic or endoscopic assistance. By the mid-70s, studies show that recurrence rates declined dramatically as the extent of surgery grew. Gradually, there was a trend away from limited intranasal procedures and a trend towards more open extranasal en bloc resections. By the early 80s, lateral rhinotomy and medial maxillectomy became the gold standard for the treatment of inverted papilloma due to limitations of the transnasal approach and the tendency of inverted papillomas to recur and their associations with carcinoma. Some authors do concede that the conservative management of inverted papillomas is appropriate when these tumors are limited to the lateral nasal wall and are small in size. This concession can be attributed to the fact that lateral rhinotomy, as previously discussed, isn’t without complications. Other procedures, including midfacial degloving, were explored. In 1981, the first report of 15 patients treated purely endoscopically was reported. Since then, numerous authors have published their experience with the management of inverted papilloma endoscopically. Many studies in the 80s and early 90s recommend that endoscopic approach be limited to lesions confined to the lateral nasal wall or that extend only into adjacent sinuses. In the latter part of the 90s and into this decade, there has been a trend towards the management of inverted papillomas endoscopically due to rapid expansion of surgical techniques, advancements and instrumentation: improved visualization, with modern fiberoptic telescopes; and the improved imaging by CT scans and MRIs, which provide better preoperative planning as well as postoperative surveillance. There is a growing body of literature to support the use of endoscopic surgery and the resection of inverted papillomas with recurrence rates comparable to open procedures. Many studies done after the ‘90s have recurrence rates for endoscopic procedures similar to that of lateral rhinotomy. In addition, with the gradual improvement in endoscopic instrumentation and technique, the treatment of more extensive inverted papillomas endoscopically is increasing. A few authors have advocated using the endoscopic approach for more extensive lesions via endoscopic medial maxillectomy or SSES. These authors have demonstrated recurrence rates similar to that of open procedures. While there seems currently to be a sufficient body of literature to support the treatment of endoscopic surgery for more limited lesions, there still are insufficient studies to prove that endoscopic surgery for more extensive inverted papillomas have comparable recurrence rates with open procedures. The treatment of inverted papilloma endoscopically is still a relatively recent development. Treatment of more extensive lesions endoscopically is even more so. More time and further studies are definitely needed to determine the efficacy of endoscopic treatment of extensive inverted papillomas. Finally, long-term follow-up care is critical in patients who have had inverted papilloma. Many recurrences are within the first two years following treatment; and most occur by five to 10 years after treatment. Follow-up should occur for at least five years, every four months during the first postoperative year and every six months at least for the next five years. Finally, what to take away from this talk. First, that inverted papilloma is a benign sinonasal lesion that most commonly arises in the lateral nasal wall. It has a propensity for recurrence and local aggressiveness. Preoperative assessment is crucial: CT scan to determine the extent of disease and biopsy, of course, to provide a diagnosis. The standard of treatment currently still is lateral rhinotomy with medial maxillectomy. It is known to have ex ellent rates of cure, but it has significant morbidity. Advancements in diagnosis and treatment of sinus disease have led to successful use of endoscopic techniques in the treatment of inverted papilloma yielding a similar recurrence rate to medial maxillectomy. Endoscopic treatment of larger, more extensive lesions are successful in preliminary reports but more time is needed for follow-up and further study. Finally, the propensity for delayed recurrence and incidence of malignancy make a long and careful follow-up necessary. Case Presentation DH is a 49 year-old male who presented with a six months history of a left nasal mass and left nasal congestion. Patient reported occasional epistaxis and purulent rhinorrhea. No visual changes or HA. His past medical history is notable only for hypertension. He currently takes Amlodipine and Hydrochlorothiazide. He has no allergies to medications. He reports a 29 pack year history tobacco use, and occasional alcohol and cocaine use. Physical exam was notable for extensive left nasal mass extending to the right posterior nasal cavity. The remainder of his physical exam was unremarkable. The first biopsy obtained in clinic revealed squamous mucosa parakeratosis and acanthosis. A second biopsy demonstrated atypical squamous proliferation. CT scan revealed a large left nasal vault mass with bony erosion of the nasal bones and upper portion of the maxilla. The mass extended up to the cribriform plate, upper nasopharynx, left ethmoid air cells, and possibly into the left maxillary sinus. Patient was taken to the operating room where he underwent endoscopic resection of the left nasal mass, a left maxillary antrostomy, and left Caldwell-Luc. He tolerated the procedure well and currently without evidence of recurrent disease. Bibliography: Alba JR, Diaz MAA, Perez A, Rausell N, Basterra J. Inverted papilloma of the sphenoid sinus. Acta Oto-Rhino-Laryngologic Belg 2002:56:399-402. Baruah P, Deka RC. 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A rare location of bilateral inverted papilloma of the nose and paranasal sinuses. Rhinology 2002;40:220-222. Yoon J-H, Kim C-H, Choi E-C. Treatment outcomes of primary and recurrent inverted papilloma: An analysis of 96 cases. J Laryngol Otol 2002;116:699-702. Grand Rounds Archive | Department Home page BCM Public | BCM Intranet | Privacy Notices | Contact BCM | BCM Site Map | ©2001-2006 Baylor College of Medicine
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