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Head and Neck Pathol (2014) 8:269–286 DOI 10.1007/s12105-014-0527-7

ORIGINAL PAPER

Carcinoma Ex-Schneiderian (Malignant Transformation): A Clinicopathologic and Immunophenotypic Study of 20 Cases Combined with a Comprehensive Review of the Literature

Jeremy Nudell • Simion Chiosea • Lester D. R. Thompson

Received: 22 December 2013 / Accepted: 3 February 2014 / Published online: 12 February 2014 Ó Springer Science+Business Media New York 2014

Abstract Schneiderian papilloma (SP) are uncommon for CK5/6 (86 %), p63 (86 %), CK7 (luminal, tumors with malignant transformation even less common. 50 %), p53 (83 %), and p16 (25 %). In situ hybridization The histologic criteria to define malignant transformation detected human papillomavirus in 26 %. Surgery was often are not well developed nor is the immunohistochemical accompanied by (n = 13), with a mean of profile reported in a large series of . 20 cases of 2.4 years of follow-up. Five patients developed a recurrence malignant transformation of SP included 7 females and 13 between 0.8 and 3.3 years. Carcinomas ex-SP are less males, aged 38–86 years (mean 60.7 years). Patients pre- common and are associated with better outcome than pre- sented most frequently with a mass (n = 11) and obstruc- viously reported. Patients tend to present with a synchro- tive symptoms (n = 7), present for 38.7 months (mean). nous , developing in an inverted type SP, with Most patients had no previous history of SP (n = 13); squamous carcinoma the most common . metachronous carcinoma was identified in 7 patients an Development of metachronous carcinomas ex-SP was average of 34.4 months after the first diagnosis of SP, with always preceded by SP recurrence in this series. 1–4 recurrences of SP. With a mean size of 4.1 cm, the majority of tumors involved a combination of more than Keywords Sinonasal tract Á Schneiderian papilloma Á one anatomic site (n = 10), followed by the Malignant transformation Á Review Á only (n = 5) or only (n = 3). Histologically, Á HPV 17 were inverted and 3 exophytic type SP. There were 17 squamous cell carcinomas, 2 mucoepidermoid carcinomas and 1 sinonasal undifferentiated carcinoma, comprising Introduction from 10 to 95 % of the tumor volume. Malignant histologic features included atypical mitoses, necrosis, bone , Schneiderian papilloma (SP) are uncommon benign sin- , decreased transmigrating neu- onasal tract tumors. Malignant transformation is reported trophils, paradoxical maturation, dyskeratosis and/or peri- to be around 27 %, although in daily practice the trans- neural invasion (n = 3). Patients tended to present with formation rate seems much lower. The criteria used to advanced stage (n = 14, Stage III and IV). Immunohisto- establish malignant transformation are not well defined. chemical studies showed positive reactions in the While there have been a few series in the English liter- ature that have reported malignant transformation in SP (Table 1), the information is shrouded within data about & J. Nudell Á L. D. R. Thompson ( ) SP in general, about human papillomavirus (HPV) find- Department of , Woodland Hills Medical Center, Southern California Permanente Medical Group, 5601 De Soto ings, significance of squamous in SP, or about Avenue, Woodland Hills, CA 91365, USA malignancies in general (Table 2). Therefore, there is no e-mail: [email protected] single, large, comprehensive evaluation of primary malignant transformation of SP with respect to their S. Chiosea Department of Pathology, University of Pittsburgh, Pittsburgh, clinical findings, histomorphology, immunohistochemical PA, USA reactivity, HPV findings, and management. The purposes 123 270 Head and Neck Pathol (2014) 8:269–286

Table 1 Review of the English literature on carcinoma ex-Schne- Table 1 continued iderian papilloma [2–17] Characteristics Total: N = 59 Characteristics Total: N = 59 Patients with recurrence (n = 18) 4.3 a Gender Patients without recurrence (n = 36) 4.1 Women 11 This table does not include the series reported in this study Men 48 a Parameter was not stated in all cases Age (in years)a b Patients may have experienced more than one symptom Range 32–83 Mean 61.3 Women (mean) 57.6 Men (mean) 62.1 of this study was to attempt to identify any specific his- a Symptom duration (in months) tologic and immunophenotypic features which can be Range 0.5–540 used to aid in the diagnosis of malignant transformation Mean 62.6 of SP. Women (mean) 204.0 Men (mean) 48.6 Symptoms at presentationa,b Materials and Methods Mass, facial swelling 17 Obstructive symptoms 15 The records of 20 patients with tumors diagnosed with Epistaxis 8 ‘‘Schneiderian papilloma’’ and ‘‘carcinoma’’ (any type) Pain and/or headache 8 were selected. The primary sites included the nasal cavity Optic symptoms (proptosis, ptosis, diplopia) 8 and paranasal sinuses, nasopharynx, and ear and temporal Drainage, discharge, crusting 6 bone. In all cases, focal areas of residual SP were present Nerve changes (paralysis, palsy, paresthesias, 2 within the material that showed carcinoma. However, numbness, , trismus, tingling) review of previous material, when available, was also Otic symptoms 1 performed as a point of comparison and documentation of Locationa metachronous versus synchronous histologic malignant Mixed (more than one anatomic site) 38 development. Fourteen of the cases were identified from a Maxillary sinus only 8 review of all SP diagnosed during a 10 consecutive-year Nasal cavity only 8 period of cases within the Southern California Permanente Lateralitya Medical Group (including 10 different medical centers). Right 15 An additional 6 cases were obtained from the University of Left 19 Pittsburgh Medical Center (IRB approval #991206), Bilateral 1 between 2008 and 2013. Papilloma type Materials within the files were supplemented by a Inverted 43 review of the patient demographics (gender, age, race); Exophytic 3 symptoms and physical findings and duration of symptoms, Oncocytic 13 and past surgical history specifically related to SP. We Carcinoma type reviewed imaging and operative reports and obtained fol- (including in situ) 49 low-up information by direct communication with the 6 referring pathologist, patient’s physician, or the patient. Sinonasal undifferentiated carcinoma 2 Follow-up data, available for all patients, included infor- Carcinoma, not otherwise specified 2 mation regarding presence of locally recurrent or meta- All patients with follow-up (n = 54) (mean years of survival) static disease, treatment modalities used, and the current Follow-up range 0.3–15.9 patient status. The fragmented nature of most samples Alive, no evidence of disease (n = 25) 5.9 precluded confident evaluation for the adequacy of exci- sion. Preoperative imaging studies were personally Alive, with disease (n = 3) 2.5 reviewed in 14 cases, including computed tomography and Dead, no evidence of disease (n = 3) 3.0 magnetic resonance imaging studies, establishing size, Dead, with local disease (n = 14) 3.5 exact site of origin, and tumor extent. All patients were Dead, with disseminated disease (n = 9) 1.2 staged according to the 2010 American Joint Commission

123 Head and Neck Pathol (2014) 8:269–286 271

Table 2 Incidence and References Total no. of No. of Synchronous Metachronous % Carcinoma percentage of malignant carcinomas transformation [2, 4, 6, 7, 9, 11– 13, 16, 18–24, 26, 27, 29–31, Norris [11]281104 33–35, 37–40] Norris [12]292117 Skolnick [33]3351415 Hyams [23] 149 19 n/r n/r 13 Snyder [13]3987121 Lasser [24]1742224 Ridolfi [30]301013 Abildgaard-Jensen [20]213 2 1 14 Kristensen [38]83743 8 Woodson [35]90413 4 Christensen [21]39761 18 Segal [31]3030310 Weissler [21] 223 11 8 3 5 Klemi [7]1932116 Myers [26]3375221 Phillips [29] 112 8 8 0 7 Furuta [22]2675227 Outzen [27]671012 Dolgin [4]4254112 Bielamowicz [19]61105 5 16 Kapadia [6] 800 56 n/r n/r 7 Vrabec [16] 101 8 7 1 8 Beck [18]39103726 Lawson [39] 112 6 4 2 5 Lesperance [9]511468 27 Buchwald [2]575329 Nachtigal [40] 72 8 n/r n/r 11 Kaufman [37]34321 9 Current series 740 14 9 5 1.9 Total 3,177 240 100 63 7.6

on Staging [1]. This clinical investigation was microscope]); atypical mitotic figures (present or absent, conducted in accordance and compliance with all statutes, and defined by abnormal chromosome spread, tripolar or directives, and guidelines of the Code of Federal Regula- quadripolar forms, circular forms, or indescribably tions, Title 45, Part 46, and with an IRB approval #5216 bizarre). Lymph-vascular invasion (LVI) required the from Southern California Permanente Medical Group with presence of neoplastic cells within an endothelial lined respect to human subjects in research. space, with or without thrombus and whether free floating The macroscopic pathology observations were gathered or attached to the endothelium. Stromal-epithelial retrac- from the gross descriptions, including exact tumor loca- tion was carefully excluded, seeking endothelial cells tion, lateralization, and tumor size (in centimeters). before definitive LVI was noted, but without performing Hematoxylin and eosin-stained slides from all cases were immunohistochemistry for a vascular marker. Bone nee- reviewed, with a range of 1–42 slides reviewed per case ded to be destroyed by the neoplastic cells to qualify for (mean 11 slides/case). Specific histologic features were bone invasion. recorded, including cellular pleomorphism (mild, moder- Immunophenotypic analysis was performed in all cases ate, severe [anaplastic]); to stroma ratio with suitable material by a standardized EnvisionTM (divided into quartiles); mitotic figures (number of mitotic method employing 4 lm-thick, formalin fixed, paraffin figures per 10 high power fields (HPF) [magnification at embedded sections. Table 3 documents the pertinent, 409 with a 109 objective lens using an Olympus BX41 commercially available immunohistochemical antibodies

123 272 Head and Neck Pathol (2014) 8:269–286

Table 3 Immunohistochemical panel Antigen/antibody/clone Company Dilution Antigen Number of cases with Reaction recovery positive reactions pattern

Cytokeratin (AE1/AE3:M3515) Dako, Carpinteria, CA 1:40 CC1, 30 min 14/14 (100 %) S, D, C CK7 (OV-TL-12/30) Dako 1:200 CC1, 30 min 7/14 (50 %) S, D-F, C CK5/6 (D5/16 B4) Dako 1:25 E2, 20 min 12/14 (86 %) S, D, C Epithelial membrane antigen Ventana Medical Systems, Neat CC1, 30 min 13/14 (93 %) S, F, C, L (EMA)(E29) Tucson, AZ CK903 (34ßE12; 1/5/10/14) Enzo Life Sciences, Neat n/a 11/14 (86 %) S, D, C Farmingdale, NY CEAm (CLO1-cea ab-1) Lab Vision/NeoMarkers, 1:250 CC1, 30 min 13/14 (93 %) S, L, C Fremont, CA p63 (7jul) Leica Microsystems, 1:40 E2, 30 min 12/14 (86 %) S, D, N Buffalo Grove, IL p53 (DO-7) Dako Neat CC1, 30 min 15/18 (83 %) S, N, 1–90 % p16INK4a (E6H4) MTM Laboratories Neat CC1, 30 min 5/20 (25 %) S, F-D, N&Ca CD56 (123C3.D5) Lab Vision/NeoMarkers, Neat CC1, 30 min 2/14 (14 %) S, D, C Fremont, CA Ventana Neat CC1, 30 min 0/14 (0 %) n/a EBER (EBER1 DNP) Ventana (BenchMark) n/a n/a 0/14 (0 %) n/a Ki-67 (MIB-1) Dako 1:100 CC1, 30 min 2–90 % S, N HPV (ISH)(Y1404) Dako n/a n/a 5/19 (26 %) N, dot/diffuse mm mouse monoclonal, rp rabbit polyclonal, S Strong, D Diffuse, F Focal, C Cytoplasmic, N Nuclear, L Luminal, n/a not applicable a Reactions ranged from 20 % to all cells. Only [70 % strong, diffuse, nuclear and cytoplasmic reactions were considered positive used. The analysis was performed on a single represen- Results tative block for each tumor. Epitope retrieval was per- formed, as required by the manufacturer guidelines. Prevalence of Malignant Transformation in SP Standard positive controls were used throughout, with serum used as the negative control. The antibody reac- Seven hundred and forty SP were diagnosed in a 10 con- tions were graded as absent to weak (0 to 1?), moderate secutive year period, within a population of approximately (2? to 3?) and strong (4?) , and the fraction of 3,221,390 patients (mid-year patient count, 10-year aver- positive cells was determined by separating them into age), yielding approximately 2.3 cases per 100,000 popu- diffuse, focal, or surface; nuclear and/or cytoplasmic or lation per year (Southern California Permanente Medical membrane; for the proliferation markers and p53 into four Group incidence). Within this group, there were 14 cases groups: \10 %, 11–50 %, 51–90 %, and [90 % nuclear that underwent malignant transformation, giving a 1.9 % reactivity. In situ hybridization (ISH) for HPV was per- malignant transformation prevalence for the whole popu- formed using probes targeting a wide spectrum of HPV lation of SP cases (or 1.4 cases per year; 0.04 cases per strains including 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, and 100,000 population). 52 (Y1404; Dako, Carpinteria, CA). Five-micrometer tissue sections were deparaffinized and digested with Clinical proteinase K (Roche Diagnostics, Indianapolis, IN). Cases with punctate or diffuse nuclear signal were considered The patients included 13 men and 7 women (Table 4), with a positive. mean age at presentation of 60.7 years (range 38–86 years). A review of publications in English (MEDLINE The patients were white (n = 15), black (n = 3) or unknown 1966–2013) was performed, with all cases reported as car- (n = 2) race. Most patients presented with a mass, but more cinomas within SP included in the review [2–17]. However, than one symptom was usually experienced (obstruction, cases were excluded if the information was too generalized , epistaxis, discharge, pain, polyps), for a mean and non-specific to make a meaningful interpretation of the duration of 38.7 months (range 0.5–300 months). Otic demographics, histologic features or patient outcome. Sev- symptoms included otitis, hearing loss, tinnitus or vertigo, eral publications were included to document the frequency of while ophthalmologic symptoms included diplopia and peri- malignant transformation [2–4, 6–35]. orbital swelling. No patients were asymptomatic. On average,

123 edadNc ahl(04 8:269–286 (2014) Pathol Neck and Head Table 4 Clinical characteristics for current patient series # Age, Side and Previous history Duration and symptoms Size; Diagnosis, grade, HPV Treatment Outcome race, sex site stage

1 38 B F L; NC, E, N 70 mo; sinusitis, vertigo and migraine 3.5 cm; Inverted, SCC, grade Resection; 60 Gy A, NED, no recurrences, P III 3, HPV- 6.3 year 2 62 W M L; NC N 4 mo; sinusitis, obstruction 5 cm; Inverted, SNUC, grade Wide resection; A, NED, no recurrences, III 3, HPV- 70 Gy and 6.5 year 3 72 B F R; Ma Y: 17 mo before 5 mo; mass, obstruction, discharge and 7.5 cm; Inverted, SCC, grade Medial A, NED, no recurrences, serous otitis III 3, HPV- maxillectomy 4.4 year 4 46 B M Bi; NC, Y: 7 mo before 6 mo; mass, obstruction, epistaxis, hearing 4 cm; Inverted, SCC, grade FESS; 70 Gy; A, NED, no recurrences, NP loss IVA 3, HPV-,LN? chemotherapy 4.3 year 5 55 W M L; NC, Y: 4 recurrences, with 42 300 mo; mass and hearing loss 4 cm; Inverted, SCC, grade Exenteration; A; L, local recurrence with NP, mo from 1st diagnosis to IVA 2, HPV? 66 Gy; surgery, 3.5 year Mastoid carcinoma chemotherapy 6 72 W M R; Ma N 10 mo; mass, pain, discharge, epistaxis, 2.9 cm; Inverted, Wide resection D, L, local recurrence to polyps, sinusitis, transient diplopia and II Mucoepidermoid (including skull base, with surgery, periorbital swelling carcinoma, grade 3, Caldwell Luc), 2.4 year HPV- 60 Gy 750WFL;NC N 8 mo; mass, occasional sore throat and 3 cm; I Exophytic, SCC, grade FESS; radiation A, NED, no recurrences; (septum) hoarseness 2, HPV- (unknown total 1.9 year dose) 8 58 W M R; NC; S; N 27; discharge, obstruction and sinusitis 5 cm; Inverted; SCC, grade FESS; 66 Gy A, NED, no recurrences; skull IVA 3, HPV- 1.1 year base 9 70 W F Bi; Ma Y: 2 recurrences, with 62 5 mo; mass, epistaxis 2 cm; 0 Inverted; carcinoma FESS A, L, recurrence 8 months mo from 1st diagnosis to in situ, grade 1, after primary, treated by carcinoma HPV- surgery, 1 year 10 54 W M R; NC N 6 mo; obstruction 3.0 cm; Exophytic, SCC, grade FESS A, L, incomplete excision (septum) II 3, HPV? with local disease remaining; 1.0 year 11 46 W M R; NC; N 4 mo; mass, pain, epistaxis, difficulty 3.0 cm; Inverted, SCC, grade Wide excision; A, L, disease is still present; Ma; E, breathing, weight loss IVA 2, HPV? radiation on-going; 0.3 year NP chemotherapy 12 50 W M Bi; NC; S, N 120 mo; mass, sinusitis, hearing loss, 5.4 cm; Inverted, SCC, grade Wide resection; A, NED, no recurrences, ear tinnitus IVA 2, HPV? 60 Gy; 0.4 year chemotherapy 13 76 W F R; NC; E; N 2 mo; mass, epistaxis, sinusitis, 3.7 cm; Inverted; SCC in situ, FESS; A, NED, but only 0.3 year S obstruction III grade I, HPV-, dissection LN?

123 14 79 W M R; Ma Y: 9.8 mo before 8 mo; mass, obstruction 5.3 cm; Inverted, SCC, grade Wide resection A, NED, no recurrences, but III 2, HPV- only 0.3 years

15 74 F R; Ma N 1 mo; mass 5.5 cm; Inverted, SCC, grade Wide resection Lost to follow-up 273 IVA 1, HPV- 274 Head and Neck Pathol (2014) 8:269–286

Fig. 1 a This composite image demonstrates several zones of c mo transition. A The left shows ciliated respiratory epithelium that abruptly transitions to . B The left shows a

Functional Schneiderian papilloma that abruptly transitions into an area of carcinoma. C This contains areas of Pagetoid

FESS spread of the carcinoma (SNUC was noted below). D Paradoxical Nasopharynx, maturation is noted at the base of this dysplastic area, with a small NP area suggestive of early invasion. b This composite highlights areas of transition between benign and malignant. A The left portion shows a 1.6 year only 0.3 year 5.2 year 1.2 year 2.5 year malignant transformation that blends with the right sided benign A, NED, no recurrences, A, NED, no recurrence, but Ethmoid, component. B Three different fields show unremarkable ciliated E epithelium, dysplasia, and carcinoma in situ. C The upper portion of the field shows a Schneiderian papilloma, while the lower field shows malignant transformation. D The upper field demonstrates koilocytic atypia of a benign papilloma, while the lower field shows full thickness carcinoma in situ Maxillary sinus,

Ma men presented at a younger age (57.5 vs. 66.6 years) and with

Sinonasal undifferentiated carcinoma, a longer symptom duration (53 vs. 13 months) than women (p = 0.256). When separated by anatomic site, the mean SNUC chemotherapy chemotherapy

Sphenoid, duration of symptoms was quite different: nasal cavity alone: Resection; radiation and Wide resection; radiation and Wide resection A, NED, no recurrences, Wide resection; radiation A, NED, no recurrences, Wide resection A, NED, no recurrences, S 6.0 months; maxillary sinus alone: 5.8 months; combination years, of nasal cavity and sinuses: 83.4 months (p = 0.019). yr

Frontal, Patients with epistaxis, a symptom which dictates immediate F clinical assessment, had an average of 5.4 months of symp- - - - - toms, much shorter than patients with other symptoms at an average of 50.5 months (p = 0.249). Twelve patients were local disease, ever smokers, while 7 patients were ever drinkers (available in Nasal cavity, LD

- 18 patients). NC Seven patients had prior history of SP (i.e., metachronous malignant transformation in 6 inverted and 1 exophytic SP).

Bilateral, On average these patients first presented 34.4 months before Bi grade 3, HPV the diagnosis of carcinoma ex SP (range 7.3–73.2 months). Diagnosis, grade, HPV Treatment Outcome Inverted, SCC, grade 1, HPV Inverted, SCC, grade 3, HPV Inverted, SCC, grade 1, HPV Exophytic, mucoepidermoid carcinoma, Inverted, SCC, grade 1, HPV All of these patients had 1–4 recurrences before the devel- Right,

no evidence of disease, opment of carcinoma. This cohort showed a mean age at R III IVA III II I presentation of 60.6 years, involved 5 men and 2 women, 5 stage 6 cm; 5 cm; NED Left, whites and 2 blacks, and showed bilateral disease in 5 patients L (without septal destruction). The tumors involved the sphe- Dead,

D noid only (n = 1), maxillary sinus only (n = 3) or mixed sites White,

W (n = 3). The average size was 3.8 cm. There were no statis-

Alive, tically significant differences between patients with syn- A Black, chronous and metachronous presentation. B Gray, diplopia headache Pathologic Features Male, Duration and symptoms Size; 24 mo; polyps 2.7 cm; 14 mo; mass 1.0 cm; Gy M Macroscopic Female, lymph node before before F Most tumors affected mixed anatomic sites (n = 10), with Previous history N 120 mo; mass, polyps and N unknown symptoms 3.5 cm; Y: 73 mo LN maxillary sinus only (n = 5), nasal cavity only (n = 3), sphenoid and ethmoid sinus only (1 each, respectively). E E Ma Within the nasal cavity, the septum was specifically involved Side and site

Squamous cell carcinoma, in 2 cases by an exophytic type SP. The four patients with nasopharyngeal involvement also had disease in other sites. continued SCC There were no tumors that secondarily involved the sinuses human papillomavirus, race, sex from the ear/temporal bone or lacrimal . Tumors were endoscopic sinus surgery, Table 4 # Age, 16 86 F L; E N 2 weeks; discharge and 17 63 W M Bi; NC; 18 60 W M L; Ma; 19 50 W M Bi; NC; months, 20 52 W M L; S Y: 29 mo HPV right (n = 8), left (n = 7), or bilateral (n = 5: 4 inverted, 1

123 Head and Neck Pathol (2014) 8:269–286 275

123 276 Head and Neck Pathol (2014) 8:269–286 exophytic). Tumors were on average 4.1 cm (range portion of the sample that represented malignant transfor- 1–7.5 cm); recurrent tumors were not larger than those of the mation ranged from 10 to 95 % of the sample. However, patients without a recurrence (mean 3.8 cm). The tumors were without processing all of the submitted tissue, the residual described as papillary, polypoid, sessile, pale to white-tan, and SP may not be identified or the tumor may not be classified frequently gritty, characteristics undoubtedly related to frag- accurately. Inverted (n = 17) and exophytic type (n = 3) ments of bony tissue normally present in turbinate tissue or were the SP types represented (no oncocytic type in this samples removed via curettage of the sinuses. Most patients series). In this series, there was no well established arc of presented with high stage disease: Stage 0: 1; Stage I: 2; Stage development from benign to malignant with successive II: 3; Stage III: 8; Stage IV: 6. recurrences of the SP. However, subtle changes of increased pleomorphism, increased mitoses and decreased Microscopic neutrophils could suggest a transformation (Table 5). Benign areas of inverted SP showed an endophytic In all of the cases, areas of benign SP were present (i.e., not growth of thickened squamous epithelium (8–12 cell layers just a clinical history of SP) (Fig. 1a). In general, the thick) broadly expanding into the stroma. The epithelium was bland, showing squamous to focally transitional epi- thelium, covered with columnar cells admixed with mu- Table 5 Pathology findings cocytes (goblet cells) and intraepithelial mucous . Transepithelial neutrophils were easy to identify in nearly Microscopic feature Number (n = 20) all cases, forming small abscesses in many. The cells are Invasion bland in appearance with uniform nuclei, no piling up or Bone invasion by 9 overlapping and pleomorphism limited to isolated single Lymphovascular invasion 6 cells. Atypical mitoses are not seen, but basal and parabasal Perineural invasion 3 mitoses (up to 24/10 HPFs) were identified. Focal areas of Desmoplastic response to invasion 12 surface keratinization were noted. Architecture disorder 20 Dysplasia was difficult to define, primarily due to pearls 12 inverted growth, tangential sectioning, and technical issues. Paradoxical maturation 14 Dyskeratosis, surface keratinization and increased epithe- Dyskeratosis 17 lial pleomorphism suggest dysplasia, but there is such a Mucocytes or microabscess 6 lack of reproducibility both intra- and inter-observer, that it Epithelial to stroma ratio (quartile) is better to think in terms of carcinoma in situ (severe 1st 2 dysplasia) as the only clinically significant parameter. The 2nd 1 SP were in most cases intimately associated with the areas 3rd 5 of malignant transformation (Fig. 1a, b). The carcinoma 4th 12 types included squamous cell carcinoma (SCC; n = 17), Pleomorphism mucoepidermoid carcinoma (MEC, n = 2, Fig. 2), and one Mild 2 sinonasal undifferentiated carcinoma (SNUC; Fig. 2). Two Moderate 6 of the cases showed only carcinoma in situ, but were Severe 12 associated with lymph node metastasis, suggesting non- Necrosis 13 representative surgery sampling may have accounted for Mitotic figures this discrepancy (5 and 9 slides were reviewed, respec- tively, well within the range for these types of cases). One Mean (per 10 HPF) 53 exophytic case was associated with a mucoepidermoid Range 3–280 carcinoma (Fig. 2), while the other two exophytic cases Atypical figures (present) 19 were associated with a SCC. There were 4 well differen- Carcinoma type tiated, keratinizing SCC; 5 moderately differentiated, ker- Squamous cell carcinoma 17 atinizing SCC; and 6 poorly differentiated SCC, three Mucoepidermoid carcinoma 2 keratinizing and three non-keratinizing (Fig. 2). Overall, Sinonasal undifferentiated carcinoma 1 the tumors were separated into low (n = 6), intermediate Carcinoma grade (n = 5), and high grade (n = 9; the MEC and SNUC were Low grade (grade 1) 6 all high grade). Intermediate grade (grade 2) 5 The following features, when identified, were associated High grade (grade 3) 9 with malignant transformation: architecture disorder with a HPF High power field lack of well developed maturation towards the surface 123 Head and Neck Pathol (2014) 8:269–286 277

Fig. 2 a This mucoepidermoid carcinoma shows an epidermoid and features in this poorly differentiated non-keratinizing squamous cell , with mucocytes within the tumor. There are carcinoma. c A sinonasal undifferentiated carcinoma was the no cilia to suggest they may be surface epithelium. b A non- malignancy noted in one case keratinizing squamous cell carcinoma showing lymphoepithelial-like

(Table 5; Fig. 1a, b). This feature was associated with inverted (and oncocytic) type. Foamy histiocytes were paradoxical maturation [abnormal keratinization or keratin noted within the stroma of areas of malignant epithelium pearl formation in the basal zone (Fig. 1a)], abnormal (n = 4). Mucocytes were seen in four cases, especially in keratinization, and keratin pearl formation. These are also the two cases of MEC. There was a remarkable increase in features of dysplasia, although the number of features in mitoses (Fig. 3a), but with a range of 3–280/10 HPFs, with combination was sufficient for a diagnosis of carcinoma. a mean of 53/10 HPFs in the areas of malignant transfor- Any single feature may be seen in a benign SP, but it is the mation. This is well above the average in the benign areas aggregate of findings that is diagnostic. Nuclear molding (8.7/10 HPFs). Atypical mitoses were not identified in was noted (n = 3; Fig. 3a), but was not a prominent find- areas of benign SP. ing. The nuclear to cytoplasmic ratio was intermediate Various types of invasion were noted. A desmoplastic (n = 3) to high (n = 17), showing mild (n = 2), moderate stromal response was seen in 12 cases. In general, benign (n = 6) to severe (profound) nuclear pleomorphism inverted type SP have a broad, pushing, endophytic pattern (n = 12; Fig. 3A). There was an increased epithelium to of growth, with an intact, very thin basement membrane stroma ratio, with a [90 % epithelial component in most and no desmoplasia. However, a desmoplastic stromal cases. There was a high epithelial to stroma ratio in the reaction with loss of the already quite thin basement majority of the cases (3rd and 4th quartiles), with the membrane was noted in areas of invasion. Single cell exception of the carcinoma in situ cases, where a ‘‘stroma’’ infiltration, small islands, and irregular bulbous projections ratio was not present. If the entire sample is represented by without intact basement membrane were seen. A rich epithelium only with limited stroma, additional features to inflammatory infiltrate at the advance edge was also seen in support malignancy should be identified. There was a several cases. Exophytic SP also have an intact basement decrease in the extent of transepithelial migration (elimi- membrane in benign areas, while a desmoplastic stroma nation) of neutrophils (Fig. 3b), although difficult to was noted in all three cases. Destructive bone and/or car- quantify. Neutrophils, often in microabscesses and , tilage invasion was present in nine cases (Fig. 3c). There are a characteristic feature of benign SP, especially the was an osteoblastic and/or osteoclastic response associated

123 278 Head and Neck Pathol (2014) 8:269–286 with the epithelium. This is not just bone remodeling due to Fig. 3 a A composite of various cytologic features in malignant c pressure, but is a genuine destructive bone and/or cartilage transformation. A Koilocytic atypia, pleomorphism and architectural disorganization. B Focal nuclear molding with cells that have a high invasion (Fig. 3c). Perineural invasion (PNI) was only seen nuclear to cytoplasmic ratio. Cell borders are prominent. C Increased in three cases. LVI was present in six cases (Fig. 3c). mitoses (15 in this field), including atypical forms (off center), seen in Tumor necrosis was present in 13 cases (Fig. 3d): tumor carcinoma. D Dyskeratosis and keratin pearl formation. b A A benign necrosis and comedonecrosis (n = 9), tumor necrosis alone Schneiderian papilloma with well developed transepithelial migration of neutrophils. B Neutrophils were greatly reduced or absent in areas (n = 2) or comedonecrosis alone (n = 2) was present in of carcinoma. c A A complex inverted and destructive architecture, areas of carcinoma. Ghost-tumor cell outlines within but the spicules of bone are native, and not destroyed. B The spicule degenerated material were required to qualify as tumor of bone is being destroyed by highly atypical squamous epithelium, necrosis. Mucocytes with inflammatory cells are normally associated with a desmoplastic stroma. Note osteoblasts and osteo- clasts. C Vascular invasion by a tumor thrombus. d A Central part of a SP, and so it is important that a microabscess not comedonecrosis with keratin debris is noted in this area of carcinoma. be included as evidence of necrosis. Genuine, tumor B Ghost cell outlines along with degenerated and necrotic debris are necrosis is a feature seen in malignancy that is not seen in intermixed with the viable neoplastic cells in this area of necrosis benign SP. The diagnosis of MEC versus (Fig. 4a, b). Further, p16 was reactive in the nuclei and in sinonasal tract is controversial. With a bias towards MEC, cytoplasm of stromal cells (Fig. 4a), but not specifically in these tumors showed mucocytes, transitional cells, and direct contact with the epithelium. epidermoid cells (Fig. 2). Focal dyskeratosis was present, p53 was present in 15 of 18 cases (83 %), but ranged but keratin pearl formation was absent. The tumors showed from 1 to 90 % of the nuclei (the HPV ISH positive cases bone invasion and desmoplasia, but only one case had LVI. showed only focal,\5 % nuclear reactions, mimicking the Carcinoma in situ or surface dysplasia was not seen in these recently described lack of p53 abnormalities in HPV- tumors. They had 19 and 26 mitoses/10 HPFs, with atypical positive oropharyngeal carcinomas). The reaction was mitoses noted in both, along with areas of necrosis. There stronger, with a heavier chromogen deposition in carci- was no well developed formation. noma areas, with a much weaker reaction in benign areas A meningothelial-pattern was seen in two cases (Fig. 4d). This finding was paralleled by the Ki-67 reac- (Fig. 3a); one case each had a small cell pattern and a tion, in which there was a greater degree of nuclear reac- syncytial architecture (Fig. 2); Pagetoid spread was noted tion in areas of carcinoma than in benign areas (Fig. 4e). in the SNUC case (Fig. 1a). The SNUC was arranged in a There was a stronger and greater percentage of nuclear destructive pattern of undifferentiated cells. However, the reaction noted in areas of carcinoma (Fig. 4e). Synapto- carcinoma only accounted for *40 % of the tumor vol- physin and EBER were negative in all cases. CD56 was ume. A background of concurrent sinonasal inflammatory expressed in the SNUC, while also focally positive in a polyps was seen in one case. single case of poorly differentiated SCC. The HPV by ISH showed a dot-like (integrated) nuclear Immunohistochemistry reaction in 3 of 19 (16 %) cases (Fig. 4c), present in benign and malignant areas, while a diffuse (episomal) nuclear The neoplastic cells were immunoreactive with pan-keratin reaction was seen in two additional cases (26 % total) in all cases tested (Table 3). Further, most of the cases (although a diffuse pattern was seen in 4 total cases). Two showed strong diffuse to focal reactivity with CK5/6, cases with dot-like HPV ISH were p16 IHC positive; 2 EMA, p63 and CK903. There was a topographic distribu- cases with diffuse HPV ISH pattern were p16 IHC positive; tion to the reactivity, with the various reactions highlighted while 1 diffuse HPV ISH case and 1 dot-like and diffuse in the malignant areas more intensely than in benign areas. case were p16 negative. The CK7 was only identified in 50 % of cases, with a strong, diffuse to focal reactivity in the cytoplasm. Two of Treatment and Follow-up the 14 p63-tested carcinomas ex-SP were p63 negative— SNUC and a poorly differentiated, but keratinizing, HPV- All patients were treated by surgery. The type of procedure positive SCC. varied based on the specific anatomic site of involvement. The p16 was positive in 8 of 20 (40 %) cases with a Excision, wide local excision, maxillectomy, Caldwell Luc strong, diffuse, nuclear and cytoplasmic reaction in[70 % procedure, Weber-Ferguson procedure, functional endo- of cells in 5 cases (only 3 of which were HPV ISH posi- scopic sinus surgery (FESS), degloving procedure, and tive). Three cases showed strong, nuclear and cytoplasmic exenteration were employed to remove the . reactivity in 20–40 % of cells (Fig. 4a, b). The expression Thirteen patients were further managed with radiation. was in both benign and malignant areas, often with a Patients received from 600 to 700 cGy. Seven of the gradient of reactivity, more intense in areas of carcinoma radiation patients received follow-up chemotherapy (agents 123 Head and Neck Pathol (2014) 8:269–286 279

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Fig. 3 continued

123 Head and Neck Pathol (2014) 8:269–286 281 included carboplatin, , taxotere, 5FU, and/or with a variety of symptoms and most patients experienced docetaxel). Two patients had lymph node metastasis at the more than one symptom. The Eustachian tube may be a time of presentation of the carcinoma ex-SP, without prior route for nasal or nasopharyngeal SP to expand into the history of SP, out of 14 with selected or modified radical middle ear, yielding hearing changes or vestibulo-cochlear neck dissections. Local recurrences developed in 3 findings, although primary otic SP are reported [41]. patients, within 3–18 months. Similarly, lacrimal gland SP could expand into the nasal Follow-up was available in 19 patients (Table 6). One cavity. Patients are usually symptomatic for a long time patient had died with local disease 2.4 years after initial (mean 39 months), with a longer symptom duration if more treatment. The patient had a pT2N0 Group II high grade than one anatomic site was involved (6.1 vs. 83.4 months), mucoepidermoid carcinoma arising from an inverted SP. suggesting an extension of the disease from just a single All of the remaining 18 patients remain alive (average site to multiple sites with time. follow-up, 2.6 years), although 4 patients have local Most patients experienced a mixed anatomic site pre- recurrences (n = 3) or regional lymph node metastasis sentation: nasal cavity combined with maxillary, ethmoid, (n = 1) (average follow-up, 1.5 years). Follow-up is of sphenoid, and/or frontal sinus, with possible involvement limited duration, and so definitive comparisons about cri- of the nasopharynx and ear. Similar to the reports from the teria which may predict better survival would be literature, squamous cell carcinoma is the most common unreliable. carcinoma type, with other carcinoma types less frequent. There is an approximately even distribution between tumor grades (1, 2, and 3). Discussion Extrapolating from the patients reported in the literature, 42.6 % of patients died with local or disseminated disease SP are a well described, although uncommon (n = 23 of 54 with data), an average of 2.6 years after affecting the upper aerodigestive tract. Carcinomas arising initial carcinoma diagnosis, with 5.5 % of patients alive from SP are rare, with more carcinomas identified in the with local disease (n = 3; mean 2.5 years follow-up). By inverted type and oncocytic types, with only isolated contrast, 51.9 % of patients were alive or had died without reports describing carcinomas arising from the exophytic evidence of disease (n = 28), with an average follow-up of type. Although there were no oncocytic SP in this series, it 5.6 years. By contrast, 5.3 % (n = 1) of patients in this is well known they also hold a potential risk for malignant cohort died with disease, 21 % (n = 4) are alive with transformation [6, 36]. Carcinoma ex-SP ranges from 2 to disease (mean 1.5 years), while the remaining 73.7 % 27 % in the literature, but in this series, without referral or (n = 14) are alive with no evidence of disease (mean academic institution bias, the 1.9 % rate may be a more 2.6 years). However, in this series and in the literature, the accurate rate. This current series is derived from a review follow-up periods are short. Local recurrences and meta- of all cases identified during a consecutive 10-year period, static disease seem to develop within 2 years of the car- without any selection or patient bias, except perhaps as cinoma diagnosis, suggesting very close early clinical dictated by being a resident in southern California. During follow-up and imaging evaluation to exclude further pro- this period, 740 SP were identified, of which 14 were gression or recurrence. associated with malignant transformation. Nine patients Most patients presented with high stage disease: 65 % presented with SP and a synchronous carcinoma, while five with stage III or IV disease. The majority of the patients patients had presented with SP followed by metachronous reported in the literature did not have a recurrence development of the carcinoma. Within this cohort, there (66.7 %); but, with limited follow-up data, there was no were 12 inverted type SPs, two exophytic types, and no difference in survival time between those with a recurrence oncocytic types. The overall progression of 1.9 % of SP to versus those without a recurrence (mean 4.3 vs. 4.1 years). carcinoma may be a more representative incidence of Similarly, 15.8 % in this series developed a recurrence, but malignant transformation than previously reported in the these patients all still have local disease or have died of literature [2, 4, 6, 7, 9, 11–13, 16, 18–24, 26, 27, 29–31, disease (mean 2.3 years), with the remaining 84.2 % 33–35, 37–40]. without a recurrence, alive (n = 14, mean 2.6 years) without disease or have persistent disease (n = 2, mean Clinical 0.6 years) that has not been cleared. In this clinical series, the tumors were usually removed In general, the male to female ratio of patients with car- piecemeal, making margin assessment unreliable, except cinoma ranges from 1.2 up to 6.7, with an overall average for the surgical team being able to estimate the adequacy of of about 3.4:1. Patients range in age from 32 to 86 years, excision. Radiation therapy was employed in the majority with an overall mean around 61 years. Patients presented of patients (68.4 %), a finding similar to that reported in the 123 282 Head and Neck Pathol (2014) 8:269–286 literature (59.3 %). As noted, SCC is usually managed with Fig. 4 a A composite image of p16 immunoreactivity. A Strong, c surgery followed by radiation, and since SCC is the most diffuse, nuclear and cytoplasmic reaction in the benign and malignant areas of this case. B Strong nuclear reaction (left sided) in an area of common malignancy, radiation is empirically employed in malignant transformation, mixed nuclear and cytoplasmic reactivity these patients, even though there is a different pathway of in the same area, while the area of benign papilloma showed a development. different pattern (lower). C Strong, diffuse, nuclear reaction of the whole epithelium in an area of carcinoma. D No reaction in an area of carcinoma, but the stroma shows a strong and diffuse nuclear and Pathology Features cytoplasmic reaction in the fibroblastic cells. b There was quite variable reactivity with p16. A: In an area of early invasion, there is Although most sinonasal SCC arise de novo, a subset of nuclear and cytoplasmic strong reactivity, while the remaining area is sinonasal SCC is preceded by SP, especially of inverted negative. B This carcinoma showed strong and diffuse nuclear and cytoplasmic reactivity. c A delicate, single nuclear dot reaction with type. The majority of the tumors were synchronous (car- HPV ISH in an area of carcinoma. d p53 showed a gradient of cinoma present at primary presentation) with 36 % reactivity, with a greater percentage of the nuclei showing a positive metachronous (carcinoma developing after initial treatment reaction in areas of carcinoma compared to benign areas. There was a of SP). The vast majority of these carcinomas are SCC (83 greater intensity of the stain in areas of malignancy. e Ki-67 immunoreactivity. A: Benign Schneiderian papilloma with a limited, and 85 %, literature and this series, respectively). How- basal reaction. B Increased number of nuclei positive and above the ever, mucoepidermoid, sinonasal undifferentiated carci- basal zone in an area of severe dysplasia. C Most of the nuclei are noma, and carcinoma, NOS have been reported [6, 10, 12, positive in this area of carcinoma. D Very strong, heavy nuclear 13, 15, 17]. The percentage of tumor represented by the reaction was present in areas of carcinoma carcinoma is quite variable, from 10 to 95 % of tumor volume, although not specifically correlated to outcome. An arc of development from mild, moderate, to severe trabeculae of bone are part of the turbinate tissue and dysplasia before invasive SCC is noted in many cases of sometimes these fragments of bone can be caught up in the carcinoma ex-SP reported in the literature. General limi- proliferation, while not truly representing a destructive tations to interpretation include: (1) no residual SP in the growth (Fig. 3c). When bone is seen directly destroyed by current material that shows carcinoma; (2) a history of the neoplasm, then the diagnosis of a carcinoma can be ‘‘dysplasia’’, but only carcinoma in the current sample, and confirmed. If this is the only feature present, additional levels (3) carcinoma only without known history. It is for this are recommended in order to document areas of invasion or reason that all submitted tissue should be processed when other features of malignancy. A high epithelial to stroma SP is present or suspected. Our results indicate that squa- ratio is of limited value, as it is high even in benign SP. mous dysplasia in SP preceding carcinomas is practically Finally, increased mitoses in general is a feature of malignant undetectable. By extension, MEC does not have a specific transformation. However, benign SP evaluated as part of this precursor lesion, so the presence or absence of dysplasia series had up to 25 mitoses/10 HPFs and did not have any may not be related to the development of MEC. other histologic features of malignancy. Therefore, while The histologic features most closely associated with increased mitoses can be helpful in reaching a diagnosis of carcinoma are: LVI, PNI, atypical mitoses, desmoplastic carcinoma, it is important to have a threshold of [25/10 stromal reaction, bone invasion, architectural disorder, HPFs when this feature is seen in isolation. Having said this, paradoxical maturation and keratin pearl formation, high it is most unlikely that increased mitoses would be the sole epithelial to stroma ratio, profound pleomorphism, tumor feature used in making a diagnosis of carcinoma. necrosis, increased mitoses ([25/10 HPFs), and decreased transepithelial neutrophil elimination (microabscess for- Immunohistochemistry and In Situ Hybridization mation). These are listed in order of sensitivity (i.e., if present, the diagnosis of carcinoma can be made) versus There is usually a remarkable increase in Ki-67 prolifera- order of frequency (i.e., all cases had architectural disor- tion index, compared to SP without dysplasia or invasion der). For instance, transepithelial neutrophil loss may be [44, 47]. If the Ki-67 labeling is greater than one half of the present in some benign SP, so its absence may be difficult epithelial thickness affected, the diagnosis of severe dys- to use as a criterion for malignancy. As they have been plasia or carcinoma is likely. Interestingly, the intensity of identified in the literature, a few specific points of clarifi- the reaction pattern is often much stronger than the reaction cation are proposed [40, 42–46]. seen in benign SP. p53 overexpression may be correlated to LVI, PNI, and atypical mitoses are, when present, diag- the Ki-67 index, especially when looking at severe dys- nostic of carcinoma. However, PNI is only identified in 15 % plasia and invasive SCC [44]. While a 5 % cutoff is used of cases. When interpreting bone invasion, it is best inter- for oropharyngeal carcinoma, using[25 % positive tumors preted when there is an osteoblastic or osteoclastic reaction cells as a cut-off for aberrant p53 protein expression may in direct association with the epithelial proliferation. Small help to distinguish a carcinoma ex-SP presumably 123 Head and Neck Pathol (2014) 8:269–286 283

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Fig. 4 continued associated with p53 abnormalities from carcinoma ex-SP present with synchronous SCC carcinoma, with inverted associated with HPV. HPV positive cases were p53 nega- papilloma being the most common type of pre-existing SP. tive. Otherwise, the only thing we can comfortably say SP that may undergo malignant transformation are nearly about HPV is that it is uncommon and can be identified in impossible to identify based on morphologic examination both pre-existing SP and carcinoma ex-SP. (very few appear to be caught at the stage with squamous dysplasia only). Furthermore, such attempts appear to be of uncertain clinical value as development of metachronous Summary carcinomas ex-SP was always preceded by SP recurrence in this series. The diagnosis of carcinoma ex-SP is straightfor- Based on the results of this series, it would seem that carci- ward, while the value of recognizing squamous dysplasia in nomas ex-SP are less common and are associated with better otherwise benign SP has to be studied in larger series. outcome than originally reported. Most patients seem to

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Table 6 Summary of patient outcome (in 19 available patients) 2. Buchwald C, Franzmann MB, Jacobsen GK, Juhl BR, Lindeberg H. Carcinomas occurring in papillomas of the nasal septum associated All A, A, D D, D with human papilloma virus (HPV). Rhinology. 1997;35:74–8. patients NED 3. Dingle I, Stachiw N, Bartlett A, Lambert P. Bilateral inverted papilloma of the middle ear with intracranial involvement and All patients with follow-up 19 14 4 (1.5) 1 malignant transformation: first reported case. Laryngoscope. (mean years) (2.3) (2.6) (2.4) 2012;122:1615–9. Follow-up range (years) 0.3–6.5 0.3–6.5 0.2–3.3 2.4 4. Dolgin SR, Zaveri VD, Casiano RR, Maniglia AJ. Different options Gender for treatment of inverting papilloma of the nose and paranasal sinuses: a report of 41 cases. Laryngoscope. 1992;102:231–6. Females 6 (2.6) 5 (2.9) 1 (1.0) n/a 5. Halimi M, Aghbali A, Emamverdizadeh P, Talesh KT. Inverted Males 13 9 (2.4) 3 (1.6) 1 papilloma of the palate with malignant transformation. J Oral (2.2) (2.4) Maxillofac Pathol. 2012;16:291–3. Age 6. Kapadia SB, Barnes L, Pelzman K, Mirani N, Heffner DK, \60 years 10 7 (2.5) 3 (1.6) n/a Bedetti C. Carcinoma ex oncocytic Schneiderian (cylindrical cell) (2.2) papilloma. Am J Otolaryngol. 1993;14:332–8. 7. Klemi PJ, Joensuu H, Siivonen L, Virolainen E, Syrjanen S, C60 years 9 (2.4) 7 (2.7) 1 (1.0) 1 Syrjanen K. Association of DNA aneuploidy with human papil- (2.4) lomavirus-induced malignant transformation of sinonasal transi- Size tional papillomas. Otolaryngol Head Neck Surg. 1989;100:563–7. \4.0 cm 10 6 (2.9) 3 (0.8) 1 8. Kobylecki C, GnanalinghamKK, SohC, Du Plessis D, Hamdalla HH. (2.1) (2.4) Malignant transformation of a Schneiderian papilloma presenting with isolated sixth nerve palsy. Br J Neurosurg. 2013;27:262–3. C4.0 cm 9 (2.5) 8 (2.4) 1 (3.5) n/a 9. Lesperance MM, Esclamado RM. Squamous cell carcinoma Anatomic site arising in inverted papilloma. Laryngoscope. 1995;105:178–83. Nasal cavity alone 3 (3.1) 2 (4.2) 1 (1.0) n/a 10. Maitra A, Baskin LB, Lee EL. Malignancies arising in oncocytic Single sinus alone 6 (2.0) 4 (2.2) 1 (1.0) 1 Schneiderian papillomas: a report of 2 cases and review of the (maxillary, ethmoid or (2.4) literature. Arch Pathol Lab Med. 2001;125:1365–7. sphenoid) 11. Norris HJ. Papillary lesions of the nasal cavity and paranasal sinuses. I. Exophytic (squamous) papillomas. A study of 28 cases. Mixed 10 8 (2.4) 2 (1.9) n/a Laryngoscope. 1962;72:1784–97. (2.3) 12. Norris HJ. Papillary lesions of the nasal cavity and paranasal Patients with a recurrence 3 (2.3) n/a 2 (2.5) 1 sinuses. II. Inverting papillomas. A study of 29 cases. Laryngo- (2.4) scope. 1963;73:1–17. Patients without a recurrence 16 14 2 (0.6) n/a 13. Snyder RN, Perzin KH. Papillomatosis of nasal cavity and par- (2.4) (2.6) anasal sinuses (inverted papilloma, squamous papilloma). A clinicopathologic study. Cancer. 1972;30:668–90. Grade 14. Terada T. 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