Sinonasal Papillomas and Carcinomas: A Contemporary Update With Review of an Emerging Molecular Classification

Sinonasal papillomas, also known as Schneiderian papillomas, are benign epithelial neoplasms that arise from sinonasal (Schneiderian) mucosa—an ectodermally derived epithelium comprising respiratory-type pseudostratified ciliated columnar epithelial cells, inconspicuous basal cells, and variable admixed mucus-producing goblet cells.^1–3  Although they occur over a wide age range, sinonasal papillomas more frequently present in older patients and typically show a male predilection. In general, the prognosis for sinonasal papillomas is very good; however, these tumors may recur frequently and/or be locally destructive. In addition, in a minority of cases, sinonasal papillomas may undergo malignant transformation and be associated with a synchronous or metachronous sinonasal carcinoma.^1,4  Three distinct subtypes of sinonasal papillomas—exophytic, inverted, and oncocytic—have been described, and the unique clinicopathologic, morphologic, and molecular features of each are detailed below and summarized in Table 1.

Inverted sinonasal papilloma (ISP)—the most common subtype of sinonasal papilloma—usually presents as a papillomatous “mulberry-like” mass involving the lateral nasal wall and/or paranasal sinuses.^1–3  Although benign, it frequently grows very large and may fill the nasal cavity and/or paranasal sinuses; in exceptional cases ISP may become locally aggressive and invade the underlying bone, although in such cases the possibility of malignant transformation should be rigorously excluded (see below for details). Morphologically, ISP exhibits a predominantly endophytic (inverted) growth pattern consisting of hyperplastic “ribbons” and nests of immature squamous epithelium within edematous stroma (Figure 1, A and B). Some tumors may show irritation changes with increased squamous maturation, stromal fibrosis and hyalinization, and/or focal keratosis; however, the characteristic morphologic feature of ISP is the presence of conspicuous transmigrating neutrophilic intraepithelial inflammation. Recent data from our group indicate that most ISPs harbor activating EGFR mutations, although a minor subset of tumors is associated with the presence of low-risk human papillomavirus (HPV) subtypes—in a mutually exclusive manner with EGFR mutations.^5,6 

Exophytic sinonasal papilloma (ESP)—the second most common type of sinonasal papilloma—typically presents as a polypoid “cauliflower-like” mass involving the nasal septum.^1–3  It tends to occur in slightly younger patients, has a very good prognosis despite frequent local recurrence, and rarely (if ever) undergoes malignant transformation. Morphologically, ESP resembles a benign squamous papilloma at other sites (Figure 1, C and D). It comprises exophytic papillary fronds lined by hyperplastic immature squamous epithelium with delicate fibrovascular cores. In contrast to other sinonasal papilloma subtypes, intraepithelial neutrophilic inflammation is uncommon but may be observed superficially with foci of keratosis in response to physical irritation. Similar to benign squamous papillomas at other sites, ESP is strongly associated with the presence of low-risk HPV subtypes (eg, type 6, type 11, etc)¹ ; as such, focal koilocytic change, including crenated nuclei and perinuclear halos, is frequently observed.³ 

Oncocytic sinonasal papilloma (OSP)—the least common subtype of sinonasal papilloma—typically presents as an exophytic papillary mass involving the lateral nasal wall and/or paranasal sinuses.^1–3  Its clinical course and prognosis are similar to ISP, with a low to intermediate risk of malignant progression. Morphologically, OSP has a very distinctive appearance (Figure 1, E and F). It exhibits a mixture of exophytic and endophytic growth and is composed of a hyperplastic proliferation of cuboidal to columnar epithelial cells with abundant eosinophilic (oncocytic) cytoplasm. Similar to other sinonasal papilloma subtypes, admixed foci of ciliated columnar epithelial cells may be present, although OSP characteristically contains numerous intraepithelial microcysts and neutrophilic microabscesses that impart a low-power “Swiss cheese” appearance. In contrast to ISP, recent data from our group demonstrate that OSP harbor activating KRAS mutations and are negative for EGFR mutations,⁷  and prior studies have indicated that OSPs are not associated with HPV infection.¹ 

Although only a minority of sinonasal papillomas are associated with a synchronous or metachronous sinonasal carcinoma, malignant transformation of these tumors portends worse long-term clinical outcomes, including the possibility of metastatic progression and/or death.^1,2,4  Similar to other precursor lesions, malignant transformation of sinonasal papillomas typically proceeds through a dysplasia-to-carcinoma progression; thus, the presence of dysplasia in a sinonasal papilloma is an important clinical finding and should be clearly indicated in surgical pathology reports. Dysplasia may be observed in ISP and OSP but has not been as well described in ESP.^1–4,8  In general, 2 types of dysplasia occur in sinonasal papillomas: keratinizing and nonkeratinizing. Keratinizing dysplasia is morphologically similar to keratinizing squamous dysplasia throughout the head and neck, including thick orthokeratosis, conspicuous cytologic atypia, increased architectural complexity, intraepithelial disorder, and squamous dysmaturation (Figure 2, A and B), and may be associated with concurrent or subsequent invasive keratinizing squamous cell carcinoma (Figure 2, C). Nonkeratinizing dysplasia in a sinonasal papilloma is often subtler morphologically and most frequently involves loss of transmigrating neutrophilic intraepithelial inflammation, with associated increased mitotic activity (Figure 2, D); although relatively less common, increased cytologic atypia and nuclear pleomorphism may also be observed. Similarly, although ISP may show focal exophytic growth, the presence of extensive exophytic papillomatous architecture is worrisome for malignant progression to nonkeratinizing squamous cell carcinoma (Figure 2, E and F). The molecular mechanisms of malignant progression of sinonasal papillomas have not been clearly elucidated; however, TP53 and/or CDKN2A alterations are likely involved.^1,9  Although previous studies implicated infection by high-risk HPV subtypes in malignant progression of sinonasal papillomas, contemporary studies argue against that possibility^6,10 ; indeed, recent data suggest that infection by low-risk HPV subtypes (as opposed to EGFR mutations) may be associated with an increased risk of malignant progression in ISP—although these findings need to be verified in independent studies.^5,6 

Although, as described above, sinonasal papillomas have characteristic clinical, morphologic, and molecular features, the diagnosis of sinonasal papilloma may still be challenging, and the differential diagnosis includes a number of benign and malignant entities.¹  In particular, recognition that ciliated columnar epithelial cells are a common finding in all subtypes of sinonasal papillomas (Figure 3) is important for accurate diagnosis of these lesions, because these cells may be variably present in both benign and malignant entities in the differential diagnosis. Respiratory epithelial adenomatoid hamartoma (REAH) is a benign mass-forming lesion that may occur in the setting of chronic sinusitis.¹¹  Morphologically, REAH is composed of nests of benign sinonasal epithelium with a pseudoinfiltrative endophytic appearance, which may be confused with ISP; however, the characteristic morphologic feature of REAH is the presence of prominent associated subepithelial stromal hyalinization (Figure 4, A and B). Similarly, long-standing chronic sinusitis can result in structural changes in the underlying tissue, including so-called papillary hyperplasia, which comprises broad-based papillary formations lined by benign sinonasal epithelium (Figure 4, C and D).³  Although the morphologic features of sinonasal papillary hyperplasia may raise the possibility of a sinonasal papilloma, the lack of epithelial hyperplasia, complex branching papillary structures, and/or prominent intraepithelial neutrophilic inflammation argues against such a diagnosis. The 2 major malignant entities in the differential diagnosis of sinonasal papillomas are nonkeratinizing squamous cell carcinoma and sinonasal adenocarcinoma, and these tumors will be described more in detail below.

Sinonasal carcinomas are rare, comprising less than 5% of head and neck malignancies.¹²  The most common types, squamous cell carcinoma and adenocarcinoma, have strong associations with specific environmental factors, including tobacco and dust exposures in the leather, textile, furniture, and wood industries; however, during the past several decades, infection with high-risk HPV subtypes and other unique molecular alterations have emerged as alternative oncogenic drivers for subsets of sinonasal carcinomas.¹³  Coupled with their relative rarity, the morphologic diversity of sinonasal carcinomas complicates accurate diagnosis of these tumors. In addition, the proliferation of therapeutic interventions and clinical trials targeted to specific molecular alterations (in lieu of diagnostic pathologic classifications) presents new challenges for surgical pathologists to identify these patients during routine clinical care. Thus, a diagnostic framework for approaching sinonasal carcinomas is clearly necessary for practicing surgical pathologists, and the unique clinicopathologic, morphologic, and molecular features of these tumors are detailed below and summarized in Table 2.

Squamous cell carcinoma is by far the most common malignant neoplasm of the head and neck, although the sinonasal tract is one of the least commonly involved subsites.^12,14–17  Sinonasal squamous cell carcinoma (SNSCC) occurs predominantly in older men and demonstrates a diverse morphologic spectrum, including keratinizing and nonkeratinizing types. In addition to a strong association with tobacco exposure, these tumors may be associated with HPV infection and/or a sinonasal papilloma.^1,4,18,19  Keratinizing squamous cell carcinoma frequently occurs in the context of long-standing tobacco exposure but may also be seen in association with a sinonasal papilloma. It shows morphologic features similar to those of keratinizing squamous cell carcinomas at other head and neck sites, including the presence of infiltrative irregular nests and cords of atypical keratinizing squamous epithelial cells within desmoplastic stroma (Figure 2, C). In contrast, nonkeratinizing squamous cell carcinoma is typically associated with infection by high-risk HPV subtypes—although, as described above, it may also be observed in association with a sinonasal papilloma. Indeed, during the past 20 years, HPV infection has been implicated in the pathogenesis of subsets of head and neck cancers, most notably oropharyngeal squamous cell carcinoma, where it has been shown to be associated with relatively good clinical outcomes despite frequent metastatic involvement of regional lymph nodes.²⁰  Although the prognostic implications of HPV infection in SNSCC have not been fully elucidated, recent data suggest that HPV-associated SNSCC is more common in younger patients, occurs more often in the nasal cavity (as opposed to the paranasal sinuses), and is associated with better overall survival compared with HPV-negative tumors.^18,21,22  Morphologically, nonkeratinizing SNSCC is similar to nonkeratinizing squamous cell carcinoma at other head and neck sites, including endophytic (“ribbonlike”) and/or exophytic papillary growth of immature squamous epithelium with full-thickness nuclear atypia, prominent intraepithelial disorder, and conspicuously increased mitotic and apoptotic activity (Figure 5, A and B). As its name implies, squamous maturation and keratinization are typically absent, although focal squamous differentiation may be observed in a subset of nonkeratinizing tumors. Given its strong association with infection by high-risk HPV subtypes, nonkeratinizing SNSCC usually shows p16 overexpression by immunohistochemistry (IHC) and the presence of high-risk HPV DNA or RNA by in situ hybridization (ISH; Figure 5, C). Importantly, although HPV-associated nonkeratinizing SNSCC may demonstrate a predominantly endophytic growth pattern, in contrast to ISP, it lacks the characteristic transmigrating neutrophilic intraepithelial inflammation and shows conspicuous cytologic atypia with a very high proliferative index. Furthermore, p16 overexpression by IHC and/or detection of high-risk HPV subtypes by ISH argue against the possibility of ISP or a sinonasal papilloma–associated sinonasal carcinoma, because these tumors are typically not associated with high-risk HPV infection.^6,10  Finally, similar to squamous cell carcinoma at other head and neck sites, SNSCC can show a range of variant histologic patterns, including (but not limited to) papillary squamous cell carcinoma (Figure 5, D), adenosquamous carcinoma (Figure 5, E), and basaloid squamous cell carcinoma (Figure 5, F).¹⁷ 

Despite large-scale efforts to define the molecular landscape of head and neck squamous cell carcinoma, the molecular features of SNSCC remain less well-studied—in part, because of their relative rarity in routine clinical practice. Regardless, our group has demonstrated that sinonasal papilloma–associated sinonasal carcinomas—the overwhelming majority of which are SNSCCs—show unique molecular alterations that may have important diagnostic and therapeutic implications. Indeed, similar to the sinonasal papillomas from which they arise, sinonasal papilloma–associated sinonasal carcinomas harbor frequent activating EGFR or KRAS mutations.^5,7  Importantly, these alterations were not commonly identified in SNSCC without clinical or pathologic evidence of an associated sinonasal papilloma, indicating that detection of an EGFR or KRAS mutation in SNSCC is highly suggestive of its origin in a sinonasal papilloma. Furthermore, although the type of EGFR mutation most commonly identified in ISP-associated SNSCC (ie, exon 20 insertion) is relatively resistant to reversible EGFR inhibitors (eg, erlotinib, gefitinib, etc), irreversible EGFR inhibitors (eg, neratinib, afatinib dacomitinib, poziotinib, TAK-788, etc) show more potent inhibition of this type of mutation in a preclinical model of ISP-associated SNSCC.⁵ 

In addition to conventional HPV-associated morphologic subtypes of squamous cell carcinoma (ie, nonkeratinizing, etc), a distinct subtype of HPV-associated sinonasal carcinoma has been recently described: HPV-related multiphenotypic sinonasal carcinoma (HMSC; formerly known as HPV-related carcinoma with adenoid cystic carcinoma–like features).^18,23–25  Morphologically, HMSC demonstrates overlapping features with nonkeratinizing squamous cell carcinoma and basaloid squamous cell carcinoma and frequently shows areas of cribriform growth that are reminiscent of adenoid cystic carcinoma (Figure 6, A); however, HMSC characteristically demonstrates morphologic and/or immunohistochemical evidence of myoepithelial differentiation, including admixed foci of ductal differentiation. Human papillomavirus–related multiphenotypic sinonasal carcinoma is also frequently associated with overlying epithelial dysplasia that involves the mucosal surface. Furthermore, as its name indicates, HMSC shows a very strong association with infection by high-risk HPV subtypes (in particular, type 33) and shows p16 overexpression by IHC and the presence of high-risk HPV by ISH (Figure 6, B). Based on a recent large multi-institutional international study, it appears that, despite presenting with advanced disease, HMSCs demonstrate a relatively indolent clinical behavior, with only rare reports of metastases or death due to disease.

Sinonasal undifferentiated carcinoma (SNUC) is a high-grade malignancy with a poor prognosis and limited treatment options.²⁶  Sinonasal undifferentiated carcinoma usually presents as an aggressive and infiltrative tumor of the sinonasal cavity that frequently involves underlying and adjacent structures, including bone.²⁷  Morphologically, SNUC comprises large undifferentiated cells with moderate amphophilic cytoplasm, enlarged and irregular nuclei, and prominent nucleoli, arranged singly and in solid sheets without discernible architecture (Figure 6, C); mitotic and apoptotic activity is conspicuous, and admixed comedonecrosis is frequently observed, but no squamous differentiation should be present. Tumor cells typically express pancytokeratin and may show focal p63 expression but are negative for neuroendocrine markers. Recent targeted molecular profiling of SNUC revealed highly recurrent hotspot IDH2 codon R172 mutations in most tumors^28–30 ; importantly, no IDH2 mutations were detected in SMARCB1(INI-1)–deficient sinonasal carcinoma (see below for details), suggesting that IDH2 alteration may be a disease-defining oncogenic event for SNUC. Furthermore, although not yet widely available for clinical use, multispecific mutant IDH1/2 IHC may be diagnostically useful in the evaluation of poorly differentiated sinonasal carcinomas.^28,30 

SMARCB1(INI-1)–deficient sinonasal carcinoma is a recently described diagnostic entity in head and neck pathology that may show overlapping clinicopathologic and morphologic features with other poorly differentiated or small round cell tumors of the sinonasal tract, including SNUC.^31–34  Although a significant subset of SMARCB1(INI-1)–deficient sinonasal carcinomas will show at least focal plasmacytoid/rhabdoid features (Figure 6, D), these tumors demonstrate tremendous morphologic diversity, and to date, no definitive morphologic differences have been described that can reliably distinguish SMARCB1(INI-1)–deficient sinonasal carcinoma from SNUC. As described above, in contrast to SNUC, SMARCB1(INI-1)–deficient sinonasal carcinoma does not harbor IDH2 mutations, and instead demonstrates frequent biallelic inactivation of SMARCB1—resulting in loss of nuclear INI-1 protein expression (hence the name), which can be reliably detected by IHC (Figure 6, D).^29,33 

NUT carcinoma (formerly NUT midline carcinoma) is an aggressive tumor with poor clinical outcome that frequently occurs in younger patients and typically involves midline structures, including the sinonasal tract.^35–38  Morphologically, NUT carcinoma is composed predominantly of large undifferentiated cells resembling SNUC or other high-grade/poorly differentiated sinonasal tract malignancies; however, a characteristic feature of NUT carcinoma is the presence of at least focal tumor showing abrupt squamous maturation, including keratinization (Figure 6, E), although this feature is not observed in every case. By definition, NUT carcinomas are associated with NUTM1 gene arrangements—most commonly BRD4-NUTM1—that result in NUT protein overexpression, which can be detected by IHC (Figure 6, F).^39,40 

Sinonasal adenocarcinomas are a diverse group of rare epithelial neoplasms that involve the sinonasal tract.^41–43  Although these tumors are broadly classified into salivary and nonsalivary types, for the purposes of this review we will focus on the non–salivary-type sinonasal adenocarcinomas, which are unique to the sinonasal tract. Non–salivary-type sinonasal adenocarcinomas are further subdivided into intestinal and nonintestinal types. Intestinal-type adenocarcinoma (ITAC) is an aggressive malignancy with poor long-term clinical outcome, including frequent metastatic progression and death.^41,43,44  It typically occurs in older men and has a very strong association with wood dust exposure. Morphologically, ITAC usually resembles an adenoma or adenocarcinoma of the gastrointestinal tract and by definition will express CK20 and CDX2 by IHC. Several distinct ITAC subtypes have been described, including enteric (Figure 7, A), papillary (Figure 7, B), and mucinous (Figure 7, C), and of these subtypes, papillary ITAC has the best prognosis. In contrast to colorectal adenocarcinoma, ITACs only rarely harbor activating MAPK pathway alterations (including BRAF and KRAS).^45–47  Importantly, because of overlapping morphologic features with sinonasal papillomas and non–intestinal-type sinonasal adenocarcinomas, papillary ITAC may be difficult to recognize in some cases. As its name suggests, papillary ITAC is composed predominantly of papillary structures lined by intestinal-type columnar epithelium with delicate fibrovascular cores. In contrast to sinonasal papillomas, papillary ITAC lacks apical cilia and significant intraepithelial neutrophilic inflammation, whereas the presence of CK20 and CDX2 expression by IHC essentially excludes the possibility of non–intestinal-type sinonasal adenocarcinoma.

In contrast to ITAC, non–intestinal-type sinonasal adenocarcinomas are typically low-grade tumors with an indolent clinical course—although high-grade tumors have been described^48,49 ; furthermore, there is no specific association with environmental exposures, including wood dust.⁴¹  Morphologically, these tumors are heterogeneous. They typically have a nonspecific seromucinous appearance and may show a variety of growth patterns, including papillary, tubular, acinar, and/or cribriform (Figure 7, D through F). Recently, ETV6 gene rearrangements, including ETV6-NTRK3 and ETV6-RET, have been described in small cohorts of non–intestinal-type sinonasal adenocarcinomas^50,51 ; however, very little is known about the molecular underpinnings of these tumors, perhaps in part because they represent a number of different and molecularly unrelated neoplasms with similar morphology.

Although sinonasal papillomas and carcinomas are relatively uncommon tumors of the head and neck region, surgical pathologists need to be aware of their broad morphologic spectrum because the emerging molecular understanding of these neoplasms has important clinical implications. Indeed, the recent identification of frequent activating EGFR and KRAS mutations in specific subtypes of sinonasal papilloma—as well as their associated synchronous or metachronous sinonasal carcinomas—suggests possible diagnostic and/or therapeutic utility in targeted molecular evaluation of these tumors. Similarly, the recent (and ongoing) elaboration of subtypes of sinonasal carcinoma with recurrent molecular features, including HMSC, SNUC, SMARCB1(INI-1)–deficient sinonasal carcinoma, and NUT carcinoma, indicates the need for a multimodal approach to diagnostic classification of these tumors. Although morphology remains the central component of any diagnostic framework, there is an increasing need for ancillary tools (ie, IHC, ISH, targeted sequencing, etc) to support accurate classification of sinonasal carcinomas, and thereby facilitate potential targeted therapeutic selection and/or clinical trial enrollment.