Human Papillomavirus–Related Carcinoma With Adenoid Cystic–like Features of the Sinonasal Tract (Also Known as Human Papillomavirus–Related Multiphenotypic Sinonasal Carcinoma)

Human papillomavirus–related carcinoma with adenoid cystic–like features is a tumor restricted to the sinonasal area and is more common in women than in men. No specific race predisposition or definite link to cigarette smoking is established. The age at diagnosis reported for patients with these tumors ranges from 28 to 90 years, and the clinical presentation includes nasal obstruction, stenosis, sinusitis, epistaxis, pain, epiphora, and exophthalmos. The nasal cavity, paranasal sinuses, middle turbinate, and nasal septum are the most common sites of occurrence of HPV-related carcinoma. However, the involvement of the inferior turbinate, lacrimal duct, cranial fossa, and the orbit has also been reported.^5,7  Table 1 summarizes the clinicopathologic features available in the current literature on HPV-related carcinoma with adenoid cystic–like features.

Morphologically, a predominant population of basaloid myoepithelial-type cells and scattered ductal cells (Figure 1, A and B) characterizes HPV-related carcinoma with adenoid cystic–like features. The basaloid myoepithelial-type cells bearing hyperchromatic, slightly angulated nuclei and having scant cytoplasm are usually arranged in a solid, tubular, or cribriform growth pattern. Microcytic spaces containing basophilic material are also present. The scattered ductal cells are cuboidal, with pale or eosinophilic cytoplasm and vesicular nuclei arranged as focal ductal structures surrounded by basaloid cells.^6,8  Cell spindling, cytoplasmic clearing, and plasmacytoid morphology have also been reported.⁷  Lymphovascular invasion, although rare, has been demonstrated in a case report published in 2018.⁹  Increased mitotic activity and tumor necrosis are common findings; however, nodal metastasis has not yet been identified.

Compared with AdCC, the presence of a solid pattern, focal squamous differentiation within the tumor (abrupt keratinization or scattered nonkeratinizing nests; Figure 1, C), squamous dysplasia of the surface epithelium, and tumor giant cells are more characteristic of HPV-related carcinoma with adenoid cystic–like features. In addition, the typical hyalinized tumor stroma of AdCC and bone invasion are less frequently observed in HPV-related carcinoma with adenoid cystic–like features.⁸  One large case series including 49 cases of HPV-related carcinoma with adenoid cystic–like features also reported the presence of slitlike (or hemangiopericytoma-like) vessels, epithelial-myoepithelial carcinoma–like components, sarcomatoid differentiation, and heterologous elements (chondroid and osseous) in these tumors.

Because of the presence of multidirectional phenotypes, a more broader morphologic spectrum than initially appreciated, the minimal adenoid cystic–like components in some cases, and the strong association with high-risk HPV, Bishop et al⁷  advocated that this group of tumors should be renamed HPV-related multiphenotypic sinonasal carcinoma.

The immunohistochemical profile of HPV-related carcinoma with adenoid cystic–like features is similar to that of AdCC. Both ductal and basaloid cells are positive for cytokeratin (AE1/AE3), and the expression is stronger in the ductal cells than in the luminal basaloid cells (Figure 2, A).⁴  Both ductal and basaloid cells are immunoreactive for SOX-10. The ductal cells typically express c-kit (CD117; Figure 2, B), and the basaloid cells typically express myoepithelial markers, such as S100, p63 (Figure 2, C), p40, calponin, and smooth muscle actin. Strong and diffuse p16 (Figure 2, D) immunoreactivity in both of the cells is consistently observed in HPV-related carcinoma with adenoid cystic–like features, but it is very rare in AdCC. The Ki-67 labeling index varied from 40% to 90%.

In contrast to sinonasal adenoid cystic carcinoma, which is rarely associated with HPV infection,^10–12  HPV-related carcinoma with adenoid cystic–like features is by definition associated with high-risk HPV infection, with a focus on HPV type 33 (most common) and type 35.^4,5  Andreasen et al⁶  reported 1 case with HPV type 56 infection, and Hang et al⁸  later presented the first case with HPV type 16. Unlike HPV-related carcinoma arising from uterine cervix, where latent HPV infection may be seen in more than 10% of healthy women, HPV is rarely present in normal sinonasal mucosa. The relatively HPV-deprived environment in this location supports the causative role of HPVs in the carcinogenesis.⁶ 

Although some tumors with adenoid cystic differentiation in the genitourinary or gynecologic system have been reported previously, the definite association with HPV infection remains unclear.^13–15  In a case series published in 2016,¹⁶  lower female genital tract tumors with adenoid cystic differentiation could be subdivided into 2 groups: carcinoma with mixed differentiation including the adenoid cystic component, and pure adenoid cystic carcinoma. The former shows diffuse p16 expression and is related to high-risk HPV, and the latter shows the opposite results, which indicates that they may be 2 distinct entities. More studies are needed to clarify the relationship between the HPV infection and carcinoma with adenoid cystic–like features in different anatomic sites of the human body.

The main differential diagnosis for HPV-related carcinoma with adenoid cystic–like features includes some salivary gland tumors, particularly AdCC and nonkeratinizing squamous cell carcinoma. Some morphologic features and ancillary testing that may be helpful in the differential diagnosis are summarized in Table 2.

Besides the differences in morphologic features between HPV-related carcinoma with adenoid cystic–like features and AdCC mentioned above, p16 and MYB immunostaining followed by high-risk HPV testing and MYB/MYBL1 fluorescent in situ hybridization may be an appropriate strategy for further differential diagnosis in some equivocal cases.^6,8 

The presence of a dual cell population comprising both ductal and myoepithelial cells in HPV-related carcinoma with adenoid cystic–like features can help to rule out nonkeratinizing squamous cell carcinoma, myoepithelial carcinoma, and polymorphous adenocarcinoma. Most basal cell adenocarcinomas have at least focal peripheral palisading, a low mitotic rate, and a low Ki-67 labeling index (mostly <5%), and display diffuse nuclear staining of β-catenin¹⁷ ; HPV-related carcinoma with adenoid cystic–like features generally shows the opposite results. In some situations, epithelial-myoepithelial carcinomas may be included in the differential diagnosis, but a cribriform pattern is typically absent in epithelial-myoepithelial carcinomas, except for the apocrine variant.¹⁸  If the sarcomatoid and heterologous elements are predominant, it may be difficult to differentiate HPV-related carcinoma with adenoid cystic–like features from carcinosarcoma or carcinoma ex pleomorphic adenoma. More studies focusing on the relationship between HPV infection and these tumors are required for accurate diagnosis of this condition.

As stated by Bishop et al,⁷  HPV-related carcinoma with adenoid cystic–like features should be considered in cases of a tumor containing high-grade salivary gland–like features that are difficult to assign to a specific category.

To date, no gold standard or consensus treatment for HPV-related carcinoma with adenoid cystic–like features has been established. Most patients are surgically treated with or without adjuvant chemotherapy or radiotherapy. In a recent case series, it has been stated that about 36% of the patients developed local recurrences, and 2 of the 49 patients (5%) developed distant metastases in the lung and finger following surgery. This situation of distant metastases had not been previously reported. Although 43% of the patients in that series presented with advanced tumor stage, none of them developed lymph node metastasis or died of their disease, which may indicate a relatively indolent clinical behavior compared with other sinonasal carcinomas. However, the potential for very late local recurrence was emphasized by a case with a 30-year disease-free interval.¹⁹ 

Human papillomavirus–related carcinoma with adenoid cystic-like features is a rare entity in the sinonasal area, and it is more common in female than in male individuals, with a wide age range. Although recent studies have extended the morphologic spectrum of this entity, diffuse and strong nuclear as well as cytoplasmic staining for p16 and the association with high-risk HPV infection are unique. Squamous dysplasia of the epithelium and abrupt keratinization within tumor nests are helpful for the differential diagnosis. More studies including large cohorts and long-term follow-up are required to better understand the clinical nature of this entity.

The authors thank Chun-Chieh Wu, MD; Ying-Tai Jin, MS, DDS; Che-Wei Wu, MD, PhD; and Hung-Ru Li, MD, for contributing the case data and diagnostic consultation.