Abstract
Purpose
This study aimed to perform a systematic review of the clinicopathological, prognostic features, and HPV genotyping patterns of HPV-related multiphenotypic sinonasal carcinoma (HMSC).
Methods
This study adhered to the PRISMA 2020 guidelines and was registered in the PROSPERO database. We included case reports, case series studies, and cohort studies of HMSC indexed in the PubMed, Web of Science, Scopus, Embase, and LILACS databases published between 2017 and 2025. Collected variables were analyzed descriptively, followed by association analyses using Fisher’s and Chi-squared tests, and the Kaplan-Meier method. The quality assessment of the included studies was conducted using the Joanna Briggs Institute tools.
Results
This systematic review identified 32 studies encompassing 101 HMSC cases. The majority occurred in the nasal cavity of patients in the sixth decade of life, without significant sex predilection. Microscopically, the HMSC predominantly displayed basaloid morphology with solid and cribriform growth patterns, high mitotic activity, pleomorphism, and necrosis. Most patients underwent surgical excision and experienced no recurrence or metastasis, indicating favorable outcomes. However, treatment modality, recurrence, and distant metastasis negatively affected survival rates. HMSC cases showed strong p16 expression, variable squamous/epithelial and myoepithelial marker expression, and a high Ki67 index. HPV 33 was the most prevalent type identified.
Conclusion
HMSC is a heterogeneous malignant lesion with excellent overall prognosis. Detection of transcriptionally active HPV through in situ hybridization or reverse transcriptase polymerase chain reaction is critical for definitive diagnosis of HMSC.
Supplementary Information
The online version contains supplementary material available at 10.1007/s12105-025-01830-x.
Keywords: Nasal Cavity, Paranasal Sinuses, Human Papillomavirus, Carcinoma.
Introduction
HPV-related multiphenotypic sinonasal carcinoma (HMSC) is a malignant neoplasm first described by Bishop et al. in 2013 under the designation “HPV-related carcinoma with adenoid cystic-like features” [1]. Subsequently, additional cases with similar clinicopathological and immunohistochemical features were reported, leading to the inclusion of the lesion as a provisional entity in the 4th edition of the World Health Organization (WHO) Classification of Head and Neck Tumors in 2017 [2]. Then, in the same year, the same research team that initially identified this neoplasm published the largest cohort study on the topic and proposed renaming it “HMSC”, as the tumor exhibits both surface-derived and salivary gland phenotypes and is closely associated with high-risk human papillomavirus (HPV) infection, predominantly type 33 [3]. This expanded cohort study led to the recognition of HMSC as a new entity in the latest (5th ) WHO Classification of Head and Neck Tumors, in 2022 [3–5].
HMSC is typically confined to the sinonasal tract, with most cases occurring in the nasal cavity, without significant sex predilection [3]. Clinically, most patients present symptomatic lesions of varying sizes, frequently leading to nasal congestion and epistaxis [1, 3, 6].
The “multiphenotypic” appearance of HMSC arises from the tumor’s broad histological spectrum, which exhibits multidirectional differentiation, including squamous and salivary gland-like features, particularly resembling the solid variant of adenoid cystic carcinoma (AdCC). Reflecting these divergent phenotypes, HMSC may comprise a mixed population of basaloid, clear, eosinophilic, or spindle cells, predominantly arranged in solid and cribriform architectural patterns. Additionally, its immunoprofile is characterized by the expression of both epithelial and myoepithelial markers, frequently highlighting a dual population of luminal/ductal and abluminal/myoepithelial cells [3, 7]. Microscopically, most HMSCs display high-grade features, such as marked pleomorphism, increased mitotic activity, and frequent necrosis [1, 3, 8].
Paradoxically, despite its aggressive histological features, HMSC tends to exhibit an indolent clinical course. Most patients do not develop lymph node or distant metastases, demonstrating high disease-specific survival rates. However, local recurrences are common, frequently occurring multiple times and often arising several months after initial treatment [3, 9, 10].
Currently, no established prognostic factors exist for HMSC patients, and consequently, no standardized treatment protocols have been shown to reduce recurrence rates consistently. Furthermore, the frequency of HPV types among HMSC cases remains poorly characterized. This systematic review aims to address the following question: “What are the clinicopathological profile, prognostic features, and frequency of HPV types associated with HMSC?”
Methods
Eligibility Criteria
We included case reports, case series, and cohort studies published in the English and Spanish languages on HMSC. Studies were selected based on the availability of sufficient clinicopathological information for diagnosing HMSC, including either high-quality illustrative images or well-described histological features. We excluded studies with insufficient clinicopathological data, as well as review studies, epidemiologic studies, conference abstracts, and letters to the editors.
Information Sources and Search Strategy
This systematic review was conducted according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 2020 Statement [11]. The study protocol was registered on the International Prospective Register of Systematic Reviews in Health and Social Care (PROSPERO) under the registration number CRD420251026239.
An electronic search was conducted across the MEDLINE/PubMed, Scopus, Web of Science, Embase, and LILACS databases in April 2025, with no time restrictions applied. Additional searches were performed in the grey literature, and the reference lists of the included studies were cross-checked to identify any potentially missing articles from the scientific database searches. The full search strategy for each database is provided in Supplementary Table 1.
Selection Process
Two independent reviewers (J.P.G.P. and D.G.R.) screened all titles and abstracts identified through the initial search. Studies meeting the predefined eligibility criteria based on title/abstract review proceeded to full-text assessment. The same reviewers then evaluated these selected studies in full-text format, including those identified through manual reference searches. Any disagreements between reviewers were resolved through consensus discussion, with unresolved cases adjudicated by a third author (C.D.S.) serving as arbitrator.
Data Collection Process and Data Items
Two authors (J.P.G.P. and D.G.R.) independently extracted the data from selected studies and recorded the variables in an Excel© spreadsheet (version 2203). The extracted data encompassed authors’ names and their countries, publication year, study design, number of analyzed HMSC cases, patient demographics (sex and age), lesion characteristics (location, duration), clinical features (symptomatology, management), outcomes (recurrence, metastasis, follow-up, status), and diagnostic findings (histopathology, immunohistochemistry, HPV genotyping). Any discrepancies between the reviewers were resolved through consensus or by consulting a third author (C.D.S.).
Study Risk of bias Assessment
The study risk of bias assessment was performed through the Joanna Briggs Institute – University of Adelaide tool for case reports, case series, and cohort studies. Each appraisal item was independently evaluated by two authors, as recommended, and then was classified as “yes”, “no”, “unclear,” or “not applicable”. Studies were categorized by their overall risk of bias based on the percentage of “yes” responses received: studies scoring > 70% “yes” were classified as low risk, those scoring 50–70% as moderate risk, and studies scoring < 50% as high risk of bias.
Effect Measures
The collected data were analyzed descriptively and presented as absolute and relative frequencies. When applicable, we reported measures of central tendency and dispersion, including mean with standard deviation and median values.
Synthesis Methods
The extracted variables were grouped into three main domains: clinicodemographic features, histopathological and immunohistochemical features, and HPV-genotyping profile. For cases where the original studies did not explicitly report specific variables (either their presence or absence), these data points were classified as not available (NA).
Statistical Analysis
Statistical analyses were performed using IBM SPSS software version 22 (IBM Corporation, Armonk, NY). Clinicopathological and prognostic features were analyzed descriptively and presented as absolute and relative frequencies. Association between variables was evaluated using Fisher’s exact test and Chi-squared test.
Survival analysis was conducted using the Kaplan-Meier method to determine overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS). OS was defined as the time from diagnosis to either the last follow-up (alive, NOS [not otherwise specified]) or death (dead, NOS). DSS was calculated as the interval between diagnosis and the last follow-up (alive and free of disease) or death from the disease. DFS was measured from diagnosis to the last follow-up (disease-free) or occurrence of local recurrence. Differences in DSS curves across clinical variables were assessed using the Log-Rank test. For all analyses, a p-value less than 0.05 was considered statistically significant.
Results
Study Selection
This systematic review analyzed 32 articles, comprising 24 case reports, 4 cohort studies, and 4 case series studies, which documented a total of 101 HMSC cases, as shown in Fig. 1 [3, 6, 7, 9, 10, 12–38]. The complete dataset is available in Supplementary Table 2, Supplementary Tables 3, and Supplementary Table 4. The studies were published between 2017 and 2025 and originated from the following countries: the United States of America contributed the majority with 12 studies (37.50%), followed by South Korea and Taiwan with 3 studies each (9.38%). India, Japan, and Spain accounted for 2 studies each (6.25%). Single studies came from Australia, Brazil, Canada, Mexico, Sweden, Switzerland, Tanzania, and Thailand, each representing 3.13% of the total.
Fig. 1.
Selection process flowchart of the studies included in this systematic review
Clinical Features
The full information regarding the demographic and clinical features of HMSC patients was provided in Table 1 and Supplementary Table 2. The patients’ sex and ages were described in 97 and 101 cases, respectively. The analysis revealed a slight female predominance, with 50 cases (51.55%) occurring in women compared to 47 (48.45%) cases in men, yielding a female-to-male ratio of 1.06:1. Female patients were slightly younger (n = 50/ 51.55%; mean age 51.94 ± 10.90 years) than male patients (n = 47/ 48.45%; mean age 55.96 ± 13.08 years). Overall, HMSC patients presented a considerable age variation, spanning from 28 to 90 years, with an overall mean age of 53.84 ± 11.60 years and a median age of 52 years.
Table 1.
Clinicodemographic, treatment, and prognostic features of HMSC cases included in this systematic review
| Variable | n (%) | p- value |
|---|---|---|
| Sex (n = 97) |
0.066b 1.000c 0.238d |
|
| Female | 50 (51.55) | |
| Male | 47 (48.45) | |
| Female: male ratio | 1.06:1 | |
| Age (n = 101) | ||
| 00–10 years | 0 (0.00) |
1.000a 0.572b 1.000c 0.238d |
| 11–20 years | 0 (0.00) | |
| 21–30 years | 3 (2.97) | |
| 31–40 years | 13 (12.87) | |
| 41–50 years | 25 (24.75) | |
| 51–60 years | 29 (28.71) | |
| 61–70 years | 20 (19.80) | |
| 71–80 years | 8 (7.92) | |
| 81–90 years | 3 (2.97) | |
| 91–100 years | 0 (0.00) | |
| Mean age (Standard deviation) | 53.84 (11.60) years | |
| Median age | 52 years | |
| Female mean age (Standard deviation) | 51.94 (10.90) years | |
| Male mean age (Standard deviation) | 55.96 (13.08) years | |
| Range | 28–90 years | |
| Anatomic location (n = 101) | ||
| Nasal cavity (NOS) | 63 (62.38) | - |
| Multiple | 19 (18.81) | |
| Middle turbinate | 5 (4.95) | |
| Ethmoid sinus | 3 (2.97) | |
| Nasal septum | 3 (2.97) | |
| Tonsil | 3 (2.97) | |
| Maxillary sinus | 2 (1.98) | |
| Inferior turbinate | 1 (0.99) | |
| Paranasal sinus (NOS) | 1 (0.99) | |
| Sinonasal (NOS) | 1 (0.99) | |
| Lesion size (n = 65) | ||
| Range | 0.7–9.5 cm |
0.449b 1.000c 0.312d |
| Mean size (Standard deviation) | 3.96 (2.34) cm | |
| Median size | 3.5 cm | |
| Lesion duration (n = 40) | ||
| Meantime months (standard deviation) | 33.65 (84.13) |
0.081b 0.200c 0.071d |
| Range | 1-456 months | |
| Symptoms (n = 77) | ||
| Epistaxis | 46 (59.74) | - |
| Nasal obstruction | 27 (35.06) | |
| Pain | 10 (12.99) | |
| Discharge | 5 (6.49) | |
| Stenosis | 5 (6.49) | |
| Rhinorrhea | 4 (5.19) | |
| Headache | 3 (3.90) | |
| Anosmia | 3 (3.90) | |
| Epiphora | 2 (2.60) | |
| Bleeding | 2 (2.60) | |
| Hyposmia | 1 (1.30) | |
| Hypogeusia | 1 (1.30) | |
| Nasal swelling | 1 (1.30) | |
| Oxophthalmos | 1 (1.30) | |
| Paresthesia | 1 (1.30) | |
| Sinusistis | 1 (1.30) | |
| Tenderness | 1 (1.30) | |
| Symptom duration (n = 17) | ||
| Range | 1–36 months | - |
| Mean duration (Standard deviation) | 7.41 (7.98) months | |
| Median duration | 3 months | |
| Treatment (n = 82) | ||
| Surgery | 36 (43.90) |
0.032a 0.138b 0.077c 0.030d |
| Surgery + RT | 32 (39.02) | |
| Surgery + RT + CT | 9 (10.98) | |
| CT + RT | 2 (2.44) | |
| RT | 2 (2.44) | |
| Surgery + RT + CT + IT | 1 (1.22) | |
| Recurrence (n = 76) | ||
| No | 56 (74.68) |
0.159a 1.000c 0.006d |
| Yes | 19 (25.00) | |
| No curative treatment | 1 (1.32) | |
| Range | 2–192 months | |
| Meantime (Standard deviation) | 53.84 (47.47) months | |
| Mediantime | 36 months | |
| Lymph node metastasis (n = 78) | ||
| No | 76 (97.44) |
1.000a 0.125d |
| Yes | 2 (2.56) | |
| Distant metastasis (n = 80) | ||
| No | 73 (91.25) |
1.000a 0.125c |
| Yes | 7 (8.75) | |
| Clinical stage at diagnosis (n = 56) | ||
| T1N0M0 | 22 (39.29) | - |
| T2N0M0 | 12 (21.43) | |
| T3N0M0 | 11 (19.64) | |
| T4N0M0 | 4 (7.14) | |
| T4aN0M0 | 6 (10.71) | |
| T4bN0M0 | 1 (1.79) | |
| Follow-up (n = 67) | ||
| Range | 1-204 months | - |
| Mean follow-up time (Standard deviation) | 30.43 (37.92) months | |
| Median follow-up time | 12 months | |
| Status (n = 67) | ||
| Alive and free of disease | 62 (92.54) |
0.159b 1.000c 1.000d |
| Alive with disease | 3 (4.48) | |
| Dead of disease | 1 (1.49) | |
| Dead due to other causes | 1 (1.49) |
NOS: not otherwise specified, RT: radiotherapy, CT: chemotherapy, IT: immunotherapy, a: survival, b: recurrence, c: lymph node metastasis, d: distant metastasis
The anatomical distribution of HMSC was documented in all 101 cases, comprising 10 different sites. The nasal cavity (not otherwise specified, NOS) (n = 63/ 62.38%) was the most described location. A significant subset of cases (n = 19/ 18.81%) presented as large lesions involving multiple anatomical sites. Other reported locations showed considerably lower frequencies: the middle turbinate was involved in 5 cases (4.95%), while the ethmoid sinus, nasal septum, and tonsil each contributed 3 cases (2.97%). The maxillary sinus, inferior turbinate, paranasal sinus NOS, and sinonasal NOS represented the rarest sites, with just 1 case each (0.99%).
Lesion size was available for 65 patients, ranging from 0.7 cm to 9.5 cm, with a mean of 3.96 ± 2.34 cm and a median of 3.5 cm. Lesion duration was reported for 40 patients, ranging from 1 to 456 months, with a mean duration of 33.65 ± 84.13 months.
Symptomatology was documented in 77 patients, with the majority exhibiting multiple concurrent symptoms. The most prevalent symptoms included epistaxis (n = 46/ 59.74%), nasal obstruction (n = 27/ 35.06%), and pain (n = 10/ 12.99%). Symptom durations ranged from 1 to 36 months, with a mean of 7.41 ± 7.98 months and a median of 3 months.
Treatment data were available for 82 patients, representing 6 different therapeutic approaches. The majority of the patients underwent surgical excision alone (n = 36/ 43.90%), while a substantial portion received surgery followed by radiotherapy (n = 32/ 39.02%). Other management modalities included surgery with adjuvant radiotherapy and chemotherapy (n = 9/ 10.98%), chemotherapy followed by radiotherapy, and radiotherapy alone (n = 2/ 2.44% each). A single patient received combined treatment with surgery, radiotherapy, chemotherapy, and immunotherapy (1.22%).
At diagnosis, lesions were staged according to the American Joint Committee on Cancer staging system (AJCC) (n = 56) as follows: T1N0M0 (n = 22/ 39.29%), T2N0M0 (n = 12/ 21.43%), T3N0M0 (n = 11/ 19.64%), T4N0M0 (n = 4/ 7.14%), T4aN0M0 (n = 6/ 10.71%), and T4bN0M0 (n = 1/ 1.79%).
Recurrence data were available for 76 patients. Most patients did not experience relapsing tumors (n = 56/ 74.68%), while 19 (25%) patients developed recurrent lesions in intervals ranging from 2 to 192 months (mean 53.84 ± 47.47 months, median 36 months). A single patient (1.32%) did not undergo complete surgical excision of the primary lesion, and we did not consider a true recurrence.
Lymph node status was reported for 78 patients, and distant metastasis for 80 patients. The majority showed no evidence of lymph node involvement (n = 76/ 97.44%) or distant metastasis (n = 73/ 91.25%). Lymph node metastasis was rare (n = 2/ 2.56%), while distant metastasis occurred in 7 cases (8.75%).
Follow-up data were available for 67 patients, with durations ranging widely from 1 to 204 months (mean 30.43 ± 37.92 months, median of 12 months). At the last follow-up assessment, most patients were alive without evidence of disease (n = 62/ 92.54%). Three patients (4.48%) remained alive with active disease. Disease-specific mortality was low (n = 1/1.49%), with one additional patient (1.49%) deceased from unrelated causes.
Histopathological Features
The full dataset of histopathological features of HMSC was available in Supplementary Tables 3 and Table 2. Figure 2 provides an illustrative HMSC case from the author’s files.
Table 2.
Histopathological features of HMSC cases included in this systematic review
| Histopathological feature | n (%) |
|---|---|
| Dysplasia of overlying epithelium (n = 86) | |
| No | 26 (30.23) |
| Yes | 60 (69.77) |
| Cells appearance (n = 101) | |
| Basaloid cells | 99 (98.02) |
| Eosinophilic cells | 49 (48.51) |
| Clear cells | 47 (46.53) |
| Spindle cells | 31 (30.69) |
| Plasmacytoid cells | 5 (4.95) |
| Nuclear characteristics (n = 100) | |
| Hyperchromatic nuclei | 79 (79.00) |
| Vesicular nuclei | 20 (20.00) |
| Hyperchromatic and vesicular nuclei | 1 (1.00) |
| Mitotic figures (n = 71) | |
| Rare (NOS) | 1 (1.23) |
| Frequent (NOS) | 17 (20.99) |
| Mitoses per 10 high fields range | 3–150 |
| Mean mitoses per 10 high fields (Standard deviation) | 39.02 (8.15) |
| Median mitoses per 10 high fields | 38 |
| Pleomorphism (n = 73) | |
| Mild | 1 (1.37) |
| Moderate | 4 (5.48) |
| Moderate to intense | 1 (1.37) |
| Intense | 67 (91.78) |
| Necrosis (n = 85) | |
| No | 29 (34.12) |
| Yes | 56 (65.88) |
| Vascular invasion (n = 66) | |
| No | 64 (96.97) |
| Yes | 2 (3.03) |
| Perineural invasion (n = 71) | |
| No | 64 (90.14) |
| Yes | 7 (9.86) |
| Arrangement pattern (n = 101) | |
| Solid | 96 (95.05) |
| Cribriform | 78 (77.23) |
| Tubular | 43 (42.57) |
| Ribbon-like | 7 (6.93) |
| Nested | 4 (3.96) |
| Trabecular | 2 (1.98) |
| Lobular | 1 (0.99) |
| Cords | 1 (0.99) |
| Glomeruloid | 1 (0.99) |
| Papillary | 1 (0.99) |
| Other histological features (n = 93) | |
| Bizarre multinucleated cells | 26 (27.96) |
| Hyaline matrix deposition | 19 (20.43) |
| Squamous differentiation | 16 (17.20) |
| Bone invasion | 13 (13.98) |
| Sarcomatoid differentiation | 5 (5.38) |
| Chondroid material | 3 (3.23) |
| Hemangiopericytoma-like vessels | 3 (3.23) |
| Epithelial-myoepithelial carcinoma-like | 3 (3.23) |
| Keratinization | 2 (2.15) |
| Cartilage invasion | 1 (1.08) |
| Myxoid stroma | 1 (1.08) |
| Osseous material | 1 (1.08) |
NOS: not otherwise specified
Fig. 2.
Histopathological and immunohistochemical features of an HMSC originating in the nasal cavity of a 44-year-old male patient. RT-PCR (Anyplex II HPV28) confirmed transcriptionally active HPV 33. (A) A hypercellular polypoid lesion. (B) Surface epithelium exhibiting severe dysplasia, contiguous with the infiltrative neoplasm. (C) Tumor cells displayed a basaloid morphology, arranged in tubular and ductal patterns. True ductal structures featured luminal cells with scant yet intensely eosinophilic cytoplasm. (D-E) The tumor showed alternating cribriform areas with microcystic spaces containing basophilic secretions, alongside cords and single-cell structures embedded in a highly hyaline matrix. (F) Focal clear cell changes were observed in some regions. (G) Tumor cells exhibited block-like p16 expression. (H) Diffuse p63 positivity. Biphasic immunoreactivity of S100 (I) and calponin (J). (K) CK5/6 expression was strong in myoepithelial cells but weak in luminal cells. (L) INI1 expression remained preserved in tumor cells
The epithelial dysplasia status of the overlying epithelium was available for 86 patients. Most cases (n = 60/ 69.77%) exhibited dysplastic changes of varying degrees and thickness of the overlying epithelium.
Histopathological analysis demonstrated that tumors were typically composed of heterogeneous cell populations, frequently containing an admixture of basaloid, eosinophilic, clear, spindle, and plasmacytoid cells within the same tumor. Among 101 characterized cases, cellular composition included basaloid cells (n = 99/ 98.02%), eosinophilic cells (n = 49/ 48.51%), clear cells (n = 47/ 46.53%), spindle cells (n = 31/ 30.69%), and plasmacytoid cells (n = 5/ 4.95%). Nuclear morphology assessment on included cases (n = 100) focused on the predominant nuclear pattern within each tumor. The HMSC cohorts revealed predominantly round-to-oval or irregular nuclei, with hyperchromasia being the most frequent feature (n = 79/ 79%). A subset of tumors (n = 20/ 20%) displayed vesicular nuclei characterized by coarse chromatin and prominent nucleoli. A single case (1%) reported concurrent nuclear patterns.
Mitotic activity was variably reported across 71 cases. One case (1.23%) documented mitotic figures (NOS), while 17 cases (20.99%) reported frequent mitoses (NOS). Among quantitatively assessed tumors (n = 53), mitotic counts ranged from 3 to 150 per 10 high-power fields (mean 39.02 ± 8.15, median 38).
Among 73 cases, the degree of pleomorphism was characterized as mild (n = 1/ 1.37%), moderate (n = 4/ 5.48%), moderate to intense (n = 1/ 1.37%), and intense (n = 67/ 91.78%).
The assessment of 85 patients revealed tumor necrosis in most cases (n = 56/ 65.88%), with varying degrees of involvement. Vascular invasion (n = 2 of 66/ 3.03%) and perineural invasion (n = 7 of 71/ 9.86%) were uncommon findings.
Histopathological evaluation of 101 cases revealed that most tumors exhibited multiple architectural patterns in varying proportions. The most frequent arrangement patterns included solid (n = 96/ 95.05%), cribriform (n = 78/ 77.23%), and tubular (n = 43/ 42.57%).
Additional histopathological features observed in 93 patients included bizarre multinucleated giant cells (n = 26/ 27.96%), hyaline matrix deposition (n = 19/ 20.43%), foci of squamous differentiation (n = 16/ 17.20%), and bone invasion (n = 13/ 13.98%).
Immunohistochemical Markers
The immunohistochemical (IHC) profile of HMSC was assessed in all 101 cases, covering 44 different markers. Diffuse and strong p16 expression was observed in 96 cases, with a single case being p16 negative [6]. The remaining markers exhibited variable positivity, ranging from diffuse expression in all cells to highlighting a dual population of luminal (ductal) and abluminal (myoepithelial) cells. Among the most frequently reported markers were p63 protein (81 positive, 0 negative), p40 protein (64 positive, 1 negative), S100 (63 positive, 1 negative), AE1/AE3 (61 positive, 0 negative), SMA (50 positive, 1 negative), c-KIT/CD117 (66 positive, 1 negative), calponin (42 positive, 0 negative), CK7 (18 positive, 0 negative), and SOX10 (15 positive, 0 negative). In contrast, cases tested for synaptophysin (n = 4), chromogranin-A (n = 3), desmin (n = 2), calretinin (n = 2), CD34 (n = 2), and NUT (n = 2) were uniformly negative. The proliferation index measured by Ki67 was reported as high (NOS) in 1 case. For the remaining cases, the percentage of Ki67-positive cells ranged from 35 to 80%, with a mean of 50.83%. The complete list of IHC markers analyzed in the HMSC cases in this systematic review is provided in Supplementary Tables 4 and Table 3. Figure 2 illustrates a representative HMSC case with key immunohistochemical features.
Table 3.
Immunohistochemical markers employed on HMSC cases included in this systematic review
| IHC marker | Positive | Negative |
|---|---|---|
| p16 | 96 | 1 |
| p63 | 81 | 0 |
| c-KIT/CD117 | 66 | 1 |
| p40 | 64 | 1 |
| S100 | 63 | 1 |
| AE1/AE3 | 61 | 0 |
| SMA | 50 | 1 |
| Calponin | 42 | 0 |
| CK7 | 18 | 0 |
| SOX10 | 15 | 0 |
| CK5/6 | 6 | 0 |
| LEF-1 | 4 | 0 |
| EMA | 3 | 0 |
| INI1 | 3 | 0 |
| MYB | 3 | 0 |
| CAM 5.2 | 2 | 0 |
| CEA | 2 | 0 |
| b-catenin | 1 | 1 |
| CD10 | 1 | 0 |
| CK19 | 1 | 0 |
| CK7/8 | 1 | 0 |
| CK8 | 1 | 0 |
| CK903 | 1 | 0 |
| epCAM | 1 | 0 |
| GFAP | 1 | 1 |
| SMMS-1 | 1 | 0 |
| Vimentin | 1 | 0 |
| WT-1 | 1 | 0 |
| Synaptophysin | 0 | 4 |
| Chromogranin | 0 | 3 |
| Desmin | 0 | 2 |
| Calretinin | 0 | 2 |
| CD34 | 0 | 2 |
| NUT | 0 | 2 |
| CD56 | 0 | 1 |
| C-erB2 | 0 | 1 |
| AR | 0 | 1 |
| CK14 | 0 | 1 |
| D2-40 | 0 | 1 |
| EBER | 0 | 1 |
| Factor VIII | 0 | 1 |
| Fli-1 | 0 | 1 |
| Ki67 (high NOS) | 1 | |
| Ki67 range | 35 − 80% | |
| Ki67 mean | 50.83% | |
IHC: immunohistochemical, NOS: not otherwise specified
HPV Genotyping in HMSC
HPV genotype status was evaluated in 98 patients. Most cases used multiple testing methods, including in situ hybridization (ISH) (n = 69) and reverse transcription polymerase chain reaction (RT-PCR) (n = 45). Both ISH and RT-PCR assays employed probes and primers targeting both high-risk (HR) HPV types as well as specific HPV types.
By ISH, 66 cases (95.65%) were positive for HR HPV. Among HPV-specific probes, 33 cases (47.83%) detected HPV 33, 3 cases (4.35%) were positive for HPV 16, and 1 case (1.45%) for HPV 16/18. RT-PCR results revealed 21 cases (46.67%) positive for HPV 33, 6 cases (13.33%) for HPV 35, 6 cases (13.33%) for HPV 16, and 4 cases (8.89%) for HPV 56. Additionally, 2 cases (4.44%) were positive for unspecified HR HPV, while single cases (2.22% each) tested positive for HPV 52, HPV 33/51, HPV 18, an unknown HPV type, HPV 26, and HPV 82. Overall, HMSC cases were associated with HR-HPV types (especially HPV 33), while a single case was positive for intermediate-risk HPV (HPV 26). Table Supplementary 4 and Table 4 provide the full genotyping data of HMSC patients included in this systematic review.
Table 4.
HPV genotyping of HMSC cases included in this systematic review
| Genotyping exam | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ISH (n = 69) | RT-PCR (n = 45) | ||||||||||||||
| HPV type | HR | 33 | 16 | 16/18 | 33 | 35 | 16 | 56 | HR | 52 | 33/51 | 18 | unkn | 26 | 82 |
| n | 66 | 33 | 3 | 1 | 21 | 6 | 6 | 4 | 2 | 1 | 1 | 1 | 1 | 1 | 1 |
| Frequency | 95.65% | 47.83% | 4.35% | 1.45% | 46.67% | 13.33% | 13.33% | 8.89% | 4.44% | 2.22% | 2.22% | 2.22% | 2.22% | 2.22% | 2.22% |
ISH: in situ hybridization, RT-PCR: reverse transcription polymerase chain reaction, HPV: human papillomavirus, n: number, unkn: unknown, HR: high risk
Statistical Analysis
Fischer’s test revealed that patients undergoing surgery followed by adjuvant therapies showed significantly reduced distant metastasis rates (p = 0.030) and improved survival at the last follow-up (p = 0.032). Additionally, patients without recurrence also exhibited lower distant metastasis frequency (p = 0.006). Despite these statistically significant findings, the low disease-specific mortality rate indicated the necessity for additional research to clarify the relationship between treatment type and risk of distant metastases and recurrences (Supplementary Table 5).
The survival analysis revealed excellent short-term outcomes for HMSC patients, with 1-year OS at 98.5% and 5-year OS at 94.4%. The 1-year DSS was 100%, and the 5-year DSS was 95.5%. However, DFS showed a marked decline over time, dropping from 94.7% at 1 year to 36.8% at 5 years and just 10.5% at 10 years. Kaplan-Meier curves and the Log-Rank test highlighted significantly worse 2-year DSS outcomes (0%) for patients receiving only complementary therapies (Log-rank < 0.001) compared to those treated with surgery alone (100%) or surgery followed by adjuvant therapies (100%). These findings, consistent with the association test results, underscore the need for further investigation into treatment-related survival impacts (Fig. 3).
Fig. 3.
Kaplan-Meier analysis of clinicopathological variables in HMSC cases included in this systematic review
Determination of the Methodological Quality of the Included Studies
A critical appraisal of case reports (n = 24), cohort studies (n = 4), and case series studies (n = 4) was described in Supplementary Table 6. Of all case reports, 7 (29.16%) were classified as low risk of bias, 11 (45.83%) were classified as moderate risk of bias, and 6 (25%) were classified as high risk of bias. All cohort studies (n = 4/ 100%) were classified as moderate risk of bias. Among case series studies, 3 (75%) were classified as moderate risk of bias and one (25%) as low risk of bias.
Discussion
As the first systematic review to comprehensively evaluate HMSC, this study provides crucial insights into the tumor’s clinicopathological features, immunohistochemical profile, prognostic markers, and HPV type distribution. Our findings reveal previously undocumented evidence concerning prognostic factors and the prevalence of specific HPV types in this rare malignancy, advancing understanding of its biological behavior and clinical management.
Our systematic review identified no significant sex predilection among HMSC patients, consistent with previous studies published in English literature [3, 6, 33]. While isolated reports suggest male predominance, these findings were derived from studies with limited sample sizes, potentially reflecting selection bias rather than true epidemiological patterns [7, 14, 21]. This demographic profile significantly differs from other HPV-associated head and neck carcinomas, particularly oropharyngeal squamous cell carcinoma, which shows strong male predominance [39]. These discrepancies highlight the need for larger, multicenter studies to establish definitive demographic patterns in HMSC.
The peak prevalence of HMSC in our analysis occurred between the fourth and seventh decades of life, with the highest frequency observed among patients in their fifties. This age distribution aligns with previous reports, confirming HMSC as predominantly an adult-onset malignancy [3, 5]. Clinically, the tumors showed strong predilection for the nasal cavity, with most patients presenting nonspecific symptoms of nasal obstruction and epistaxis [35, 40]. The common nature of these symptoms frequently led to initial misdiagnosis as benign inflammatory conditions, often resulting in significant diagnostic delays [41–43].
Microscopically, HMSC presents as a heterogeneous neoplasm with diverse cytological and architectural features, reflecting its multiphenotypic nature [3, 35]. The tumor consists of either basaloid cells featuring round-to-oval or irregular hyperchromatic nuclei and inconspicuous nucleoli or cells with vesicular nuclei and prominent nucleoli [1, 3, 9]. Its growth patterns often mimic other salivary gland tumors, including solid and cribriform nests and islands resembling the solid variant of AdCC, a clear biphasic proliferation of ductal and myoepithelial cells similar to epithelial-myoepithelial carcinoma, or nonspecific salivary gland adenocarcinoma patterns [3]. A frequently observed feature is the prominent deposition of hyaline matrix, which further supports the salivary gland phenotype [19]. The tumor may also demonstrate clear or spindle cells and produce heterologous elements such as osseous and cartilaginous tissues, features typically associated with myoepithelial differentiation in salivary gland tumors like pleomorphic adenoma and myoepithelial carcinoma [3, 44, 45]. HMSC cases can also exhibit squamous differentiation, characterized by eosinophilic cells, areas of abrupt keratinization, or neoplastic cells displaying intercellular bridges [7, 9, 18]. Although no standardized grading system exists for HMSC, morphologically the tumor is often considered a high-grade lesion. This is supported by the presence of high mitotic activity, frequent necrosis, and commonly observed bizarre multinucleated giant cells. On the other hand, vascular and perineural invasion are uncommon findings [3]. Our results were entirely consistent with these morphological descriptions.
The immunoprofile of HMSC further supports its divergent differentiation, demonstrating co-expression of both epithelial/squamous markers and myoepithelial markers, along with a diffuse and, strong p16 positivity [1, 3, 8]. p16 exhibits a block-like positivity pattern in > 70% of tumor cells, similar to other HPV-associated head and neck neoplasms, serving as a reliable indicator of HPV infection [3, 39]. Importantly, one reported case showed p16 negativity despite demonstrating active HR-HPV DNA/ RNA by ISH, representing a significant diagnostic pitfall in HMSC evaluation [6]. Other immunohistochemical markers displayed variable expression patterns, ranging from diffuse positivity to staining patterns that highlight the mixed epithelial-myoepithelial cell populations characteristic of HMSC [3, 8, 9]. SOX10 is typically diffusely expressed in HMSC cells, though it may be absent in overlying dysplastic epithelium [6]. The frequent positivity of HMSC for c-KIT/CD117, a marker typically associated with AdCC, is a pitfall that may lead to misdiagnosis, especially in limited biopsy specimens [46]. Additionally, HMSC is consistently negative for neuroendocrine markers, such as synaptophysin and chromogranin [18].
The broad histological and immunohistochemical spectrum of HMSC leads to significant diagnostic overlap with several entities. Metatypical AdCC is a variant with sinonasal tract and skull base predilection, frequently demonstrating squamous differentiation. Although some AdCC cases may exhibit equivocal p16 expression, they are consistently negative for HR-HPV types and frequently show molecular alterations involving MYB and NFIB genes [47]. Basaloid squamous cell carcinoma (BSCC) shares morphological similarities with HMSC, characterized by basaloid cells arranged in adenoid-like and pseudoglandular patterns, often accompanied by frequent hyaline stroma and necrosis. Although BSCC is frequently positive for SOX10 and HR-HPV, it is strongly associated with chronic tobacco and alcohol exposure, occurs predominantly in the hypopharynx and larynx, and is more common in men; these features may provide key distinctions between HMSC and BSCC [48, 49]. NUT carcinoma is composed of monotonous cells with vesicular nuclei that often show abrupt keratinization. Although both tumors express AE1/AE3, p40 protein, and p63 protein, NUT carcinoma is definitively distinguished by its characteristic nuclear speckled NUT immunoreactivity, a feature consistently absent in HMSC [4].
HPV is a driver etiologic factor for HMSC, with most cases being related to HPV 33 infection, as confirmed by our results. While less common, other HR-HPV types may also be implicated, including rare cases with concurrent infections by multiple HPV types [9], and a single reported case had been associated with intermediate-risk HPV 26 [32]. Although our analysis revealed no statistically significant correlation between HPV type and clinical outcomes or tumor location, we observed that tonsillar HMSC cases were occasionally linked to HPV 16, a subtype strongly associated with oropharyngeal squamous cell carcinoma at this anatomical site [50]. While diffuse p16 positivity strongly suggests HPV infection, definitive confirmation requires molecular testing via RT-PCR or ISH [40]. We hypothesize that HPV coinfection may contribute to a subset of HMSC cases, with multiplex PCR assays (e.g., Anyplex II HPV28) enabling more accurate detection of multiple HPV subtypes than single-target HPV PCR probes [9].
Our analysis revealed that combined surgery and adjuvant therapy was associated with lower mortality and fewer distant metastases, while the absence of recurrences correlated with reduced distant spread. Notably, patients treated with surgical excision alone also demonstrated high survival rates with low recurrence and metastasis. Adjuvant radiotherapy is contraindicated in T1 sinonasal carcinomas (which comprised most cases in this study) due to high toxicity risks, being reserved for advanced-stage disease, unresectable tumors, and positive surgical margins [51]. Endoscopic surgical excision remains the preferred treatment for HMSC patients, given the tumor’s indolent behavior, potential for recurrences (often requiring multiple interventions), and consequent preservation of postoperative quality of life [14, 51]. We encourage larger studies to further evaluate the apparent benefits of adjuvant radiotherapy in HMSC management.
This systematic review has some limitations, largely due to the limited existing literature on HMSC. Consequently, the inclusion criteria were confined to case reports, case series, and cohort studies, which are study designs typically considered to provide low levels of evidence. First, many studies, particularly those with large sample sizes, failed to provide individual patient stratification, limiting our ability to analyze specific histopathological correlations with prognostic outcomes. Second, most studies employed non-specific HPV genotyping probes, preventing accurate characterization of the HPV type distribution in HMSC. Finally, incomplete follow-up reporting in numerous studies constrained our survival analysis capabilities. To improve the knowledge of HMSC, we recommend conducting carefully documented case reports and case series studies following the CARE guidelines, along with cohort studies that adhere to the STROBE statement [52, 53]. This standardized approach would enhance data reliability and facilitate meaningful comparisons across future studies.
Conclusion
HMSC is a malignant neoplasm that predominantly affects the nasal cavity of patients in the sixth decade of life, with no sex predilection. Clinically, most cases present as symptomatic lesions with an indolent clinical course. Histologically, tumors typically consist of basophilic cells arranged in multiple architectural patterns, mainly in solid and cribriform patterns, frequently showing necrosis, squamous differentiation, pleomorphism, and high mitotic activity, while vascular and perineural invasion are uncommon. The characteristic immunoprofile demonstrates strong diffuse p16 positivity, with variable expression of squamous/ epithelial and myoepithelial markers. Most cases were associated with HPV 33. While lymph node and distant metastasis are infrequent, local recurrences develop in a significant proportion of patients, often several months after treatment. Despite its aggressive histological features, HMSC generally shows favorable outcomes, with most cases achieving high survival rates following surgical excision.
Electronic Supplementary Material
Below is the link to the electronic supplementary material.
Acknowledgements
We gratefully acknowledge Dr. Roman Carlos’ significant contributions to this study, including the provision of tumor samples that were instrumental to our research. Dr. Carlos passed away in 2021, but his scientific contribution remains valuable to this work.
Author Contributions
J.P.G.P. wrote the main manuscript text, prepared tables and figures, and conducted statistical analyses. All authors reviewed the manuscript.
Funding
J.P.G.P., D.G.R., R.A.O.V., I.S.A., and L.M.F. received funding from the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Finance Code 001.
Data Availability
No datasets were generated or analysed during the current study.
Declarations
Competing Interests
The authors declare no competing interests.
Conflict of interest
The authors declare that they have no conflict of interest.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Jacks Jorge and Ciro Dantas Soares are jointly supervised this work.
References
- 1.Bishop JA, Ogawa T, Stelow EB, Moskaluk CA, Koch WM, Pai SI et al (2013) Human papillomavirus-related carcinoma with adenoid cystic-like features. Am J Surg Pathol 37. 10.1097/PAS.0b013e31827b1cd6.: 836–44 [DOI] [PMC free article] [PubMed]
- 2.Stelow EB, Bishop JA (2017) Update from the 4th edition of the world health organization classification of head and neck tumours: tumors of the nasal cavity, paranasal sinuses and skull base. Head Neck Pathol 11:3–15. 10.1007/s12105-017-0791-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Bishop JA, Andreasen S, Hang JF, Bullock MJ, Chen TY, Franchi A et al (2017) HPV-related multiphenotypic sinonasal carcinoma. Am J Surg Pathol 41:1690–1701. 10.1097/PAS.0000000000000944 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Thompson LDR, Bishop JA (2022) Update from the 5th edition of the world health organization classification of head and neck tumors: nasal cavity, paranasal sinuses and skull base. Head Neck Pathol 16:1–18. 10.1007/s12105-021-01406-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Agarwal A, Bhatt AA, Bathla G, Kanekar S, Soni N, Murray J et al (2023) Update from the 5th edition of the WHO classification of nasal, paranasal, and skull base tumors: imaging overview with histopathologic and genetic correlation. Am J Neuroradiol 44:1116–1125. 10.3174/ajnr.A7960 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Hsieh MS, Lee YH, Jin YT, Huang WC (2018) Strong SOX10 expression in human papillomavirus-related multiphenotypic sinonasal carcinoma: report of 6 new cases validated by high-risk human papillomavirus mRNA in situ hybridization test. Hum Pathol 82:264–272. 10.1016/j.humpath.2018.07.026 [DOI] [PubMed] [Google Scholar]
- 7.Hang J, Hsieh M, Li W, Chen J, Lin S, Liu S et al (2017) Human papillomavirus-related carcinoma with adenoid cystic-like features: a series of five cases expanding the pathological spectrum. Histopathology 71:887–896. 10.1111/his.13301 [DOI] [PubMed] [Google Scholar]
- 8.Andreasen S, Bishop JA, Hansen TVO, Westra WH, Bilde A, von Buchwald C et al (2017) Human papillomavirus-related carcinoma with adenoid cystic-like features of the sinonasal tract: clinical and morphological characterization of six new cases. Histopathology 70:880–888. 10.1111/his.13162 [DOI] [PubMed] [Google Scholar]
- 9.Ahn B, Kim E, Oh H, Chae YS, Kim CH, Lee Y et al (2019) Human papillomavirus-related multiphenotypic sinonasal carcinoma with late recurrence. J Pathol Transl Med 53:337–340. 10.4132/jptm.2019.04.02 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Miyamaru S, Sanuki T, Miyamoto Y, Nishimoto K, Masuda M, Honda Y et al (2023) Human papillomavirus-related multiphenotypic sinonasal carcinoma: a report of two patients and review of the literature. Auris Nasus Larynx 50:473–477. 10.1016/j.anl.2022.03.019 [DOI] [PubMed] [Google Scholar]
- 11.Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD et al (2021) The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 372:n71. 10.1136/bmj.n71 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Abraham ZS, Ngimba CP, Malango AE, Mrema A, Saleh MA, Vuhahula E (2022) Human papillomavirus-related carcinoma with adenoid cystic-like features of the sinonasal tract: case report and literature review. Int J Surg Case Rep 97:107462. 10.1016/j.ijscr.2022.107462 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Adamane SA, Mittal N, Teni T, Pawar S, Waghole R, Bal M (2019) Human papillomavirus-related multiphenotypic sinonasal carcinoma with unique HPV type 52 association: a case report with review of literature. Head Neck Pathol 13:331–338. 10.1007/s12105-018-0969-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Beaumont C, Nadeau S, Champagne PO, Beauchemin M, Villemure-Poliquin N (2024) HPV-related multiphenotypic sinonasal carcinoma: a clinicoradiological series of 3 cases with full endoscopic surgical outcome. Ear Nose Throat J. 10.1177/01455613241247729 [DOI] [PubMed] [Google Scholar]
- 15.Brzezinska K, Hammad A (2020) Human papillomavirus-related multiphenotypic sinonasal carcinoma: a recent discovery. A case report and literature review. Head Neck Pathol 14:473–479. 10.1007/s12105-019-01069-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Ching D, Pirasteh S, Ly C (2019) HPV-related multiphenotypic sinonasal carcinoma: a unique case. Int J Surg Pathol 27:888–892. 10.1177/1066896919866508 [DOI] [PubMed] [Google Scholar]
- 17.Chouake RJ, Cohen M, Iloreta A (2018) HPV-related carcinoma with adenoid cystic-like features of the sinonasal tract. Laryngoscope 128:1515–1517. 10.1002/lary.26957 [DOI] [PubMed] [Google Scholar]
- 18.Chu Y, Mullaney K, DiNapoli SE, Cohen MA, Xu B, Ghossein R et al (2024) FGFR1/2/3-rearranged carcinoma of the head and neck: expanded histological spectrum crossing path with high-risk HPV in the sinonasal tract. Histopathology 84:589–600. 10.1111/his.15099 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Crawford MP, Stelow EB (2021) Human papillomavirus-related multiphenotypic sinonasal carcinoma. AJSP Rev Rep 26:256–258. 10.1097/PCR.0000000000000465 [Google Scholar]
- 20.Cubides-Córdoba M, Sánchez-Fernández P, Mendoza-Pacas G, Cabal V, García-Marín R, Lorenzo-Guerra S et al (2024) Whole exome sequencing of HPV-related multiphenotypic sinonasal carcinoma. Front Oncol 14:1448213. 10.3389/fonc.2024.1448213 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Devins KM, Baloch Z, LiVolsi V (2020) Unusual human papillomavirus-related neoplasms of the head and neck: a case series and review of literature. AJSP Rev Rep 25:3–7. 10.1097/PCR.0000000000000353 [Google Scholar]
- 22.Ethirajan P, Lakshmanan A, RS A CR (2025) HPV-related multiphenotypic sinonasal carcinoma: a case with aggressive morphology but favorable prognosis. Cureus 16:e78030. 10.7759/cureus.78030 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Sáenz González A, Morera Serna E, Quintero Duarte A, Ramos Asensio R (2019) Recurrence of HPV-related carcinoma with adenoid cystic-like features. Acta Otorrinolaringol Esp 70:119–121. 10.1016/j.otorri.2018.02.005 [DOI] [PubMed] [Google Scholar]
- 24.Hodgson C, Bayon R, Jensen C, Robinson R, Rajan K (2021) HPV-related carcinoma of the oropharynx with squamous cell and adenoid cystic carcinoma-like features. Head Neck Pathol 15:1007–1016. 10.1007/s12105-020-01233-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Hwang S, Ok S, Lee H, Lee E, Park I (2015) HPV-related carcinoma with adenoid cystic-like features of the inferior turbinate. Auris Nasus Larynx 42:53–55. 10.1016/j.anl.2014.07.005 [DOI] [PubMed] [Google Scholar]
- 26.Jung S, Kim M, Min K, Jeong J (2024) HPV-related multiphenotypic sinonasal carcinoma. Ear Nose Throat J 103:543–547. 10.1177/01455613221112334 [DOI] [PubMed] [Google Scholar]
- 27.Kuroda N, Kawaji H, Arai Y, Otsuki Y, Miura K, Minato H et al (2022) Radiation therapy for brain invasion by HPV-related multiphenotypic sinonasal carcinoma. Neuropathology 42:45–51. 10.1111/neup.12762 [DOI] [PubMed] [Google Scholar]
- 28.Liao C, Yu H, Lu T, Chen Y, Chen J (2020) Endoscopic view of HPV-related multiphenotypic sinonasal carcinoma. Ear Nose Throat J 99:96–98. 10.1177/0145561319884199 [DOI] [PubMed] [Google Scholar]
- 29.Morishita Y, Sakashita S, Tomioka T, Okano W, Shinozaki T, Higashino T et al (2023) HPV-related multiphenotypic sinonasal carcinoma. Auris Nasus Larynx 50:151–155. 10.1016/j.anl.2021.10.008 [DOI] [PubMed] [Google Scholar]
- 30.Remirez-Castellanos A, Piña-Sanchez P, Mantilla-Morales A, Valenzuela-Gonzalez W, Candanedo González F (2023) Recurrent HPV-related multiphenotypic sinonasal carcinoma with HPV genotype 56. Cureus 15:e40413. 10.7759/cureus.40413 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Rodarte A, Parikh A, Gadkaree S, Lehmann A, Faquin W, Holbrook E et al (2019) HPV-related multiphenotypic sinonasal carcinoma with early metastatic disease. J Neurol Surg Rep 80:e41–e43. 10.1055/s-0039-3399571 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Ruangritchankul K, Jitpasutham T, Kitkumthorn N, Thorner PS, Keelawat S (2018) Human papillomavirus-related multiphenotypic sinonasal carcinoma: first case report associated with an intermediate-risk HPV type and literatures review. Hum Pathol Case Rep 14:20–24. 10.1016/j.ehpc.2018.05.008 [Google Scholar]
- 33.Rupp NJ, Camenisch U, Seidl K, Rushing EJ, Anderegg N, Broglie MA et al (2020) HPV-related multiphenotypic sinonasal carcinoma: four cases that expand the morpho-molecular spectrum and include occupational data. Head Neck Pathol 14:623–629. 10.1007/s12105-019-01079-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Shah A, Lamarre E, Bishop J (2018) HPV-related multiphenotypic sinonasal carcinoma with late recurrence. Head Neck Pathol 12:623–628. 10.1007/s12105-018-0895-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Vieira GS, Perin MY, Figueiredo-Maciel T, Risuenho AJG, Carvalho de Oliveira V, Macedo LT et al (2023) Induction chemotherapy response of HPV-related multiphenotypic sinonasal carcinoma: first-ever reported therapeutic outcome and a brief literature review. Oral Oncol 146:106555. 10.1016/j.oraloncology.2023.106555 [DOI] [PubMed] [Google Scholar]
- 36.Ward M, Kernig M, Willson T (2021) HPV-related multiphenotypic sinonasal carcinoma. Laryngoscope 131. 10.1002/lary.28598.:106– 10 [DOI] [PubMed]
- 37.Zupancic M, Holzhauser S, Cheng L, Ramqvist T, Du J, Friesland S et al (2022) HPV and polyomaviruses in adenoid cystic carcinoma with adenoid cystic-like features. Viruses 14:1040. 10.3390/v14051040 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Reinders A, Gao J, Smile T (2024) HPV-related multiphenotypic sinonasal carcinoma with intracranial extension. Cureus 16:e68824. 10.7759/cureus.68824 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Bishop JA, Guo TW, Smith DF, Wang H, Ogawa T, Pai SI et al (2013) Human papillomavirus-related carcinomas of the sinonasal tract. Am J Surg Pathol 37. 10.1097/PAS.0b013e3182698673.:185– 92 [DOI] [PMC free article] [PubMed]
- 40.Bishop JA, Westra WH (2018) Human papillomavirus-related multiphenotypic sinonasal carcinoma: an emerging tumor type with a unique microscopic appearance and a Paradoxical clinical behaviour. Oral Oncol 87:17–20. 10.1016/j.oraloncology.2018.10.011 [DOI] [PubMed] [Google Scholar]
- 41.Hodzic Z, Rowan NR, Kashiwazaki R, Willson TJ, Wang EW, Lee SE (2017) A systematic review of sinonasal Oncocytomas and oncocytic carcinomas: diagnosis, management, and technical considerations. Int Forum Allergy Rhinol 7:514–524. 10.1002/alr.21902 [DOI] [PubMed] [Google Scholar]
- 42.Harvey RJ, Dalgorf DM (2013) Sinonasal malignancies. Am J Rhinol Allergy 27:S35–S38. 10.2500/ajra.2013.27.3894 [DOI] [PubMed] [Google Scholar]
- 43.Eggesbo HB (2012) Imaging of sinonasal tumours. Cancer Imaging 12:136–152. 10.1102/1470-7330.2012.0015 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Pérez-de-Oliveira ME, Leonel ACLS, de Castro JFL, Carvalho EJA, Vargas PA, Perez DEC (2019) Histopathological findings of intraoral pleomorphic adenomas: a retrospective study of a case series. Int J Surg Pathol 27:729–735. 10.1177/1066896919854181 [DOI] [PubMed] [Google Scholar]
- 45.Lavareze L, Scarini JF, de Lima-Souza RA, Kimura TC, Gondak RO, Egal ESA et al (2023) Clinicopathological and survival profile of patients with salivary gland myoepithelial carcinoma: a systematic review. J Oral Pathol Med 52:101–108. 10.1111/jop.13395 [DOI] [PubMed] [Google Scholar]
- 46.Mino M, Pilch BZ, Faquin WC (2003) Expression of KIT (CD117) in neoplasms of the head and neck: an ancillary marker for adenoid cystic carcinoma. Mod Pathol 16:1224–1231. 10.1097/01.MP.0000096046.42833.C7 [DOI] [PubMed] [Google Scholar]
- 47.Mathew EP, Todorovic E, Truong T, Dickson BC, Enepekides D, Poon I et al (2022) Metatypical adenoid cystic carcinoma. Am J Surg Pathol 46:816–822. 10.1097/PAS.0000000000001850 [DOI] [PubMed] [Google Scholar]
- 48.Rooper LM, McCuiston AM, Westra WH, Bishop JA (2019) SOX10 Immunoexpression in basaloid squamous cell carcinomas: a diagnostic pitfall for ruling out salivary differentiation. Head Neck Pathol 13:543–547. 10.1007/s12105-018-0990-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49.El-Morfy SK (2012) PV-related squamous cell carcinoma variants in the head and neck. Head Neck Pathol 6:55–62. 10.1007/s12105-012-0363-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 50.Lechner M, Liu J, Masterson L, Fenton TR (2022) HPV-associated oropharyngeal cancer: epidemiology, molecular biology and clinical management. Nat Rev Clin Oncol 19. 10.1038/s41571-022-00603-7.:306– 27 [DOI] [PMC free article] [PubMed]
- 51.Thariat J, Carsuzaa F, Marcy PY, Verillaud B, de Gabory L, Ferrand FR (2021) Precision postoperative radiotherapy in sinonasal carcinomas after endonasal endoscopic surgery. Cancers (Basel) 13:4802. 10.3390/cancers13194802 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 52.Gagnier JJ, Kienle G, Altman DG, Moher D, Sox H, Riley D (2013) The CARE guidelines: consensus-based clinical case reporting guideline development. BMJ Case Rep 2013:bcr2013201554. 10.1136/bcr-2013-201554 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 53.von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP (2008) The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol 61:344–349. 10.1016/j.jclinepi.2007.11.008 [DOI] [PubMed] [Google Scholar]
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Supplementary Materials
Data Availability Statement
No datasets were generated or analysed during the current study.