HPV-related Multiphenotypic Sinonasal Carcinoma Research Articles

Morphologic Spectrum of HPV-associated Sinonasal Carcinomas.

High-risk human papillomavirus (HR-HPV) infection has been increasingly recognized as a risk factor for sinonasal tract carcinomas. However the prevalence and prognostic significance of HPV-associated sinonasal carcinomas is not well known due to limited studies and inconsistency in HPV testing modalities in literatures. Morphologically, HPV-associated sinonasal carcinomas encompass a diverse group of tumors. HPV-associated sinonasal adenocarcinoma has not been reported. The purpose of this study was to determine the prevalence, morphologic spectrum and prognostic implication of HPV-associated sinonasal carcinomas. This cohort included 153 sinonasal carcinomas. Tissue microarrays were constructed. P16 immunohistochemistry and HR-HPV E6/7 in-situ Hybridization (ISH) were performed. Carcinomas were deemed HPV-associated based on a positive ISH testing. Clinicopathologic data was collected. 28/153 (18%) sinonasal carcinomas were HPV-associated. HPV-associated carcinomas consisted of 26 (93%) squamous cell carcinomas and variants, 1 (3.5%) HPV-related multiphenotypic sinonasal carcinoma and 1 (3.5%) adenocarcinoma. The HPV-associated adenocarcinoma closely resembled HPV-associated endocervical adenocarcinoma morphologically. HPV-associated carcinomas occurred in 8 (29%) women and 20 (71%) men with a median age of 66 years old. HPV-associated carcinomas were predominantly located at nasal cavity. A trend toward improved overall survival and progression free survival in HPV-associated carcinomas patients was observed, yet without statistical significance. Our study identifies a novel HPV-associated sinonasal adenocarcinoma subtype, highlights the broad morphologic spectrum of HPV-associated sinonasal carcinomas, and supports routine p16 testing during pathology practice regardless of tumor subtype followed by a confirmatory HR-HPV testing. This practice is critical for studying the clinical behavior of HPV-associated sinonasal carcinomas.

HPV-related multiphenotypic sinonasal carcinoma: report of a case

HPV-related multiphenotypic sinonasal carcinoma: report of a case

HPV-Related Multiphenotypic Sinonasal Carcinoma: A Clinicoradiological Series of 3 Cases With Full Endoscopic Surgical Outcome.

Context: Human papillomavirus (HPV)-related multiphenotypic sinonasal carcinoma (HMSC), formerly known as HPV-related carcinoma with adenoid cystic like features, is a rare tumor subtype with unusual correlation between radiological, histopathological, and surgical findings. The shared histological characteristics with other sinonasal tumors make the diagnosis challenging. Optimal surgical and oncological treatments for this rare condition remains to be clearly defined. Methods: The objective of the study was to describe the unique characteristics and endoscopic surgical treatment of this rare tumor. In this retrospective case series, all patients with an HMSC diagnosis treated in our tertiary center were selected. Results: Three HMSC cases were identified, including 2 male and 1 female patients. All cases originated from the posterior nasal cavity. One case presented with a tumor of 8.9 cm × 6.4 cm × 8.7 cm, which is the largest tumor volume described to date. All patients received exclusively endoscopic surgical treatment, followed by adjuvant radiation therapy. No patient showed clinical or radiological sign of disease recurrence, or regional or distant metastasis, with a follow-up ranging from 9 months to 4 years. In 2 cases, initial diagnoses incorrectly suggested adenoid cystic or basaloid squamous cell carcinoma. HPV-DNA testing confirmed the presence of HPV in all cases, with identification of strains 16 and 18. Conclusion and Relevance: HMSC represents a newly identified diagnosis that constitutes a significant challenge for both clinicians and pathologists. It is crucial to acknowledge its indolent clinical course and the apparent contradiction between aggressive radiological features and the noninvasive nature of surgical findings. Skull base surgeons should be aware that, despite these complexities, endoscopic treatment is achievable in the majority of cases. This understanding is essential for the effective management of HMSC.

HPV related multiphenotypic sinonasal carcinoma: two case reports

HPV related multiphenotypic sinonasal carcinoma: two case reports

Exploring HPV as an Etiologic Factor for Breast Cancer

Abstract Introduction/Objective Breast ducts communicate with skin, which can expose one to infectious agents. Recent studies demonstrate differences between breast microbiome in normal tissues versus tumor, suggesting a potential role in carcinogenesis. Human Papilloma Virus (HPV) is the etiologic factor in numerous cancers, and studies suggest it may play a role in breast carcinoma. A recent case report identified an analogue to HPV-related multiphenotypic sinonasal carcinoma in the breast. This sinonasal tumor, closely associated with HPV type 33, consists of adenoid cystic-like morphology, basaloid and/or squamous cytology and multi-lineage differentiation (ductal and myoepithelial). Our aim was to determine if HPV is a driver of breast carcinomas with the outlined phenotype by testing with immunohistochemistry (IHC) for p16 and in-situ hybridization (ISH) for High Risk HPV (HR-HPV) E6/E7 mRNA. Methods/Case Report Breast cases from 2010- June 2022 were searched with the terms “adenoid cystic,” “myoepithelial differentiation,” or “basaloid.” Cases of adenoid cystic carcinoma with a diagnostic fusion were excluded. Those with basaloid and/or squamous morphologic features containing ductal and myoepithelial differentiation proven by IHC were included. Nine identified cases were submitted for p16 IHC and HR-HPV ISH. Results (if a Case Study enter NA) Patients ranged in age from 50 to 85. No cases resulted with positive HR-HPV, however all cases displayed staining for p16. All cases with benign breast tissue (6/9) exhibited some p16 positivity within luminal and myoepithelial cells. Conclusion HR-HPV ISH is a sensitive test; however, no cases were positive. Most tumors and benign breast expressed p16 in some form. p16 in basal-like breast cancer has been described, but only 3/7 cases with biomarkers were triple negative. Accordingly, p16 is not a reliable screening tool if detection of HPV becomes clinically relevant in the future. In this series, the phenotypic features assessed do not appear to be consistent harbingers of HPV infection. More studies are needed to assess the breast microbiome and oncogenic organisms to identify potential new therapeutic targets.

Challenging differential diagnoses in small biopsies from the sinonasal tract.

Sinonasal biopsy specimens are a challenging area in anatomic pathology. The small, often fragmented or crushed nature of these biopsies can hinder morphologic assessment. Additionally, many of the tumors in this area are rare and share morphologic, and sometime immunophenotypic similarities. In many cases, immunohistochemistry is helpful if not necessary to reach a specific diagnosis. In other cases, a specific diagnosis is not possible and a differential diagnosis must be given on a biopsy specimen despite access to a well-equipped immunohistochemistry laboratory. This review article groups some of the more challenging entities in the sinonasal region based on morphologic patterns. These include low grade squamoid lesions such as sinonasal (Schneiderian) papilloma and DEK::AFF2 rearranged carcinoma, glandular neoplasms such as intestinal and non-intestinal type sinonasal adenocarcinoma, high-grade carcinomas such as HPV-related multiphenotypic sinonasal carcinoma, NUT carcinoma and SWI/SNF deficient carcinomas, small round blue cell tumors such as teratocarcinosarcoma, neuroendocrine carcinoma and olfactory neuroblastoma, and finally, low grade spindle cell neoplasms such as glomangiopericytoma, biphenotypic sinonasal sarcoma and solitary fibrous tumor.

Diagnostic algorithm for challenging blue cell sinonasal carcinoma

The newly emerging sinonasal carcinomas have demonstrated diverse morphologies and specific molecular rearrangements along with deviant clinical behavior from conventional counterparts. We aim to propose a diagnostic algorithm that is based on molecular findings of each sinonasal cancer and is considering the new entities has been called upon. Such a diagnostic algorithm should help diagnostic pathologists establish a diagnosis of a challenging sinonasal blue cell carcinomas and researchers performing retrospective analysis of archival cases. Along with consulting our archival cases, literature mining was conducted to retrieve the immunohistochemical and molecular findings regarding the newly emerging entities. Our proposed algorithm distinguishes poorly differentiated (non) keratinizing SNSCC, from anaplastic myoepithelial carcinoma, NUT midline carcinoma, SMARCB1/SMARCA4-deficient teratocarcinosarcoma, SMARCB1/SMARCA4-deficient carcinosarcoma, olfactory neuroblastoma, sinonasal undifferentiated carcinoma, HPV-related multiphenotypic sinonasal carcinoma and other adenocarcinomas. By incorporating morphologic features, immunohistochemical markers, and molecular investigations, the algorithm enhances the accuracy of diagnosis, particularly in cases where comprehensive molecular testing is not readily available. This algorithm serves as a valuable resource for pathologists, facilitating the proper diagnosis of sinonasal malignancies and guiding appropriate patient management.

HPV-RELATED MULTIPHENOTYPIC SINONASAL CARCINOMA: AN AGGRESSIVE AND CHALLENGING CASE REPORT

A 54-year-old male patient complained of self-limited epistaxis for two years, the symptoms worsening one year ago. Systemic arterial hypertension for 14 years was reported in the anamnesis. Physical examination revealed an irregular nodule in the left nasal fossa with yellowish secretion, friable to aspiration. MRI revealed an expansile image in the left nasal cavity, measuring 8.3 × 4.3 × 2.8 cm, extending into the nasopharynx, ethmoid, right nasal cavity, and cortical bone of the hard palate. An incisional biopsy was performed. Morphologically, a malignant cellular proliferation with solid basaloid appearance admixed with adenoid cystic-like areas. IHC were positive for AE1/AE3, CK7, p63, and calponin, with focal labeling for CD117 and α-SMA. p16 had diffuse cytoplasmic and nuclear positivity. Ki-67 index was 80%. The morphological and immunohistochemical aspects were conclusive for HPV-related multiphenotypic sinonasal carcinoma. Already in stage IV, the tumor was considered unresectable, and the patient is under oncological treatment and follow-up with chemoradiotherapy. A 54-year-old male patient complained of self-limited epistaxis for two years, the symptoms worsening one year ago. Systemic arterial hypertension for 14 years was reported in the anamnesis. Physical examination revealed an irregular nodule in the left nasal fossa with yellowish secretion, friable to aspiration. MRI revealed an expansile image in the left nasal cavity, measuring 8.3 × 4.3 × 2.8 cm, extending into the nasopharynx, ethmoid, right nasal cavity, and cortical bone of the hard palate. An incisional biopsy was performed. Morphologically, a malignant cellular proliferation with solid basaloid appearance admixed with adenoid cystic-like areas. IHC were positive for AE1/AE3, CK7, p63, and calponin, with focal labeling for CD117 and α-SMA. p16 had diffuse cytoplasmic and nuclear positivity. Ki-67 index was 80%. The morphological and immunohistochemical aspects were conclusive for HPV-related multiphenotypic sinonasal carcinoma. Already in stage IV, the tumor was considered unresectable, and the patient is under oncological treatment and follow-up with chemoradiotherapy.

HPV-related multiphenotypic sinonasal carcinoma, HPV type 35-related: a case report

Most HPV-related head and neck carcinomas arise in the oropharynx, but can also arise in the sinonasal tract. The entity now referred to as HPV-related multiphenotypic sinonasal carcinoma (HMSC) was previously known as HPV-related carcinoma with adenoid cystic carcinoma-like features. This tumour is characterised by an association with high-risk HPV subtypes (commonly type 33), a sinonasal location and histologic phenotype resembling both adenoid cystic carcinoma and surface derived squamous cell carcinoma.

HPV-related Multiphenotypic Sinonasal Carcinoma: A Case Report

HPV-related Multiphenotypic Sinonasal Carcinoma: A Case Report

Human papillomavirus-related carcinoma with adenoid cystic-like features of the sinonasal tract: Case report and literature review.

Introduction and importanceHPV-related carcinoma with adenoid cystic carcinoma-like features currently known as HPV-related multiphenotypic sinonasal carcinoma (HMSC) is a rare distinct head and neck high-risk HPV-related carcinoma. The high-risk HPV subtypes implicated are particularly type 33,35 and 56. So far this is the first reported rare case of a variant of sinonasal carcinoma in Tanzania.Case presentationWe present a 59-year old female who presented with a history of right-sided nasal obstruction and intermittent epistaxis for about one year and later on had ipsilateral proptosis. A provisional diagnosis of advanced right-sided malignant sinonasal tumor was made. Trans nasal biopsy revealed HMSC.Clinical discussionThe patient had a right sided fixed neck mass that measured about 7.5 × 8.2 cm. Magnetic resonance imaging (MRI) of the paranasal sinuses revealed a T1 weighted contrasted images that showed a huge extensive enhancing mass (estimated to measure 4.5 × 4.4) involving the nasal cavity, bilateral ethmoid sinuses, frontal and sphenoid sinuses and also the tumor exhibit intracranial extension (anterior cranial fossa) and tend to compress medial walls of both orbits though more marked on the right side. Histopathology and immunohistochemistry confirmed HPV-related multiphenotypic sinonasal carcinoma. The disease was staged to be T4bN3aM0 and the patient was referred for palliative chemoradiation.ConclusionAlthough HMSC presents at advanced stage in close to half of cases and has a high-grade histological appearance it paradoxically exhibits a relatively indolent manner with frequent local recurrences. Prompt histopathological diagnosis is important to prevent metastases and HMSC-related deaths.

Update from the 5th Edition of the World Health Organization Classification of Head and Neck Tumors: Nasal Cavity, Paranasal Sinuses and Skull Base.

The World Health Organization Classification of Head and Neck Tumours recently published the 5th edition. There are new entities, emerging entities, and significant updates to the taxonomy and characterization of tumor and tumor-like lesions, specifically in this article as it relates to nasal cavity, paranasal sinuses and skull base. Importantly, the number of diagnostic entries has been reduced by creating category-specific chapters for soft tissue, hematolymphoid, melanocytic, neuroectodermal, and metastatic tumors. Bone and salivary gland tumors are also not separately reported in the sinonasal tract, but included in the jaw and salivary gland sections, respectively. Repetition of characteristic entities in each anatomic site was also reduced, instead highlighting only the unique features in each anatomic site. Two new entities (SWI/SNF complex-deficient sinonasal carcinomas and HPV-related multiphenotypic sinonasal carcinoma) will be highlighted in this review, with a discussion of several emerging entities. There is a short description of updated information for all 24 diagnostic entities included in this edition to allow the reader a snapshot of current state of knowledge, but to encourage more investigation and further broaden understanding of these diverse and rare entities.

HPV-Related Multi-Phenotypic Sinonasal Carcinoma with Aggressive Clinical Behavior; A Rare Case

Abstract Introduction/Objective Human Papilloma Virus (HPV)-related multiphenotypic sinonasal carcinoma, previously known as HPV-related sinonasal carcinoma with adenoid cystic carcinoma-like features, is a rare type of sinonasal carcinoma with both epithelial-derived and salivary gland-type morphologic features. It is associated with high-risk HPV, but lacks MYB gene rearrangements. Methods/Case Report We report a case of a 59-year-old male who presented with a rapidly growing sinonasal mass. On MRI, a left nasal cavity lesion was identified growing laterally along the frontal process of the maxilla, extending into the middle meatus and into the maxillary sinus. Patient underwent a complex left medial maxillectomy, spheno- ethmoidectomy, and sinusotomy. On gross evaluation, the left inferior turbinate and sidewall demonstrated a 4 cm unremarkable turbinate with attached friable soft tissue. Microscopic examination revealed sections of carcinoma with various architectural patterns comprised of foci with adenoid cystic carcinoma-like morphology, basaloid squamous cell carcinoma and adenocarcinoma. The tumor showed positive immunostaining for P40, but focal reactivity to S100 and rare scattered reactivity with CD117. INI-1 immunostain was retained in tumor cells. P16 immunostain was strong and diffuse and high-risk cocktail HPV RNA ISH was positive. However, MYB FISH testing was equivocal. Morphologic and immunophenotypic findings were consistent with HPV-related multiphenotypic sinonasal carcinoma. The tumor involved the olfactory nerve fibers requiring a skull base resection and showed extension into the dura mater. Results (if a Case Study enter NA) NA Conclusion HPV related multiphenotypic sinonasal carcinoma is a recently described entity that can pose significant diagnostic challenge. It typically has an indolent clinical course with potential for late recurrences. This case study highlights the potential aggressive nature of this type of sinonasal carcinoma, despite association with high-risk HPV, and use of ancillary testing in aiding diagnosis.

A Case of HPV-related Multiphenotypic Sinonasal Carcinoma (HMSC)

A Case of HPV-related Multiphenotypic Sinonasal Carcinoma (HMSC)

Sinonasal analogue HPV related breast multiphenotypic carcinoma, a report of a case with the first description in the breast

BackgroundHigh grade basal-like breast carcinomas are triple negative, express basal cytokeratins, and are known for the overall poor prognosis and aggressive behavior. HPV related multiphenotypic sino-nasal carcinoma has overlapping histology with basal-like breast carcinomas, but carry the defining feature of association with high risk HPV.Case presentationWe present a case of a perimenopausal woman with a non-healing ulcerated lesion involving the nipple and breast following a trauma. Biopsy performed showed an HPV-positive basal-like carcinoma with squamous differentiation involving the breast, analogous to multiphenotypic carcinoma previously described in the sinonasal tract.ConclusionThis is the first report of a case of a high- risk HPV related basal-like carcinoma with squamous differentiation, described in the literature. We highlight the morphology and immunophenotype of this lesion and its recognition when compared to other multiphenotypic lesions of the breast, and suggest that pathologists should consider HPV evaluation when encountering similar basal-like tumors involving the breast.

39. HPV-related multiphenotypic sinonasal carcinoma, an emerging entity in an unusual location: A case report

Background: Human papillomavirus (HPV)–related multiphenotypic sinonasal carcinoma (HMSC), originally known as HPV-related carcinoma with adenoid cystic carcinoma-like features, is a distinct tumour recently described in the sinonasal tract. This peculiar tumour exhibits morphologic features of a salivary gland tumour including admixed ductal and myoepithelial elements, as well as displays an unusual pattern of surface involvement with atypical squamous cells. It is associated with high-risk HPV. Most cases usually present as a large and destructive sinonasal mass with high-grade histologic features. Aim: We present a case report of HMSC arising in the floor of mouth of a 57-year-old Chinese man. Methods (clinical history): The patient was an ex-smoker who presented with a floor of mouth ulcer. The lesion was biopsy and was called a submucosal adenoid cystic carcinoma. Subsequently, the patient underwent wide resection of floor of mouth tumour, marginal mandibulectomy and neck dissection. Results (pathological findings): Macroscopic examination revealed an ulcerative tumour measuring 2.5 cm, extending to the margins. Microscopically, the tumour was composed of basaloid cells showing variable growth patterns including a cribriforming pattern that closely resembles adenoid cystic carcinoma. It was continuous with the mucosa that showed dysplastic squamous epithelium. On immunohistochemistry, the myoepithelial cells were positive for the myoepithelial markers. p16 was positive in both squamous and epithelial components. Metastatic carcinoma was present in two of the harvested lymph nodes. The patient developed pulmonary and liver metastases after two years of follow-up, which were confirmed histologically. Conclusions: This is the first case of HMSC reported in the floor of mouth, which behaves more aggressively as opposed to those arise from the sinonasal tract. It is important to recognise HMSC as they have a different clinical behaviour. The clue to the diagnosis is recognising the atypical squamous cells on the surface, corroborated by p16 positivity in tumour cells.

HPV-Related Multiphenotypic Sinonasal Carcinoma: Four Cases that Expand the Morpho-Molecular Spectrum and Include Occupational Data

HPV-related multiphenotypic sinonasal carcinoma (HMSC) is a recently described distinct tumor entity of the sinonasal tract associated with high-risk subtypes of human papilloma virus (HPV), predominantly type 33. The biological behavior seems to be less aggressive than the often high-grade, highly proliferative morphology implies; however, recurrences are frequent. Most of the cases present as polypoid tumors within the nasal cavity. Microscopic morphology frequently encompasses adenoid cystic-like features or features reminiscent of other salivary gland tumors. Here, we describe four cases of this rare entity, all observed in women. The polypoid tumors were within the nasal cavity, leading to obstruction, facial pain and epistaxis. The morphology was predominantly basaloid, solid and adenoid cystic-like in two of four cases, one with additional glomeruloid features. Another case showed basaloid tumor cells with prominent mature squamous differentiation and extensive keratinization. A single case showed a predominantly solid and reticular growth pattern. All cases were diffusely positive for p16 (100%), expressed SOX10, LEF-1 and partially S-100, and harbored HPV high-risk types 33, 56 (2×) and 82. No recurrences or metastases were detectable after 3-50months of follow-up. Of note, three of four patients were nurses/nursing assistant. We expand the morphological spectrum by describing a glomeruloid growth pattern and extensive mature keratinization, and add HPV type 82 to the molecular spectrum. The finding of HMSC among predominantly nurses in our cohort warrants further epidemiological studies in larger cohorts.

SOX10 Immunoexpression in Basaloid Squamous Cell Carcinomas: A Diagnostic Pitfall for Ruling out Salivary Differentiation.

SOX10 immunoexpression is increasingly recognized in salivary gland tumors, including but not limited to those with myoepithelial, serous acinar, and intercalated duct differentiation. However, SOX10 expression has not been extensively evaluated in other epithelial tumors that can mimic salivary origin. Basaloid squamous cell carcinoma (SCC) is a unique variant of SCC that shows morphologic overlap with several salivary tumors, including adenoid cystic carcinoma, basal cell adenocarcinoma, and myoepithelial carcinoma. We performed SOX10 immunohistochemistry on 22 basaloid SCCs and 280 non-basaloid SCCs. If tissue was available, we also performed immunohistochemistry for S100 and p16, and in-situ hybridization for high-risk HPV RNA. SOX10 was positive in 13/22 basaloid SCCs (59%), including 5/6 (83%) that were HPV-positive and 6/12 (50%) that were HPV-negative. Only 2/12 basaloid SCC (17%) demonstrated focal S100 expression. All non-basaloid SCCs were SOX10 negative. Frequent positivity for SOX10 in basaloid SCC presents a significant diagnostic pitfall for distinguishing these tumors from various basaloid salivary carcinomas. The preponderance of SOX10 expression in the basaloid variant of HPV-positive SCC also presents a diagnostic challenge in separating it from HPV-related multiphenotypic sinonasal carcinoma. SOX10 may be more broadly considered a marker of basal differentiation and should not be assumed to be specific for salivary origin in epithelial head and neck tumors.

Human papillomavirus-related multiphenotypic sinonasal carcinoma: First case report associated with an intermediate-risk HPV type and literatures review

HPV-related Multiphenotypic sinonasal carcinoma (previously known as HPV-related carcinoma with adenoid cystic carcinoma-like features) is very rare tumor of which only 55 cases are reported. All cases to date are related to high-risk types of HPV including 16, 31, 33, 35 and 56. We report of a case of a nasal mass in a 50-year-old female. Biopsy demonstrated typical features of an HPV-related multiphenotypic sinonasal carcinoma, with both basaloid and ductal type cells. Tumor cells were arranged in lobulated sheets, with focal cribriform and microcystic growth patterns. The majority of tumor cells expressed myoepithelial markers (S-100 protein, smooth muscle actin and p63) and the ductal cells were immunopositive for CD117. Polymerase chain reaction and sequencing identified HPV type 26. HPV 26 becomes the first intermediate risk type that may be associated with HPV-related multiphenotypic sinonasal carcinoma.

HPV-related Multiphenotypic Sinonasal Carcinoma: An Expanded Series of 49 Cases of the Tumor Formerly Known as HPV-related Carcinoma With Adenoid Cystic Carcinoma-like Features.

Human papillomavirus (HPV)-related multiphenotypic sinonasal carcinoma (HMSC), originally known as HPV-related carcinoma with adenoid cystic carcinoma-like features, is a peculiar neoplasm that is restricted to the sinonasal tract, exhibits features of both a surface-derived and salivary gland carcinoma (particularly adenoid cystic carcinoma), and is associated with high-risk HPV. Given the limited number of published cases, the full clinicopathologic spectrum of this neoplasm is unclear. Here, we present an updated experience of 49 cases. All cases of HMSC were obtained from the authors' files. Immunohistochemistry for p16, c-kit, and myoepithelial cell markers (S100, actin, calponin, p63, and/or p40) was performed along with RNA in situ hybridization for HPV (type 33-specific as well as a high-risk cocktail). Fluorescence in situ hybridization studies for fusions of MYB, NFIB, and MYBL1 was performed on a subset of cases. Clinical follow-up was obtained from medical records. A total of 49 cases of HMSC were collected. Twenty-eight (57%) were from women and 18 (43%) from men, ranging in age from 28 to 90 years (mean, 54 y). Of 40 cases with detailed staging information, 43% of HMSCs presented with a high T-stage (T3 or T4). Histologically, most grew predominantly as solid nests of basaloid cells exhibiting high mitotic rates and frequent necrosis, with histologic and immunohistochemical evidence of myoepithelial differentiation. Most cases also demonstrated foci of cribriform and/or tubular growth, along with an inconspicuous population of ducts. Thirty-four (69%) cases demonstrated an unusual pattern of surface involvement where markedly atypical squamous cells colonized tracts of the sinonasal mucosa. Less consistent histologic features included squamous differentiation within the invasive tumor (n=6), sarcomatoid transformation (n=5) including overt chondroid differentiation (n=3), and prominent epithelial-myoepithelial carcinoma-like growth (n=3). All cases were positive for p16 by immunostaining and HPV by RNA in situ hybridization. Thirty-three (67%) were positive for HPV 33. No cases tested for MYB, MYBL1, or NFIB gene fusions were positive. In the 38 cases with follow-up data, (mean follow-up, 42 mo) 14 recurred locally and 2 metastasized (lung, finger). There were no regional lymph node metastases, and no tumor-related deaths. HMSC is a distinct sinonasal neoplasm characterized by myoepithelial differentiation, frequent surface epithelial involvement, and the presence of high-risk HPV (especially type 33). Although it classically exhibits a cribriforming pattern that closely resembles adenoid cystic carcinoma, our expanded series highlights a histologic spectrum that is much broader than previously recognized, warranting a change in terminology. HMSC usually presents as a large and destructive sinonasal mass with high-grade histologic features, but it paradoxically behaves in a relatively indolent manner, underscoring the importance of distinguishing HMSC from true adenoid cystic carcinoma, squamous cell carcinoma, and other histologic mimickers.