Fine-needle aspiration cytology of palisading adenocarcinoma: The first cytology report of a newly described salivary gland neoplasm.

Here, we report the first cytology findings of the newly characterized entity, palisading adenocarcinoma of the salivary gland, diagnosed in the sublingual gland of a 61-year-old female. The liquid-based cytology showed a moderately cellular aspirate containing three-dimensional clusters and trabeculae of tumor cells of various sizes. The cells had dark ovoid nuclei, finely granular chromatin, inconspicuous to punctate nucleoli, and ample cyanophilic cytoplasm with indistinct cell borders. In conventional smears, the cells displayed frequent crush artifacts and anisonucleosis resembling endocrine-type atypia. The background was clean, devoid of secretions, and contained singly dispersed tumor cells with stripped nuclei. Interestingly, concentrically laminated globules of extracellular matrix surrounded by the tumor cells were identified. Mitotic figures and tumor necrotic debris were absent. The cytologic findings correlated with the histologic findings of the excision specimen. The cytologic differential diagnosis and tumor grading of palisading adenocarcinoma were briefly discussed.

Follicular Dendritic Cell Sarcoma of the Parotid Gland: A Case Report and Review of Literature.

Follicular dendritic cell sarcoma of the parotid gland is an extremely rare tumor, with only six cases reported in the literature. A 51-year-old female had a 3.0 cm tumor resected from the right parotid gland. The tumor exhibited solid sheets, whorls, fascicular pattern, and syncytium appearance with an indistinct cell border. The lymphocytic infiltrate was sprinkled throughout the neoplasm, with focal prominent perivascular cuffing. Immunohistochemically, it was positive for follicular dendritic cell markers CD21, CD23, and CD35. We aim to enhance the understanding of this neoplasm and alert pathologists to this rare entity in this region to avoid misdiagnosis.

Perineural invasion is a poor prognostic factor for sinonasal squamous cell carcinoma.

OBJECTIVES: In this study, our primary objective is to elucidate the correlation between sinonasal squamous cell carcinoma (SCC) and perineural invasion (PNI), a topic that has received limited attention in prior literature. Furthermore, we have undertaken an examination of various other clinicopathological factors. MATERIALS AND METHODS: We retrospectively reviewed the medical records of patients aged ≥ 20 years with newly diagnosed sinonasal cancer and received treatment and care at a tertiary medical center. We excluded patients who did not have an SCC diagnosis, those who underwent palliative surgery, and individuals with insufficient follow-up data at the study endpoint. Ultimately, a total of 49 eligible participants were included in our further analysis. RESULTS: PNI and advanced T staging were associated with increased risk of local recurrence (LR). Furthermore, PNI was significantly associated with an adverse prognosis in terms of LR-free survival. Participants with PNI had significantly worse overall survival (OS), disease-free survival (DFS), and disease-specific survival (DSS). Patients with LR had significantly worse OS, DFS, and DSS. CONCLUSION: PNI is associated with an elevated risk of LR and reduced OS, DFS, and DSS in patients with sinonasal SCC. These findings can facilitate the formulation of more targeted and effective treatment strategies for sinonasal SCC in clinical practice.

New Histopathologic Risk Model for Early T-stage Oral Squamous Cell Carcinoma: Focusing on a Modified Worst Pattern of Invasion System and a New Tumor Budding Score.

Oral squamous cell carcinoma (OSCC) is treated based on the TNM staging. However, early T-stage OSCC still exhibits substantial nodal metastasis and death rates. Recent literature highlights the independent prognostic value of worst pattern of invasion (WPOI) and tumor budding in OSCC. Nevertheless, WPOI-5 is uncommon in early T-stage OSCC, and the definitions of tumor budding and WPOI-4 overlap. Moreover, WPOI assessment is subjective, and tumor budding evaluation varies across studies. To address these limitations, we aimed to develop a modified WPOI system and a novel tumor budding scoring system that assesses single cells and high-density tumor budding. We also evaluated a new histopathologic risk model for early T-stage OSCC. The study cohort comprised 37 pT1 and 64 pT2 OSCCs. The modified WPOI demonstrated superior interobserver agreement compared with the original system (κ value: 0.98 vs. 0.53). In the multivariate analysis, modified WPOI and tumor budding score were independent prognostic factors for nodal metastasis and disease-free survival, while modified WPOI predicted disease-specific survival. By integrating these factors, our risk model stratified the patients into 3 groups. Notably, the intermediate-risk and high-risk groups exhibited significantly higher rates of nodal metastasis, recurrence, and tumor-related death. Conversely, none in the low-risk group had nodal metastasis or succumbed to the disease. Our model offered simplified scoring and potentially improved prognostic predictions. In conclusion, we've developed a modified WPOI system, a new tumor budding scoring system, and a reliable risk model that classifies early T-stage OSCC patients into distinct risk groups with significant prognostic differences.

Palisading Adenocarcinoma: A Morphologically Unique Salivary Gland Tumor With a Neuroendocrine-like Appearance and a Predilection for the Sublingual Glands of Women.

Adenocarcinoma, not otherwise specified (NOS) is a heterogenous group of salivary gland tumors that likely contains distinct tumors that have not yet been characterized. Indeed, in recent years, cases previously diagnosed as adenocarcinoma, NOS have been recategorized into novel tumor designations such as secretory carcinoma, microsecretory adenocarcinoma, and sclerosing microcystic adenocarcinoma. We sought to describe a distinctive, hitherto-undescribed salivary gland tumor encountered in the authors' practices. Cases were pulled from the surgical pathology archives of the authors' institutions. Histologic, immunohistochemical, and clinical findings were tabulated, and targeted next-generation sequencing was performed on all cases. Nine cases were identified, arising in 8 women and 1 man ranging from 45 to 74 years (mean, 56.7 y). Seven tumors (78%) arose in the sublingual gland, while 2 (22%) arose in the submandibular gland. The cases shared a distinctive morphologic appearance. They were biphasic, with ducts scattered among a predominant polygonal cell with round nuclei, prominent nucleoli, and pale eosinophilic cytoplasm. These cells were arranged as trabeculae and palisaded as pseudorosettes around hyalinized stroma and vessels, resembling a neuroendocrine tumor. Four of the cases were well-circumscribed, while the remaining 5 showed infiltrative growth including perineural invasion in 2 (22%) and lymphovascular invasion in 1 (11%). Mitotic rates were low (mean, 2.2/10 HPFs); necrosis was absent. By immunohistochemistry, the predominant cell type was strongly positive for CD56 (9 of 9) and variably positive for pan-cytokeratin (AE1/AE3) (7 of 9) with patchy S100 (4 of 9), but negative for synaptophysin (0 of 9) and chromogranin (0 of 9), while the ducts were strongly positive for pan-cytokeratin (AE1/AE3) (9 of 9) and CK5/6 (7 of 7). Next-generation sequencing did not reveal any fusions or obvious driver mutations. All cases were resected surgically, with external beam radiation also done in 1 case. Follow-up was available in 8 cases; there were no metastases or recurrences after 4 to 160 months (mean, 53.1 mo). A dual population of scattered ducts with a predominance of CD56-positive neuroendocrine-like cells characterizes a unique salivary gland tumor which is often encountered in the sublingual glands of women, for which we propose the term "palisading adenocarcinoma." Although the tumor was biphasic and had a neuroendocrine-like appearance, it lacked convincing immunohistochemical evidence of myoepithelial or neuroendocrine differentiation. Although a subset showed unequivocally invasive growth, this tumor appears to behave in an indolent manner. Moving forward, recognition of palisading adenocarcinoma and its separation from other salivary adenocarcinomas, NOS will facilitate a better understanding of the characteristics of this previously unrecognized tumor.

Sinonasal Adenosquamous Carcinoma - Morphology and Genetic Drivers Including Low- and High-Risk Human Papillomavirus mRNA, DEK::AFF2 Fusion, and MAML2 Rearrangement.

BACKGROUND: Sinonasal adenosquamous carcinoma is rare, and there are almost no studies detailing morphology or characterizing their genetic driver events. Further, many authors have termed sinonasal tumors with combined squamous carcinoma and glands as mucoepidermoid carcinoma but none have analyzed for the presence of MAML2 rearrangement. METHODS: Cases from 2014 to 2020 were collected and diagnosed using World Health Organization criteria. They were tested for p16 expression by immunohistochemistry (70% cut-off), DEK::AFF2 fusion by fluorescence in situ hybridization (FISH) and AFF2 immunohistochemistry, MAML2 rearrangement by FISH, and low- and high-risk HPV by RNA ISH and reverse transcription PCR, respectively. Detailed morphology and clinical features were reviewed. RESULTS: There were 7 male (64%) and 4 female (36%) patients with a median age of 69 years, most Caucasian (10 of 11 or 91%). Most had tobacco exposure (8/11, 73%) and most presented with epistaxis, a visible nasal mass, and/or facial pain. Several had a precursor papillomas (3 of 11, 27%). The squamous component had variable keratinization, 5 of 11 (46%) of which would be described as keratinizing, 3 non-keratinizing, and 2 with mixed features. All had gland formation, by definition, and 2 of 11 (18%) had ciliated tumor cells. None of the 11 cases had MAML2 rearrangement and one had DEK::AFF2 fusion with associated positive nuclear AFF2 protein immunostaining. Most were p16 positive (7 of 11, 64%) and all 7 of these were hrHPV positive either by RNA ISH or RT-PCR. Two of the p16-negative tumors were positive for lrHPV by RNA ISH. Treatment included surgery alone (4 of 11, 36%), surgery with adjuvant radiation (5 of 11, 45%), and surgery with radiation and chemotherapy (2 of 11, 18%). Four of 11 patients (36%) suffered disease recurrence, two requiring re-operation and who were disease free at last follow-up, one receiving additional chemotherapy and who was alive with disease. The other elected to undergo palliative therapy and died of disease. CONCLUSION: Sinonasal adenosquamous carcinoma is a somewhat heterogeneous tumor not infrequently arising ex papilloma and having various drivers including high- and low-risk HPV and rarely DEK::AFF2 fusion. The prognosis appears favorable when proper treatment is possible.

Tumor-associated tissue eosinophilia promotes angiogenesis and metastasis in head and neck squamous cell carcinoma.

Eosinophils are terminally differentiated leukocytes that participate in the process of chronic inflammation and allergy and are able to release multiple cytokines into the surrounding tissue environment. Tumor-associated tissue eosinophilia (TATE) is the presence of eosinophils in the tumor or in the neighboring stroma and has been observed in various types of cancer. In head and neck squamous cell carcinoma (HNSCC), the clinical relevance of TATE has not been concluded yet because of the inconsistent results in different studies. In our study, we focus on the prognostic effects of TATE on HNSCC and how TATE can influence tumor behavior and tumor microenvironment. We first showed that in both the TCGA-HNSC cohort and our cohort of patients with HNSCC who had received curative surgery, TATE is correlated with worse overall survival. To investigate the underlying mechanism of how TATE leads to poor clinical outcomes, we showed that activated eosinophils produce a variety of cytokines and chemokines, and activated TATE-derived culture medium promotes tumor migration mainly through CCL2. We also showed that eosinophils are capable of inducing angiogenesis and that HNSCC samples enriched with TATE are highly correlated with tumor angiogenesis. Furthermore, HNSCC enriched with TATE had more aggressive pathological features, including regional lymph node metastasis, perineural invasion, lymphovascular invasion, and tumor growth. Lastly, we showed that HNSCC enriched with TATE is associated with immunosuppressive tumor microenvironment. Taken together, our results suggest that TATE promotes cancer metastasis and angiogenesis which results in a poor clinical outcomes in HNSCC.

Nuclear expression of AFF2 C-terminus is a sensitive and specific ancillary marker for DEK::AFF2 carcinoma of the sinonasal tract.

DEK::AFF2 carcinoma of the sinonasal tract is an emerging entity. The tumor is typically characterized by papillary proliferation of non-keratinizing squamous epithelial cells with monotonous cytologic features, which may mimic other sinonasal tumors. The confirmation of this gene fusion has thus far relied solely on next-generation sequencing, fluorescence in situ hybridization (FISH), or reverse transcription polymerase chain reaction (RT-PCR). This current study aimed to validate an immunohistochemical assay for AFF2 C-terminus as an ancillary marker. We first analyzed publicly available RNA sequencing data of sinonasal tumors from the national center for biotechnology information (NCBI) sequence read archive and identified 3 DEK::AFF2 carcinomas out of 28 sinonasal tumors. The gene expression of AFF2 was significantly higher in the fusion-positive cases compared to the wild-type tumors (p < 0.001), while DEK was not. We then optimized an immunohistochemical assay with an anti-AFF2 C-terminus antibody for ancillary diagnosis. Seventeen DEK::AFF2 carcinomas, including 11 cases with predominantly low-grade morphology and one showing glandular differentiation, as well as 78 DEK FISH-negative sinonasal tumors were evaluated by AFF2 immunohistochemistry (IHC). Sixteen of the 17 DEK::AFF2 carcinomas showed nuclear AFF2 expression in ≥30% of tumor cells, including one decalcified case that failed FISH and RT-PCR confirmation. The one case that was negative for AFF2 IHC in the tumor cells also lacked expression in the internal positive control. It was thus considered a failure of the IHC rather than a truly negative case and was excluded from the statistical analysis. All DEK FISH-negative sinonasal tumors were negative for nuclear AFF2 expression. The nuclear expression of AFF2 IHC showed 100% sensitivity and specificity for DEK::AFF2 carcinoma. Accordingly, AFF2 IHC is a highly sensitive and specific ancillary marker that distinguishes DEK-AFF2 carcinoma from the other sinonasal tumors with overlapping morphological features and may be an especially useful alternative for decalcified specimens.

Invasive Fungal Rhinosinusitis with and without Orbital Complications: Clinical and Laboratory Differences.

BACKGROUND: Invasive fungal rhinosinusitis (IFS) is a rare but often fatal disease. There are limited studies regarding IFS with orbital complications (IFSwOC). The present study aimed to identify the clinical signs associated with IFSwOC and prognosticators of the disease. METHODS: A retrospective case series was conducted of patients histopathologically confirmed IFS or fungal rhinosinusitis with clinically apparent neuro-orbital complications who underwent surgery between 2008 and 2018. Demographic data, presenting symptoms and signs, culture data, laboratory results, and patient outcomes were obtained from medical records. RESULTS: A total of 38 patients were identified, including 9 patients with IFSwOC, and 29 patients with IFS without orbital complications (IFSsOC). The clinical signs associated with developing orbital complications include headache, fever, sphenoid sinus, or posterior ethmoid sinus involvement, CRP level ≥ 1.025 mg/dL, or ESR level ≥ 46.5 mm/h. In IFSwOC group, male, posterior ethmoid sinus involvement, WBC count ≥ 9000 µL, CRP level ≥ 6.91 mg/dL, or ESR level ≥ 69 mm/h were correlated with a significantly poorer prognosis. CONCLUSION: IFS patients with sphenoid or posterior ethmoid sinus involvement, headache or fever as presenting symptoms, elevated CRP, and ESR level were at risk of developing orbital complications. Timely surgical debridement followed by systemic antifungal treatment may improve treatment outcomes.

DEK-AFF2 fusion-associated papillary squamous cell carcinoma of the sinonasal tract: clinicopathologic characterization of seven cases with deceptively bland morphology.

A novel DEK-AFF2 fusion has been recently identified in four cases of basaloid to nonkeratinizing squamous cell carcinoma (SCC) in the sinonasal tract and middle ear with high-grade morphology. The exceptional response to immune checkpoint inhibitor in the first reported case highlights the potential clinical importance of identifying tumors with DEK-AFF2 fusions. We herein reported the first series of seven cases of DEK-AFF2 fusion-associated sinonasal SCC with deceptively bland morphology, including four cases of low-grade papillary Schneiderian carcinoma, which is a recently described tumor type with unknown molecular underpinnings. The DEK gene rearrangement was confirmed by DEK break-apart fluorescence in situ hybridization and DEK-AFF2 fusion transcripts were detected by reverse transcription polymerase chain reaction. In contrast to the previously reported DEK-AFF2 fusion-positive high-grade carcinomas, these tumors had a monotonous and bland morphology and were all initially diagnosed as sinonasal papilloma (SP) of various types, with or without dysplasia or carcinoma in situ. The tumor was characterized by mixed exophytic and inverted patterns, broad papillary fronds, acantholytic change, cellular monotony, dense neutrophilic infiltrates, and peripheral palisading. All tumors were diffusely positive for p40 or p63 and negative for NUT and p16. Molecular drivers associated with SP, including EGFR and KRAS mutations and both high and low-risk human papillomavirus infection, were negative in all cases. Although there was no overt stromal invasion or desmoplastic reaction in the initial specimens, these tumors tended to progress locoregionally through a prolonged clinical course and occasionally develop lymph node metastases, high-grade transformation, or extensively local destruction eventually leading to death. These justify more aggressive clinical management. Therefore, we propose the new terminology "DEK-AFF2 fusion-associated papillary SCC of the sinonasal tract" to better describe this clinicopathologically and molecularly distinct entity.

Developing a novel meatal areolar tissue autograft for minimally invasive tympanoplasty.

BACKGROUND: We developed an easy and minimally invasive method of transmeatal tympanoplasty using meatal areolar tissue (MAT) grafts to achieve less postoperative morbidity or surgical scarring. We compared the functional and anatomical results of the developed method with conventional endaural tympanoplasty with a temporalis fascia (TF) graft. METHODS: In this retrospective cohort study, 58 patients (59 ears) with simple chronic otitis media who underwent type I tympanoplasty between January 2016 and August 2018 were included. All surgeries were performed in a tertiary referral hospital and by the same senior surgeon. The tympanic membrane (TM) was repaired with either a TF or an MAT graft. RESULTS: Healing of the perforated TM and improvement in a hearing test by air-bone gap (ABG) closure were identified. Postoperative wound conditions were also evaluated. Twenty-eight ears were grafted with MAT, and 31 ears were grafted with TF. Graft success was observed in 26 patients (92.9%) in the MAT group and 28 patients (90.3%) in the TF group. Both groups showed functional improvement compared with the preoperative measurements. The postoperative pure tone audiogram (p = 0.737), ABG closure (p = 0.547), and graft success rate (p = 0.726) were not significantly different between the two groups. Neither wound dehiscence nor keloid formation was observed in our patients. CONCLUSION: Both MAT and TF grafts revealed satisfactory surgical and functional results. Compared with the conventional endaural approach with TF grafts, the new transmeatal approach method with an MAT graft causes relatively minimal trauma and results in better wound cosmetics. This method represents an easy, minimally invasive surgery and shows comparatively good results.

Clinicopathological study of intraductal carcinoma of the salivary gland, with emphasis on the apocrine type.

Intraductal carcinoma (IC) is a rare salivary gland tumor with low- to intermediate-grade cytological features. It is further classified into intercalated duct type and apocrine type based on its distinct histologic and immunohistochemical expression. Conventional salivary duct carcinoma (SDC) is an aggressive carcinoma with high-grade features and is usually associated with poor prognosis. In this study, immunohistochemistry and mutation analyses (including HRAS/PIK3CA mutations, RET rearrangement, and human epidermal growth factor receptor 2 [HER2] amplification) of 9 ICs (including 3 pure ICs, 6 ICs with invasive carcinoma) and 24 conventional SDCs were performed and the results were compared. Four intercalated duct-type cases were positive for SOX10 and S100 and negative for AR; five apocrine-type cases showed opposite results. All five apocrine-type cases had cysts with relatively circumscribed tumor borders and morphologically mimicking breast low-grade ductal carcinoma in situ or papillary carcinoma. RET fusion is detected in half of the 4 intercalated duct-type IC but not in the apocrine-type or conventional SDC. HER2 amplification was only observed in conventional SDC. The monoclonal antibody (clone RBT-NRAS) against NRAS Q61R is a sensitive and specific marker used for detecting HRAS Q61R mutation in the salivary gland tumors. The apocrine-type IC had different cytological grades, distinct tumor growth patterns, and no evidence of low- to high-grade transition, suggesting that apocrine-type IC should be distinguished from apocrine SDC with an in situ component.

Metastatic Tumors of the Sinonasal Cavity: A 15-Year Review of 17 Cases.

Extranasal cancers that metastasize to the sinonasal cavity are very rare. To date, there are only limited reports regarding this rare condition within the literature. Therefore, we retrospectively reviewed all patients diagnosed with metastatic cancer of the sinonasal tract from 2003 to 2018 at a tertiary academic medical center. Patient demographic data, clinical presentation, treatment modalities, and outcomes were investigated. There were a total of 17 patients (9 males and 8 females) included in the analysis. The mean age was 56.8 years (range 27-80). The most common primary malignancies were hepatocellular carcinoma (n = 3) and gastrointestinal tract adenocarcinoma (n = 3). The most common site of metastasis was the nasal cavity (n = 8). Five patients received radical tumor resection and the others underwent radiotherapy, chemotherapy, or combined chemoradiotherapy. The 2-year survival was 28%. In summary, metastasis to the sinonasal cavity remains extremely rare. A high degree of suspicion regarding the possibility of metastatic spread to the sinonasal region is necessary for patients with a previous history of malignancy who present with new sinonasal symptoms. The treatment strategy of sinonasal metastatic cancer is usually palliative therapy and the prognosis remains poor. However, early detection and diagnosis, coupled with aggressive treatment, may improve patient quality of life.

Macrophage-secreted interleukin-35 regulates cancer cell plasticity to facilitate metastatic colonization.

A favorable interplay between cancer cells and the tumor microenvironment (TME) facilitates the outgrowth of metastatic tumors. Because of the distinct initiating processes between primary and metastatic tumors, we investigate the differences in tumor-associated macrophages (TAMs) from primary and metastatic cancers. Here we show that dual expression of M1 and M2 markers is noted in TAMs from primary tumors, whereas predominant expression of M2 markers is shown in metastatic TAMs. At metastatic sites, TAMs secrete interleukin-35 (IL-35) to facilitate metastatic colonization through activation of JAK2-STAT6-GATA3 signaling to reverse epithelial-mesenchymal transition (EMT) in cancer cells. In primary tumors, inflammation-induced EMT upregulates IL12Rß2, a subunit of the IL-35 receptor, in cancer cells to help them respond to IL-35 during metastasis. Neutralization of IL-35 or knockout of IL-35 in macrophages reduces metastatic colonization. These results indicate the distinct TMEs of primary and metastatic tumors and provide potential targets for intercepting metastasis.

Sinonasal seromucinous hamartoma.

INTRODUCTION: Seromucinous hamartoma (SH) is a rare benign glandular proliferation of the sinonasal tract and nasopharynx. Only few cases have been reported in recent years. MATERIALS AND METHODS: We performed a retrospective medical record review of seven patients diagnosed with sinonasal SH who underwent endoscopic endonasal surgery. RESULTS: There were 5 males and 2 females, ranged in age from 40 to 98 years (mean 60 years, SD ± 18.9). Two lesions arise from middle turbinate, two from uncinate process, and 3 (but 4 specimens) from nasal septum. Pathological features revealed a polypoid lesion with submucosal proliferation of seromucinous glands arranged in lobular and haphazard patterns. In immunohistochemical study, the seromucinous glands of SH were reactive for cytokeratin, including CK7, CK19, HMWK, but negative for CK20. CONCLUSION: Sinonasal SH is a rare diagnosis characterized by a polypoid lesion with a haphazard proliferation of seromucinous glands. The rhinologists should consider it in the differential diagnosis of a polypoid lesion in the nasal cavity.

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.

Human papillomavirus-related carcinoma with adenoid cystic-like features: a series of five cases expanding the pathological spectrum.

AIMS: Human papillomavirus (HPV)-related carcinoma with adenoid cystic-like features is a newly described entity of the sinonasal tract. In this study, we evaluated histomorphology, immunophenotype and molecular testing to identify potentially helpful features in distinguishing it from classic adenoid cystic carcinoma (AdCC). METHODS AND RESULTS: We retrospectively collected five HPV-related carcinomas with adenoid cystic-like features and 14 AdCCs of the sinonasal tract. All histological slides were retrieved for morphological evaluation. As comparing with AdCC, HPV-related carcinomas with adenoid cystic-like features were associated with squamous dysplasia of surface epithelium (80% versus 0%, P < 0.01) and the presence of a solid growth pattern (100% versus 29%, P = 0.01), but less densely hyalinized tumour stroma (20% versus 86%, P = 0.02). Squamous differentiation in the invasive tumour was seen in three HPV-related carcinomas with adenoid cystic-like features, two of them showing abrupt keratinization and one with scattered non-keratinizing squamous nests. Diffuse p16 staining in ≥75% of tumour cells was noted in all HPV-related carcinomas with adenoid cystic-like features but in only one AdCC (100% versus 7%, P < 0.01). High-risk HPV testing gave positive results in all HPV-related carcinomas with adenoid cystic-like features (four associated with type 33 and one associated with type 16) but not in AdCCs. MYB rearrangement was tested in four HPV-related carcinomas with adenoid cystic-like features, and all were negative. CONCLUSIONS: This study has further clarified the histological spectrum of this tumour type, and reports the first HPV type 16-related case. Diffuse p16 staining followed by HPV molecular testing is useful in distinguishing HPV-related carcinomas with adenoid cystic features from classic AdCCs.

High neuroendocrine component is a factor for poor prognosis in gastrointestinal high-grade malignant mixed adenoneuroendocrine neoplasms.

BACKGROUND: High-grade malignant mixed adenoneuroendocrine carcinoma (MANEC) is a highly malignant combined neoplasm formed by an adenocarcinomatous component and a poorly differentiated (Grade 3) neuroendocrine (NE) carcinoma. METHODS: Tumors from 21 patients with gastrointestinal high-grade malignant MANECs or tumors with varying percentages of Grade 3 NE component were examined, and the NE component was confirmed by morphological analysis and immunohistochemical staining. Patients were divided into high NE (NE component > 50% in the primary tumor) and low NE (NE component ≤ 50% in the primary tumor) component groups. RESULTS: High NE component was a poor prognostic factor for patients with high grade MANEC (p = 0.021). Out of 13 patients with high-grade malignant MANEC, eight had a pure NE component, one had a pure adenocarcinomatous component, and four had mixed-type cancer in the metastatic lymph nodes. We further enrolled eight patients who had a Grade 3 NE component in the primary tumor and found that the pure NE component in tumor emboli and distant liver metastases were more frequent in the high NE than in the low NE component group (p = 0.012 and p = 0.046, respectively). CONCLUSION: The predominant tumor component in primary tumors was a prognostic factor and could predict tumor emboli and liver metastases pathology in high-grade malignant MANECs.