Salvage skull base surgery after proton beam therapy for recurrent sinonasal malignancies: A retrospective study.

BACKGROUND: This study aimed to examine treatment outcomes and postoperative complications associated with salvage skull base surgery following radical proton beam therapy (PBT). METHODS: Nine patients who underwent salvage skull base surgery following curative PBT as the initial treatment at our institution between September 2002 and May 2023 were retrospectively reviewed. RESULTS: The cohort comprised four males and five females with a mean age of 48.1 years. The average proton dose administered during initial therapy was 68.5 Gy (relative biological effectiveness). Among the salvage surgeries, eight were anterior skull base surgeries, and one was an anterior middle skull base surgery. No local recurrences or perioperative deaths were observed. Postoperative complications occurred in three patients (33.3%), all experiencing surgical site infections, with one also having cerebrospinal fluid leakage. CONCLUSION: The study demonstrates that salvage skull base surgery after PBT effectively achieves local control and safety in patients with recurrent sinonasal malignancies.

Risk factors for late postoperative bleeding after partial glossectomy for tongue cancer.

BACKGROUND: Partial glossectomy is the most common procedure for early-stage tongue cancer. Although late postoperative bleeding occasionally occurs, the associated risk factors have not been adequately identified. AIMS/OBJECTIVES: We aimed to investigate the rate and risk factors for late postoperative bleeding after transoral partial glossectomy with or without neck dissection for tongue cancer at our institution. MATERIAL AND METHODS: We analysed 211 patients who had undergone transoral partial glossectomy between January 2016 and January 2023. The potential risk factors associated with late postoperative bleeding were investigated using univariate and multivariate logistic regression analyses. RESULTS: Of the 211 patients, 40 (19%) showed late postoperative bleeding, with 19 (9%) classified as grade IIIa (Clavien-Dindo classification). Regarding all grades, late postoperative bleeding was significantly higher in patients aged <70 years and in those with polyglycolic acid (PGA) sheets (p = .046 and .030, respectively). For grade ≥ IIIa, late postoperative bleeding was significantly higher in patients with a history of anticoagulant/platelet administration, a mucosal defect covered with fibrin glue and a PGA sheet (p = .045 and .026, respectively). CONCLUSIONS AND SIGNIFICANCE: The findings of this study suggest that primary closure decreases the frequency of late postoperative bleeding.

Radiation-induced xerostomia and cariogenic dietary habits.

PURPOSE: Despite the availability of various prevention methods, dental caries continue to be diagnosed in patients receiving head and neck radiotherapy (RT). Since conventional approaches do not evaluate posttreatment alterations in dietary behaviors, we aimed to assess the influence of radiation-induced xerostomia on post-RT cariogenic dietary habits in patients. METHODS: Fifty-seven patients completed the Xerostomia Questionnaire (XQ) and answered questions regarding daily cariogenic food and beverage (CFB) intake, daily tooth brushing, fluoride application, and subjective total taste acuity (STTA). They also underwent evaluations to determine the Simplified Oral Hygiene Index (OHI-S) score, Saxon test score, number of decayed-missing-filled teeth (DMFT), and proportion of DMFT to the test teeth (DMFT rate). Clinical records were searched for information regarding RT modalities, including the median of the mean dose to the parotid glands, days after the completion of RT, submandibular gland resection, whole-neck irradiation, and the DMFT value and rate before RT. The patients were divided into low and high XQ score groups based on the median XQ score of 47.5 for the two sample tests. Univariable and multivariable regression analyses were used to identify independent factors for frequent CFB intake. RESULTS: Higher XQ scores were associated with a significantly greater frequency of CFB intake (p = 0.028*). Regression analysis also identified a higher XQ score (p = 0.017*) as an independent risk factor for frequent CFB intake. CONCLUSION: Radiation-induced xerostomia increased the frequency of CFB intake.

A Japanese Family Meeting the Clinical Diagnostic Criteria for MEN1 with a MEN1 Variant of Uncertain Significance.

Multiple gastroenteric, pancreatic, and pituitary neuroendocrine neoplasms (NENs) were diagnosed in a 74-year-old man with a history of primary hyperparathyroidism (PHPT). Germline testing demonstrated a variant of MEN1 (c.1694T>A, p.L565Q), whose pathogenicity was classified as a variant of uncertain significance (VUS) according to the ACMG/AMP guidelines. The same germline variant was detected in the patient's son and daughter, who also showed PHPT or hypercalcemia and met the clinical diagnostic criteria for multiple endocrine neoplasia type 1 (MEN1). During surveillance of the son, multiple pancreatic tumors suggestive of NENs were detected. The pathogenicity of the current MEN1 variant was re-evaluated as likely pathogenic, based on additional family data.

Extent of thyroidectomy and paratracheal lymph node dissection in total pharyngolaryngectomy for pyriform sinus cancer, and recurrence, survival, and postoperative hypoparathyroidism: A multicenter retrospective study.

BACKGROUND: Total pharyngolaryngectomy (TPL) is standard treatment for hypopharyngeal cancer. However, extensive thyroidectomy and paratracheal nodal dissection (PTND) can cause hypoparathyroidism. We sought to determine the optimum extent of resection. METHODS: We analyzed the clinicopathological information of 161 pyriform sinus cancer patients undergoing TPL from 25 Japanese institutions. Rates of recurrence and risk factors for hypoparathyroidism, as well as incidence of pathological contralateral level VI nodal metastasis and stomal recurrence, were investigated. RESULTS: The extent of thyroidectomy and nodal dissection were not independent risk factors for recurrence. Incidences of contralateral level VI nodal involvement and stomal recurrence were 1.8% and 1.2%, respectively. Patients undergoing hemithyroidectomy/ipsilateral PTND did not develop stomal recurrence and had the lowest incidence of hypoparathyroidism. Prognosis in patients without tracheostomy prior to hemithyroidectomy/ipsilateral PTND was comparable to that with more extensive resections. CONCLUSIONS: Hemithyroidectomy/ipsilateral PTND may be sufficient for pyriform sinus cancer cases without tracheostomy.

Impact of Mutations in Subunit Genes of the Mammalian SWI/SNF Complex on Immunological Tumor Microenvironment.

BACKGROUND/AIM: Recently, inactivating somatic mutations of SWI/SNF chromatin-remodeling genes in cancers have been reported. However, few studies have been performed regarding the immunological analysis of the tumor microenvironment (TME) in chromatin remodeling complex gene-mutated tumors. In the present study, we identified cancer patients harboring various mammalian SWI/SNF complex mutations and investigated the immunological features in those mutated cancers. PATIENTS AND METHODS: Cancer patients harboring any type of chromatin remodeling complex gene mutation were selected and clinicopathological features were compared between chromatin remodeling complex gene expression-low and expression-high groups. Specifically, expression levels of immune response-associated genes and cancer-associated genes were compared between the SMARCA4 expression-low and expression-high groups using volcano plot analysis. RESULTS: Among cancers harboring PBRM1, SAMRACA4 and ARID2 gene mutations, T-cell marker and mature B-cell marker genes were up-regulated in the tumor. Specifically, T-cell effector genes (CD8B, CD40LG), central memory marker genes (CD27, CCR7) and mature B-cell marker genes (CD20, CD38, CD79 and IRF4) were up-regulated, and cancer-associated genes including MYB, MYC and AURKB genes were down-regulated in the SMARCA4 expression-low group. Remarkably, heatmap of gene expression and immunohistochemistry (IHC) data demonstrated that the tertiary lymphoid structure (TLS) gene signature of mature B cells was up-regulated in SMACA4 gene-mutated stomach cancers. CONCLUSION: These results suggest that immune tumor microenvironment status, such as mature B cell recruitment featuring the TLS gene signature and immune activation mediated by cancer signal down-regulation, might contribute to the classification of SMARCA4 gene-mutated tumors as immune checkpoint blockade therapy-sensitive target tumors.

Clinicopathological Features of Buccal Squamous Cell Carcinoma with Focus on Patients Who Never Smoke and Never Drink.

Introduction Oral carcinoma has been reported at a substantial proportion in patients who never smoke and never drink. However, the proportion may vary by subsite and ethnicity. Objective We aimed to determine the clinicopathological features of buccal squamous cell carcinoma (SCC) in a Japanese population. Methods We retrospectively analyzed the records of patients diagnosed with buccal SCC at our institution from September 2002 to November 2015. We reviewed the gender, age, tumor status, treatment, smoking, alcohol drinking, multiple primary cancers, and prognosis of the patients. The overall and cause-specific survival rates were calculated, and the effects of clinicopathological variables were assessed by univariate analysis. Furthermore, the cause of death was evaluated. Results Among the 63 patients (men: 38; women: 25) included in the present study, 29 (46.0%) never smoked or drank. Women were almost 5 years older than men ( p = 0.014). The number of women in the group who never smoked or drank was disproportionately higher than that of those in the smoker or drinker groups ( p < 0.001). In total, 29 patients (46.0%) had 59 multiple primary cancers, including 26 oral cancers. Surgeries and radiotherapy were performed in 57 (90.5%) and 6 (9.5%) cases, respectively. The 5-year overall survival and disease-specific survival rates were 74.6 and 78.8%, respectively. Conclusion Our study confirms that buccal SCC may develop in older adult Japanese patients, especially in women who have never smoked or drank. These patients could be at risk for second primary malignancy.

Multidisciplinary tumor board for head and neck cancer from the perspective of medical oncologists-optimizing its effectiveness.

Head and neck cancer (HNC) treatment is becoming increasingly multidisciplinary, and patient characteristics vary. Therefore, a multidisciplinary tumor board (MTB) is essential in clinical practice. This review provides insights into the benefits and tips for improving head and neck MTB from the perspective of medical oncologists. The MTB is a platform to discuss the optimal application of the standard of care to each case, reach a consensus, and establish a recommendation to support patients' decision-making. A productive and educational MTB also provides an opportunity to share information on ongoing clinical trials with physicians. Case presentations should be systematic to discuss all new and challenging cases before, during, and after the treatment. Human resource development, particularly of head and neck medical oncologists, is crucial. The type of multidisciplinary network between medical staff and the extent of patient intervention differs among MTB teams. Subsequently, a virtual MTB can establish a medical network between institutions that will contribute to the equalization and centralization of head and neck oncologic care.

Generation of novel complete HLA class I monoallelic cell lines used in an MHC stabilization assay for neoantigen evaluation.

Immunogenic neoantigens derived from somatic mutations in cancer have been identified through clinical studies with the cloning of tumor-infiltrating T cells, and cancer driver gene mutation-derived epitopes have been reported; however, these are rare. At present, the validation of epitopes predicted in silico is difficult as human T-cell clonal diversity cannot be reproduced in vitro or in experimental animal models. To confirm the epitope peptides presented by human leukocyte antigen (HLA) class I molecules predicted in silico, biochemical methods such as major histocompatibility complex (MHC) stabilization assays and mass spectrometry-mediated identification have been developed based on HLA-A*02:01 monoallelic T2 cells and HLA-C*01:02 monoallelic LCL721.221 cells. Therefore, in the present study, to prevent confusion due to peptide cross-presentation among HLA molecules, HLA class I monoallelic B-cell clones were generated from the TISI cell line by knocking out HLA-ABC and TAP2, and knocking in HLA alleles. To explore cancer driver mutations as potential targets for immunotherapy, exome sequencing data from 5,143 patients with cancer enrolled in a comprehensive genome analysis project at the Shizuoka Cancer Center were used to identify somatic amino acid substituted mutations and the 50 most frequent mutations in five genes, TP53, EGFR, PIK3CA, KRAS and BRAF, were identified. Using NetMHC4.1, the present study predicted whether epitopes derived from these mutations are presented on major HLA-ABC alleles in Japanese individuals and synthesized 138 peptides for MHC stabilization assays. The authors also attempted to examine the candidate epitopes at physiological temperatures by using antibody clone G46-2.6, which can detect HLA-ABC, independent of ß2-microglobulin association. In the assays, although the peptide-induced HLA expression levels were associated with the predicted affinities, the respective HLA alleles exhibited varying degrees of responsiveness, and unexpectedly, p53-mutant epitopes with predicted weak affinities exhibited strong responses. These results suggested that MHC stabilization assays using completely monoallelic HLA-expressing B-cell lines are useful for evaluating the presentation of neoantigen epitopes.

Perioperative Factors Aggravating Pharyngocutaneous Fistula After Total Laryngectomy: A Single-Center Retrospective Analysis Using the Clavien-Dindo Classification.

BACKGROUND: Pharyngocutaneous fistula formation represents a major postoperative complication following total laryngectomy. We aimed to investigate the risk factors for pharyngocutaneous fistula development after total laryngectomy and to identify factors that lead to severe cases of pharyngocutaneous fistula. METHODS: Patients who underwent total laryngectomy between January 2013 and February 2021 were included in the study and were divided into 2 groups: Those with and without pharyngocutaneous fistula. The severity of pharyngocutaneous fistula was graded using the Clavien-Dindo classification. RESULTS: Patients with pharyngocutaneous fistula experienced longer operative time, greater intraoperative blood loss, greater decrease in perioperative hemoglobin level, and longer postoperative hospitalization. Unlike in lower-severity cases, patients with grade IIIb pharyngocutaneous fistula underwent preoperative radiotherapy or chemoradiotherapy; preoperative treatment was thus a risk factor for higher severity of pharyngocutaneous fistula (odds ratio, 35; P = 0.004). CONCLUSION: Salvage laryngectomy was found to be a predictor of severe pharyngocutaneous fistula development. Prolonged operative time, increased intraoperative blood loss, and decreased postoperative hemoglobin level were found to be predictors of postlaryngectomy pharyngocutaneous fistula formation.

Head pleomorphic sarcoma showing murine double minute 2 amplification without a well-differentiated liposarcoma component in a pediatric patient.

BACKGROUND: Murine double minute 2 (MDM2) is an oncogene that inhibits p53, leading to decreased apoptosis. Sarcomas showing MDM2 amplification are rare among pediatric patients. CASE: A 14-year-old boy presented with pleomorphic sarcoma of the head showing MDM2 amplification without a well-differentiated liposarcoma component. Although chemotherapy was initially performed to reduce the tumor size before surgery, the tumor did not shrink. The patient underwent complete surgical resection. Microscopic examination revealed a positive surgical margin; thus, postoperative proton-beam radiotherapy was performed. 3 years after the therapy, no sign of recurrence was observed. CONCLUSION: Macroscopic surgical resection combined with adjuvant postoperative radiotherapy was effective against MDM2-amplified pleomorphic sarcoma refractory to neoadjuvant chemotherapy in a pediatric patient.

Groin and anterolateral thigh flaps for hemiglossectomy reconstruction: A comparison based on Japanese speech intelligibility.

OBJECTIVE: The differences in speech function between groin flap reconstruction and anterolateral thigh (ALT) flap reconstruction after hemiglossectomy have not been clarified to date. This study aimed to compare Japanese speech intelligibility after hemiglossectomy reconstruction using groin and ALT flaps of similar thickness. METHODS: Data of patients who underwent hemiglossectomy reconstruction with groin or ALT flaps between April 2010 and March 2020 were collected from the medical chart database. The ALT flap was the first choice for hemiglossectomy reconstruction, and a groin flap was used when the ALT flap was >10 mm. Cases in which speech intelligibility assessments based on Hirose's 10-point scoring system, the TKR speech test, and the Japanese speech intelligibility test for 100 monosyllables were performed after 6 months postoperatively were extracted. The per-patient scores for each assessment were initially compared between the two flap groups. Then, the results of the Japanese speech intelligibility test for 100 monosyllables were reanalyzed on a syllable-by-syllable basis. RESULTS: Among the 44 hemiglossectomy patients who underwent free-flap reconstruction during the study period, 14 (seven each in the groin flap and ALT flap groups) underwent all three conventional speech intelligibility assessments after 6 months postoperatively. The two groups showed no significant difference in postoperative speech intelligibility in any of the three patient assessment methods. However, in intergroup comparisons based on per-syllable accuracy for each of the 100 monosyllables, the groin flap group showed 19 syllables with a significantly higher accuracy, whereas the ALT flap group showed one such syllable. In particular, five out of the six alveolar consonants (/t/ and /d/) were more accurately articulated in the groin flap group. Per-syllable accuracy was significantly higher in the groin flap group (74.6% vs. 66.7%; 95% confidence interval: 4.6-11.1, p < 0.001). CONCLUSION: In patients undergoing hemiglossectomy reconstruction, our new analysis method, which compared intelligibility by syllables, showed that the groin flap yielded higher speech intelligibility than the ALT flap. This difference was evident at all four articulation points involving the tongue, whereas there was no significant difference at the two articulation points without tongue involvement.

Clinicopathological Features of Buccal Squamous Cell Carcinoma with Focus on Patients Who Never Smoke and Never Drink

Abstract Introduction Oral carcinoma has been reported at a substantial proportion in patients who never smoke and never drink. However, the proportion may vary by subsite and ethnicity. Objective We aimed to determine the clinicopathological features of buccal squamous cell carcinoma (SCC) in a Japanese population. Methods We retrospectively analyzed the records of patients diagnosed with buccal SCC at our institution from September 2002 to November 2015. We reviewed the gender, age, tumor status, treatment, smoking, alcohol drinking, multiple primary cancers, and prognosis of the patients. The overall and cause-specific survival rates were calculated, and the effects of clinicopathological variables were assessed by univariate analysis. Furthermore, the cause of death was evaluated. Results Among the 63 patients (men: 38; women: 25) included in the present study, 29 (46.0%) never smoked or drank. Women were almost 5 years older than men (p = 0.014). The number of women in the group who never smoked or drank was disproportionately higher than that of those in the smoker or drinker groups (p < 0.001). In total, 29 patients (46.0%) had 59 multiple primary cancers, including 26 oral cancers. Surgeries and radiotherapy were performed in 57 (90.5%) and 6 (9.5%) cases, respectively. The 5-year overall survival and disease-specific survival rates were 74.6 and 78.8%, respectively. Conclusion Our study confirms that buccal SCC may develop in older adult Japanese patients, especially in women who have never smoked or drank. These patients could be at risk for second primary malignancy.

Prognostic impact of the number of metastatic lymph nodes after surgery in locally advanced hypopharyngeal cancer.

BACKGROUND: Postoperative chemoradiotherapy (CRT) is a standard therapy for patients with high-risk factors for head and neck squamous cell carcinoma, including positive margin and extra-nodal extension (ENE). However, the prognostic impact of the number of pathological metastatic lymph nodes (pLNs) in hypopharyngeal carcinoma (HPC) is unclear. Thus, this study aimed to investigate postoperative prognostic factors for locally advanced hypopharyngeal squamous cell carcinoma (LA-HPSCC) with a focus on the number of pLNs. METHODS: We retrospectively analyzed medical records of 99 consecutive patients with LA-HPSCC who underwent total pharyngo-laryngo-esophagectomy (TPLE) and bilateral neck dissection (ND) between December 2002 and May 2019. RESULTS: The median follow-up time for all censored patients was 63.2 months. The median overall survival (OS) was 101.0 months (95% confidence interval [CI] 48.1-134.9). patients had pLNs ≥ 3. Forty-six (45.5%) patients were diagnosed with ENE. Twenty (20.2%) patients received postoperative CRT. The multivariate analysis revealed that pLNs ≥ 3 (median OS: 163.2 vs. 31.8 months, hazard ratio [HR] 2.39, 95% CI 1.16-4.94, p < 0.01) and ENE (median OS: 161.0 vs. 26.3 months, HR 4.60, 95% CI 2.26-9.36, p < 0.01) were significantly associated with poor prognosis and that postoperative CRT (HR 0.34, 95% CI 0.16-0.72, p < 0.01) was significantly associated with better prognosis. The cumulative incidence of distant metastasis was higher in patients with pLNs ≥ 3 than in those with pLNs < 3 (p < 0.01). CONCLUSION: pLNs ≥ 3 and ENE were significant poor prognostic factors for patients with LA-HPSCC who underwent TPLE and bilateral ND.

Immunological and Genetic Characterization of Patients With Head and Neck Cancer who Developed Recurrence.

BACKGROUND/AIM: The recurrence rate of head and neck squamous cell carcinoma (HNSCC) remains high; thus the control of recurrence is a clinical problem to be challenged. To clarify the precise mechanism, specific immunological biomarkers responsible for recurrence were investigated. PATIENTS AND METHODS: The expression levels of immune response-associated and Shizuoka Cancer Center 820 cancer-associated genes, and genetic mutations from whole-exome sequencing were compared between HNSCC patients who developed recurrence (n=8) and HNSCC patients who did not develop recurrence (n=19) using a volcano plot analysis. Cytokine and epithelial-mesenchymal transition marker genes were analyzed using quantitative PCR. Tumor-infiltrating lymphocytes, immune checkpoint molecules, and human papilloma virus status were investigated using immunohistochemistry (IHC). RESULTS: Twenty-seven evaluable patients with HNSCCs received radiation therapy after surgery. Recurrence was identified in 8 patients. TP53 mutations tended to be higher in patients who developed recurrence than in those who did not develop recurrence (75% vs. 31.6%). Gene expression profiling showed the down-regulation of T cell activation genes (ICOS, CD69 and CD83) and the upregulation of the ERBB4, EGFR, VEGF, HIF1A, TGFB1, TWIST1, IL-8, and PAX7 genes, which suggested the activation of the TP53 mutation-TGF-ß1-PAX7 pathway and epithelial-mesenchymal transition. Additionally, IHC indicated a tendency toward a reduction in T cell accumulation and an increase in M2-type macrophage infiltration in tumors that recurred. CONCLUSION: A TP53 mutation-mediated immune-suppressive state in the tumor microenvironment and TGF-ß1-PAX7-mediated EMT might contribute to the promotion of recurrence in patients with HNSCC after postoperative radiotherapy.

Incurable locoregional disease is a strong poor prognostic factor in recurrent or metastatic squamous cell carcinoma of the head and neck.

BACKGROUND: Distant metastasis is a poor prognostic factor in recurrent/metastatic squamous cell carcinoma of the head and neck. However, limited information on the prognostic impact of locoregional disease is available, despite its life-threatening features. We investigated the prognostic impact of incurable locoregional disease and distant metastasis in recurrent/metastatic squamous cell carcinoma of the head and neck. METHODS: We retrospectively analyzed 156 patients with recurrent/metastatic squamous cell carcinoma of the head and neck who received palliative chemotherapy between August 2006 and December 2019. RESULTS: The median follow-up time for all censored patients was 12.1 (range 1.9-63.5) months. The median overall survival was 12.4 (95% confidence interval 10.1-15.1) months. Incurable locoregional disease (hazard ratio: 2.31, P = 0.007), liver metastasis (hazard ratio: 2.84, P = 0.006), disease-free interval > 13 months (hazard ratio: 0.51, P = 0.041), cetuximab use (hazard ratio: 0.59, P = 0.007), and immune checkpoint inhibitor use (hazard ratio: 0.56, P = 0.006) were associated with prognosis. The number of distant metastatic sites was not associated with overall survival (1-2: hazard ratio: 0.60, P = 0.16; 3-4: hazard ratio: 1.34, P = 0.50). Patients with incurable locoregional disease had more life-threatening events than those with curable locoregional disease. CONCLUSION: The presence of incurable locoregional disease had a significant prognostic impact, whereas the number of distant metastatic sites had no prognostic impact. Liver metastasis was a poor prognostic factor for recurrent/metastatic squamous cell carcinoma of the head and neck.

Triplet induction chemotherapy followed by less invasive surgery without reconstruction for human papillomavirus-associated oropharyngeal cancers: Why is it successful or unsuccessful?

BACKGROUND: De-escalating treatments have been focused on for HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). We assessed the efficacy of a triplet induction chemotherapy (ICT) followed by surgery with or without neck dissection (ND) for locally advanced OPSCC, aiming at less invasive surgery without free-flap reconstruction and avoiding postoperative irradiation. METHODS: This was a retrospective study of 41 patients with advanced resectable HPV-positive OPSCC who underwent ICT followed by surgery of primary resection with or without ND. Patients underwent triplet ICT, including docetaxel, cisplatin, and 5-fluorouracil, or carboplatin, paclitaxel, and cetuximab. RESULTS: Twenty-nine patients had tonsillar cancer, 15 patients were current smokers, and 18 and 12 patients had T2N1M0 and T1N1M0 status (UICC 8th), respectively. After ICT, a surgical procedure without free-flap reconstruction and tracheostomy was possible in 90.2%. Pathological complete response at both the primary site and lymph nodes was achieved in 73.2%. Of the patients who underwent surgery, no adjuvant radiotherapy was required in 85.0%. Two patients (4.9%) experienced recurrence at regional lymph nodes, but were cured by salvage ND followed by adjuvant radiotherapy. CONCLUSIONS: Upfront ICT using highly responsive triplet chemotherapeutic regimens may enable us to perform less invasive surgery without free-flap reconstruction and to avoid postoperative irradiation to the locoregional field through excellent postoperative pathological features.

Molecular profile of a pleomorphic adenoma of the hard palate: A case report.

RATIONALE: Pleomorphic adenoma (PA) is the most common benign tumor of salivary glands. PAs have the potential for regional and distant metastases that preserve their benign phenotype; they also have the potential for malignant transformation. The molecular pathogenesis of malignant neoplasms has been studied extensively in recent years, unlike that of benign tumors, such as PA. PATIENT CONCERNS: In this case report, we identified the molecular signatures of a 57-year-old Japanese woman. Our patient presented with a swelling of the hard palate with an erosive appearance. DIAGNOSES: The patient was diagnosed with a right hard palate tumor suspected to be a malignant neoplasm. INTERVENTIONS: Partial maxillary resection and reconstruction were performed. OUTCOMES: There was no obstacle to swallowing or dysarthria after surgery. There was no sign of recurrent palatal tumor 4 years after the operation. Using next generation sequencing, 5 nonsynonymous mutations and CHCHD7-PLAG1 fusion genes were detected. Moreover, gene expression profiling indicated the possibility of the activation of several cancer-related signaling pathways. Although the PLAG1 gene is predicted to play a crucial role in PA tumorigenesis, its over-expression is reported to mediate multiple downstream factors. In this case, various up- and downregulated RNA signaling pathways, including MAP kinase signaling, PI3K/AKT1/MTOR signaling, JAK/STAT signaling, and PD-L1 signaling, were revealed. LESSONS: These molecular profiles of PA may elucidate the mechanism of metastasis, preserving its benign phenotype and carcinoma ex PA.

Acantholytic Squamous Cell Carcinoma and Salivary Duct Carcinoma Ex-pleomorphic Adenoma of the Submandibular Gland: A Report of Two Extremely Rare Cases with an Immunohistochemical Analysis.

Carcinoma ex pleomorphic adenoma (CXPA) is a malignant tumor of the salivary gland that arises from pleomorphic adenoma (PA). Squamous cell carcinoma (SCC) is extremely rare in the salivary glands. We report two cases of acantholytic SCC (ASCC) ex PA. Case 1 involved a 72-year-old female, and case 2 involved a 67-year-old male. Histologically, both cases involved PA, and salivary duct carcinoma (SDC) components, which were positive for androgen receptor (AR) and gross cystic disease fluid protein (GCDFP)-15 but negative for HER2, were seen in the intracapsular regions. The invasive components consisted of ASCC, which were positive for cytokeratin 5/6 and p63 but negative for AR and GCDFP-15. The SDC and ASCC components were positive for the epidermal growth factor receptor. In both cases, the cytoplasmic localization or decreased expression of E-cadherin was observed in the ASCC. In the early phase, CXPA might emerge as SDC, and it might change into SCC as it invades beyond the capsule due to changes in microenvironment. Also, the aberrant expression of E-cadherin is related to acantholysis in SCC.

Concomitant expression of ezrin and HER2 predicts distant metastasis and poor prognosis of patients with salivary gland carcinomas.

Salivary gland carcinomas (SGCs) exhibit heterogeneous biological behaviors, including the formation of distant metastases, which is a critical event associated with poor prognosis. Ezrin, which is a member of the ezrin-radixin-moesin family of plasma membrane-cytoskeleton linker proteins, may provide a marker for metastasis and poor survival of patients with cancer. The aim of the present study was to investigate the relationship between ezrin expression and the expression of HER2, p53, and Ki-67 as well as clinicopathological factors in SGCs. For this purpose, we used immunohistochemistry to analyze the expression of these proteins in tissue microarrays prepared from formalin-fixed, paraffin-embedded primary tumor tissues of 221 patients with SGCs. Using receiver operating characteristic curves, we determined cut-off values of 30% and 5.0% for high expression of ezrin and Ki-67, respectively. High ezrin expression detected in samples from 63 (28.5%) patients with SGCs significantly correlated with male sex, high-grade histopathology, high Ki-67 labeling index, HER2 overexpression, aberrant expression of p53, and distant metastasis. Multivariate analysis demonstrated that high ezrin expression was an independent prognostic factor for shorter overall survival (hazard ratio, 2.11 [1.09-4.05]; P=.027). Furthermore, concomitant high expression of ezrin and HER2 overexpression correlated significantly with shorter disease-free survival and overall survival as well as a high incidence of distant metastasis (P<.001). These findings indicate that ezrin and HER2 expression in patients with SGCs represents a high-grade histopathological subtype that requires adjuvant therapy, including molecularly targeted therapies, to decrease the risk of subsequent metastasis.