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Objective: To determine the tumor genomic, immunologic expression, and risk factors of treatment outcomes for patients with double head and neck squamous cell carcinoma (HNSCC) and esophageal squamous cell carcinoma (ESCC)., Methods: We reviewed patients with double HNSCC and ESCC between 1995 and 2014. The TP53 genomic mutation, CD8+ tumor infiltrating lymphocytes (TIL) and tumor programmed cell death ligand 1 (PD-L1) expression of paired HNSCC and ESCC were analyzed., Results: A total of 116 patients (57 metachronous and 59 synchronous) were included. There were 88 (75.86%) patients with HNSCC and 80 (68.97%) with ESCC harboured TP53 disruptive mutation. Nearly 106 (91.38%) patients had different clonality of TP53 mutation in paired HNSCC and ESCC. The immunologic expression of synchronous and metachronous patients was significantly different. Compared to the metachronous patients, the synchronous patients had significantly higher HNSCC CD8+ TIL (p = 0.03), ESCC CD8+ TIL (p < 0.001), HNSCC PD-L1+ tumor proportion score (TPS, p = 0.04), and ESCC PD-L1+ TPS (p = 0.04). Furthermore, among the synchronous patients, the immunologic expression between HNSCC and ESCC was significantly correlated. The CD8+ TIL and PD-L1 TPS had strongly (r = 0.63, p < 0.0001) and moderately (r = 0.42, p = 0.001) positive correlations, respectively. Finally, advanced stage (III/IV) HNSCC was a significant factor for disease-free (p = 0.03) and overall survival (p = 0.005)., Conclusion: In patients with double HNSCC and ESCC, nearly all HNSCC and ESCC were of multicentric origin. For the synchronous patients, there was more adaptive immune resistance in HNSCC and ESCC. The immunologic expression between paired HNSCC and ESCC was also significantly correlated., (Copyright © 2020. Published by Elsevier Ltd.)

The immunological, and especially T cell, status of the tumor microenvironment affects tumor development and the efficacy of cancer treatment. To devise suitable combination therapies based on the results of murine tumor models, a more realistic orthotopic model is required. In this study, we generated a murine model of tongue squamous cell carcinoma (SCC), in which the tumor-immune cell interactions were recapitulated, and examined tumor- and T-cell status compared to a skin-transplanted SCC model by multiplex immunofluorescence staining for epidermal growth factor receptor, CD31, CD8, CD4, and Foxp3. Administration of SCCVII cells did not induce undesirable tissue damage or inflammation. In tongue SCC, abundant T-cell infiltration was observed at the tumor margin, but not in the core. Tongue SCC predominantly showed CD8 + T or Foxp3 + regulatory T cell (Treg)-infiltration. In contrast, skin-transplanted SCC showed abundant infiltration of T cells in the whole tumor area, which was dominated by Tregs. An orthotopic tongue SCC model showed differences in tumor and T-cell status compared to the skin-transplanted SCC model. Our tongue SCC model may enhance understanding of tumor-host interactions and enable evaluation of therapeutic efficacy., Competing Interests: Declaration of competing interest The authors declare that no conflict of interest exists., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Oral squamous cell carcinoma (OSCC) is the most common malignant cancer, with high mortality rates in advanced stages. Recent studies have shown that the expression of ALPK1 mRNA and its inhibitory differentiation function are associated with cancer progression. However, the expression and clinicopathologic features of ALPK1 in OSCC remain unexplored. Herein, the authors investigated the expression patterns of ALPK1 in 39 matched OSCC patients and examined the relationship between ALPK1 protein expression and clinicopathologic factors using immunohistochemical scores. Using Western blot analysis, ALPK1 expression was found to be significantly higher in tumor tissues than that in nontumor tissues. Through an immunoreactive scoring system, a significantly higher number of advanced-stage tumor size T4 and lymph node metastasis N2 exhibited higher ALPK1 expression levels than that exhibited by T1/T2/T3 tumors and N0/N1. In addition, ALPK1 protein expression was aberrant in malignant oral cancer cell lines compared with that in pre-malignant oral epithelial cells, whereas minimal expression was observed in normal oral epithelial cells. Knockdown of ALPK1 resulted in a significant reduction in cell growth, migration, and invasion capacity in vitro. Consequently, expression of N-cadherin and vimentin decreased in ALPK1-deficient cells. Thus, these results suggest that ALPK1 serves as a potential biomarker and target for OSCC development in late stages., (Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Objective: The objective of this study was to clarify the prognostic significance of tumor-infiltrating lymphocytes (TILs) in oral squamous cell carcinoma (OSCC); the present study analyzed various TIL-related parameters., Study Design: Immunohistochemistry was performed in 87 patients with OSCC for the following TIL-related parameters: nest-CD8(+) T cells, stromal CD8(+) T cells, CD4(+) T cells, total regulatory T cells (Tregs), CCR4(+) Tregs, ratio of nest CD8(+) T cells/CCR4(+) Tregs, and ratio of stromal CD8(+) T cells/CCR4(+) Tregs., Results: In univariate analyses, the following parameters were associated with decreased survival: few nest- and stromal CD8(+) T cells and more stromal CCR4(+) Tregs, but not total Tregs. Low ratios of nest and stromal CD8(+) T cell/CCR4(+) Treg were associated with worse survival. In multivariate analysis, the stromal CD8(+) T cell/CCR4(+) Treg ratio was an independent prognostic factor., Conclusion: Host immune responses in the stroma of OSCC affect the survival of the patients. The in situ balance between effector T cells and regulatory T cells is the most important factor predicting survival., (Copyright (c) 2010 Mosby, Inc. All rights reserved.)

Antitumor immunity plays an important role in the development of and protection against malignancy. In general, patients with cancer are known to be immunologically compromised. The objective of this study was to evaluate local immunity in squamous cell carcinomas (SCCs) of the tongue and lower lip by immunohistochemistry, using anti-CD3, -CD4, -CD8, -CD25 and -zeta antibodies. Immunoexpression at the invasive front was compared considering anatomical tumor location and metastasis. The CD4/CD8 ratio was calculated for each case and associated with the variables. CD3+, CD4+, CD8+ and CD25+ cell counts were higher in SCCs of the lower lip and anti-zeta immunostaining was more evident in non-metastatic cases. CD8+ and CD25+ cell counts were also significantly correlated with tumor location (p=0.004 and p=0.004, respectively), with the observation of a larger number of these cells in SCCs of the lower lip. The CD4/CD8 ratio showed no significant association with metastasis or anatomical location. In conclusion, the clinical behavior of the oral SCC cases studied might be partially related to the immunohistochemical profile of the inflammatory infiltrate present at the invasive front., (Copyright 2009 Elsevier Inc. All rights reserved.)

Objective: Ectomesenchymal chondromyxoid tumor is a rare oral soft tissue neoplasm that should be differentiated from other neural and chondromyxoid entities. The aim of this study was to report the clinical, histological, and immunohistochemical features of 3 additional cases of this condition., Methods: Clinical data were obtained from the clinical records and all cases were evaluated through light microscopy and immunohistochemistry to cytokeratins, vimentin, S100 protein, desmin, smooth muscle actin, and glial fibrilary acidic protein., Results: All 3 cases affected the tongue as a long-lasting submucosal swelling and were managed through conservative surgery. They all showed myxoid and chondroid histological patterns, and vimentin, S100, and glial fibrilary acidic protein immunoexpression., Conclusions: These findings reinforce the typical features of ectomesenchymal chondromyxoid tumor previously described, helping to confirm and establish the clinical, histopathological, and immunohistochemical profile of this uncommon lesion.

Eosinophils are present in large numbers in some squamous cell carcinomas of the oral cavity. Whilst it is proposed that they have an 'immuno-protective' effect, this remains unproven. The contradictory reports may be due to inconsistencies in eosinophil counting. Eighty-one cases of squamous cell carcinoma (SSC) of oral tongue were examined. Two methods of eosinophil counting were performed. In the first method (classical), the eosinophils were counted per 10 HPF. In the second method (our so-called density method), the highest eosinophil density per surface area was counted for each case. The two methods were correlated. Using the classical method a number of fields in cases ranked low, contained more than 10 eosinophils. Likewise, some moderate cases contained more than 100 eosinophils. There is poor correlation between the classical and density counts. Nevertheless, good correlation between the two methods could be achieved if the boundaries of the classical method are modified. Eosinophils invariably appear in clusters. We feel that an assessment of density may well be better than classical counting, and have more relationship with function.

Squamous cell carcinoma of the oral cavity (SCC) accounts for 3% of cancers in the western world and 40% of cancers in India. The overall 5-year survival rate is only 50%. Most of the lesions appear intra-orally on the tongue. Results from a previous study demonstrated a significant increase in T and B-lymphocytes under the transformed epithelium when examining human lesions of hyperkeratosis, dysplasia and carcinoma of the tongue. In order to investigate the interaction between the host immunity and SCC, carcinogen induced SCC of the tongue was studied in mice. The water-soluble carcinogen, 4 nitroquinoline N-oxide (4NQO), was applied to BALB/c mice tongues and produced tongue SCC after a long incubation period of several months. Immunologic properties were examined systemically in the spleens and locally, at the tumor site. Examination of spleen lymphocytes from 4NQO induced mice revealed enlargement of the spleens and a significant decrease in the CD3, CD4, CD8 and CD19 cells. In the tongues, expression of TGF-beta, TNF-alpha, GM-CSF, and IL-1 beta mRNA were detected. TNF-alpha protein was detected in the affected tongues using immunoassays. mRNA expression of TNF-alpha was detected in the cancerous epithelium when extracted from the connective tissue. CD11b and CD3 cells were detected in the connective tissue under the developing carcinoma. CD11b positive cells were more prominent. The infiltrate was very scattered and not prominent as the infiltrate in the human tongue tissues. These results indicate that the growing tumor affected the immune response around the tumor and systemically. Most of the cytokines, which appeared in the affected tongues, originated from the tumor surroundings, but TNF-alpha was found also in the tumor. The interaction between the tumor and immune response components is important for diagnosis and treatment purposes.

A rare case of oral adenosquamous carcinoma in a 78-year-old woman is reported. The tumor occurred in her tongue and metastasized to the submandibular and cervical lymph nodes. Histologically, the tumor showed invasive growth involving the submucosal and muscle layers. Its solid carcinomatous nests exhibited ductal differentiation in the deeper aspects and squamous differentiation toward the surface. Histochemical examination revealed an accumulation of acid mucopolysaccharide in the ductal lumina, and the ductal cells were immunohistochemically positive for carcinoembryonic antigen, epithelial membrane antigen, cancer antigen 15-3 and Ulex europaeus agglutinin I. Ultrastructurally, tonofibrils, desmosomes and numerous cytoplasmic processes were common features of the tumor cells. In addition, true glandular structures and pseudocysts were seen in areas. Clinical features of 13 adenosquamous carcinomas in the literature were analyzed.

An outbreak of a new form of oral leucoplakia, found principally on the lateral borders of the tongue, is reported in male homosexuals in the San Francisco area. Many of the patients showed evidence of immunosuppression, and candida was often found in the lesions. The characteristic histology is similar to that of the flat wart of skin. There was immunocytochemical evidence of papillomavirus core antigen in 77% of 30 biopsy specimens, but no papillomaviruses were detected by electron microscopy in samples from 6 randomly selected patients. In 5 of these 6 patients there was evidence of a herpes-type virus. Pneumocystis carinii pneumonia has developed in 8 of 37 patients in a 33-month period. This leucoplakia may presage AIDS, may be associated with both papillomavirus and a herpes-type virus, and may offer clues to the pathogenesis of other forms of oral epithelial hyperplasia and dysplasia.

An optimal technique was sought for lymphocyte recovery from normal and chronic diseased individuals. Lymphocytes were separated by four techniques: Plasmagel, Ficoll--Hypaque, a commercial semiautomatic method, and simple centrifugation using blood drawn from ten normal individuals, ten cancer patients, and ten tuberculosis patients. The lymphocyte mixture obtained after using each method was analyzed for percent recovery, amount if contamination by erythrocytes and neutrophils, and percent viability. The results show that the semiautomatic method yielded the best percent recovery of lymphocytes for normal individuals, while the simple centrifugation method contributed the highest percent recovery for cancer and tuberculosis patients. The Ficoll-Hypaque method gave the lowest erythrocyte contamination for all three types of individuals tested, while the Plasmagel method gave the lowest neutrophil contamination for all three types of individuals. The simple centrifugation method yielded all viable lymphocytes and thus gave the highest percent viability.