Prognostic Markers and Driver Genes and Options for Targeted Therapy in Human-Papillomavirus-Positive Tonsillar and Base-of-Tongue Squamous Cell Carcinoma.

The incidence of Human-papillomavirus-positive (HPV+) tonsillar and base-of-tongue squamous cell carcinoma (TSCC and BOTSCC, respectively) is increasing epidemically, but they have better prognosis than equivalent HPV-negative (HPV-) cancers, with roughly 80% vs. 50% 3-year disease-free survival, respectively. The majority of HPV+ TSCC and BOTSCC patients therefore most likely do not require the intensified chemoradiotherapy given today to head and neck cancer patients and would with de-escalated therapy avoid several severe side effects. Moreover, for those with poor prognosis, survival has not improved, so better-tailored alternatives are urgently needed. In line with refined personalized medicine, recent studies have focused on identifying predictive markers and driver cancer genes useful for better stratifying patient treatment as well as for targeted therapy. This review presents some of these endeavors and briefly describes some recent experimental progress and some clinical trials with targeted therapy.

Hypoglycemia associated with disseminated metastatic tonsillar squamous cell carcinoma producing insulin-like growth factor-I in a Pomeranian dog.

A 13-year-old spayed female Pomeranian dog was presented for persistent, severe hypoglycemia (37 mg/dL; reference interval [RI] 75-128 mg/dL). Progressive nonregenerative anemia (hematocrit 23.3%-15.9%; RI 37.0%-55.0%) and severe thrombocytopenia (36 000/µL; RI 200-500 000/µL) were also noted. The serum insulin concentration was low (0.24 ng/mL; RI 0.302-1.277 ng/mL). Computed tomography revealed multiple splenic nodules (1-6 mm in diameter) and several hepatic nodules (7.6, 12 mm in diameter). Ultrasound-guided fine-needle aspiration of the splenic and hepatic nodules revealed low numbers of epithelial cells with mild cellular atypia, suggestive of a metastatic epithelial tumor, but the primary site was unknown at that time. On careful oral examination under general anesthesia, an enlarged right tonsil was noted grossly, and histopathologic examination of the tonsil diagnosed squamous cell carcinoma. Bone marrow aspirates and biopsies of the splenic and hepatic nodules were performed; all samples were diagnosed as metastatic carcinoma on histopathologic examination. No nodules were present in the pancreas, despite careful palpation during exploratory laparotomy. On immunohistochemistry, the neoplastic cells were positive for cytokeratin AE1/3 and insulin-like growth factor (IGF)-I but were negative for chromogranin A, PGP9.5, insulin, and inconclusive for IGF-II. This is the first report of a primary IGF-I-producing squamous cell carcinoma in the tonsil of a dog with metastases to bone marrow, liver, and spleen, resulting in hypoglycemia.

Cerebellar Hypermetabolism in a Case of Paraneoplastic Cerebellar Syndrome With the Primary Lymphoepithelial Carcinoma in Tonsil.

A 70-year-old man with cerebellar syndromes was clinically diagnosed as paraneoplastic cerebellar degeneration and underwent whole-body F-FDG PET/CT imaging for screening primary tumor. Intensely elevated tracer uptake in both cerebellar hemispheres was revealed, whereas no abnormality was found in MRI. Increased tracer uptake and swelling of the left tonsil and a cervical lymph node were found at the same time, suggesting neoplasm in tonsil with lymph node metastasis. Pathological examination demonstrated lymphoepithelial carcinoma of the left tonsil.

Extranodal involvement of diffuse large B-cell lymphoma in the head and neck: An indicator of good prognosis.

OBJECTIVE: In this study, we analyzed clinicopathological characteristics and survival outcomes according to extranodal involvement of diffuse large B-cell lymphoma (DLBCL) in the head and neck. METHODS: A retrospective analysis was conducted on 110 patients from 2004 to 2014 with CD20-positive DLBCL involving the head and neck area. Patients were categorized into two groups, extranodal and nodal, according to involvement of extranodal sites in the head and neck. Outcome measurements for the groups included clinical response to treatment and recurrence rates. RESULTS: Palatine tonsils were the most frequently involved extranodal site in the head and neck (29.1%). Among clinicopathological parameters, proportion of patients with lactate dehydrogenase over 350 IU/L (p=0.033), cell of origin (p<0.001), and treatment outcomes (p=0.007) were significantly different between the two groups. Among cell origin markers CD10, Bcl6, and MUM1, MUM1 was significantly correlated with extranodal involvement (p=0.029). Recurrence rates were similar between groups, while disease-specific survival was significantly higher in the extranodal group (p=0.011). Disease-specific survival of the extranodal group was also higher than the nodal group with extranodal involvement of other body sites (p=0.010). Among patients with negative expression of CD10 (p=0.015), Bcl6 (p=0.018), and MUM1 (p=0.005), survival was longer in the extranodal than the nodal group. CONCLUSIONS: DLBCL patients with extranodal involvement of the head and neck may have longer survival outcomes than patients with solely nodal involvement. Increased survival may be more prominent in patients with negative expression of CD10, Bcl6, and MUM1.

Characteristic Histological Findings of Asymptomatic EBV-associated Lymphoproliferative Disorders in Tonsils.

Recently, an in situ hybridization (ISH) and immunohistochemical study demonstrated that Epstein-Barr virus (EBV) infection may be involved in tonsillar hypertrophy and recurrent tonsillitis in children and young adolescents. The present study was based on 630 consecutive specimens from tonsillectomies performed at the Dokkyo University School of Medicine between 2002 and May 2017. Clinical findings were obtained from hospital records. Histologically, a "pale clear zone" was characterized by hyperplastic germinal centers with ill-defined borders and interfollicular expansion. Immunohistologically, the majority of immunoblasts were CD20-positive, whereas medium to large lymphoid cells usually expressed CD3. Among 14 lesions, numerous EBV-encoded small RNA (EBER)-positive cells were detected in 10. In 7 of these 10 lesions, EBER-positive cells were detected in germinal centers as well as in the interfollicular area. Based on our results, the "pale clear zone" suggests asymptomatic EBV infection of the tonsil. The present study demonstrated that "pale clear zones" should be taken into consideration when diagnosing asymptomatic EBV-associated LPDs in the tonsils of children and young adolescents as well as in middle-aged patients.

Treponema denticola chymotrypsin-like proteinase may contribute to orodigestive carcinogenesis through immunomodulation.

BACKGROUND: Periodontal pathogens have been linked to oral and gastrointestinal (orodigestive) carcinogenesis. However, the exact mechanisms remain unknown. Treponema denticola (Td) is associated with severe periodontitis, a chronic inflammatory disease leading to tooth loss. The anaerobic spirochete Td is an invasive bacteria due to its major virulence factor chymotrypsin-like proteinase. Here we aimed to investigate the presence of Td chymotrypsin-like proteinase (Td-CTLP) in major orodigestive tumours and to elucidate potential mechanisms for Td to contribute to carcinogenesis. METHODS: The presence of Td-CTLP within orodigestive tumour tissues was examined using immunohistochemistry. Oral, tonsillar, and oesophageal squamous cell carcinomas, alongside gastric, pancreatic, and colon adenocarcinomas were stained with a Td-CTLP-specific antibody. Gingival tissue from periodontitis patients served as positive controls. SDS-PAGE and immunoblot were used to analyse the immumodulatory activity of Td-CTLP in vitro. RESULTS: Td-CTLP was present in majority of orodigestive tumour samples. Td-CTLP was found to convert pro MMP-8 and -9 into their active forms. In addition, Td-CTLP was able to degrade the proteinase inhibitors TIMP-1, TIMP-2, and α-1-antichymotrypsin, as well as complement C1q. CONCLUSIONS: Because of its presence within tumours and regulatory activity on proteins critical for the regulation of tumour microenvironment and inflammation, the Td-CTLP may contribute to orodigestive carcinogenesis.

Cytokeratin7 expression in histologic and cytologic specimens of cystic neck metastasis from HPV positive squamous cell carcinoma of the tonsil: A case report.

The majority of cystic squamous cell carcinomas (SCCs) of the neck have been shown to be metastatic tumors from tonsillar SCCs associated with high-risk human papillomavirus (HR HPV). Recent studies have demonstrated cytokeratin (CK)7 involvement in the development of HPV positive SCC, but no report has been issued on its simultaneous expression in primary tonsillar and metastatic tumor with cystic change. We present a case of HPV positive tonsillar SCC of a 42-year-old male that initially manifested as a cystic neck mass expressing CK7, CK19, and p16 in primary and metastatic tumors. Immunohistochemical examination revealed diffuse CK19 and p16 expression, and patchy CK7 expression in the solid components of primary and metastatic tumors. However, in cystic components of metastatic tumors the expression of CK7 and CK19 was preserved but p16 expression was absent, which was consistent with immunocytochemical findings of fine-needle aspirates from cystic neck mass. In immunocytochemistry performed on aspirates of a branchial cleft cyst for the comparison of cystic SCC and benign cyst, CK19 staining was positive but CK7 and p16 staining was negative. These results suggest that CK7 immunocytochemistry on aspirated material from cystic neck mass may be a useful adjunct for distinguishing cystic metastasis of tonsillar SCC from branchial cleft cyst, although a larger scale study would be required.

Human Papillomavirus and Potentially Relevant Biomarkers in Tonsillar and Base of Tongue Squamous Cell Carcinoma.

Human papillomavirus (HPV)-positive tonsillar- and base of tongue cancer is increasing epidemically and has much better outcome than corresponding HPV-negative cancer and most other head and neck cancers with around 80% 3-year disease free survival with conventional radiotherapy and surgery. Consequently, most HPV-positive cancer patients may not require the intensified chemoradiotherapy given to many head and neck cancer patients and would, with tapered treatment, avoid several severe side-effects. Moreover, intensified therapy has not improved survival and treatment alternatives are needed. To identify patients eligible for tapered or targeted therapy, additional biomarkers are required. Several studies have, therefore, focused on finding predictive markers, some of which are also potentially targetable. To conclude, better-tailored therapy, either as tapered or targeted, is important for increasing numbers of patients with HPV-positive tonsillar- and base of tongue cancer. This review deals with some of these issues and presents some promising markers.

Comparison of the miRNA expression profiles in fresh frozen and formalin-fixed paraffin-embedded tonsillar tumors.

MicroRNAs are considered as promising prognostic and diagnostic biomarkers of human cancer since their profiles differ between tumor types. Most of the tumor profiling studies were performed on rarely available fresh frozen (FF) samples. Alternatively, archived formalin-fixed paraffin-embedded (FFPE) tissue samples are also well applicable to larger-scale retrospective miRNA profiling studies. The aim of this study was to perform systematic comparison of the miRNA expression profiles between FF and macrodissected FFPE tonsillar tumors using the TaqMan Low Density Array system, with the data processed by different software programs and two types of normalization methods. We observed a marked correlation between the miRNA expression profiles of paired FF and FFPE samples; however, only 27-38% of the differentially deregulated miRNAs overlapped between the two source systems. The comparison of the results with regard to the distinct modes of data normalization revealed an overlap in 58-67% of differentially expressed miRNAs, with no influence of the choice of software platform. Our study highlights the fact that for an accurate comparison of the miRNA expression profiles from published studies, it is important to use the same type of clinical material and to test and select the best-performing normalization method for data analysis.

IFR4/MUM1-positive lymphoma in Waldeyer ring with co-expression of CD5 and CD10.

IRF4/MUM1-positive lymphoma is a new subgroup of germinal center-derived B-cell lymphoma, predominantly involving the Waldeyer ring (WR) in children. CD5 expression is rare in these lymphomas. We report a 7-year-old Chinese male with B-cell lymphoma. Evaluation of his specimen by morphology, immunohistochemistry, and FISH analysis demonstrated IRF4/MUM1-positive lymphoma with strong and extensive CD5 and CD10 positivity. Despite the lack of t(14;18)(q32;q21) rearrangement, BCL2 protein was expressed. Our report highlights the clinicopathologic features of IFR4/MUM1-positive lymphoma in WR with co-expression of CD5 and CD10, and thereby provides insight into this newly recognized disease entity.

PD-L1 expression in tonsillar cancer is associated with human papillomavirus positivity and improved survival: implications for anti-PD1 clinical trials.

In this study, we examined PD-L1 expression by immunohistochemistry in 99 patients with tonsillar cancer and known human papillomavirus (HPV) status to assess its clinical significance. We showed that the pattern of PD-L1 expression is strongly related to HPV status. The PD-L1 positivity rate was 83.3% in HPV-positive cases and 56.9% in HPV-negative cases (p < 0.05). Patients with HPV-positive/PD-L1-positive cancer had significantly better event free survival and overall survival compared with patients with HPV-negative/PD-L1-negative cancer. Relative to those patients with HPV-negative/PD-L1-negative disease who had the highest risk of death, patients with HPV-positive/PD-L1-positive cancers had a 2.85 fold lower risk of developing an event (HR 0.35, 95% CI: 0.16-0.79) and a 4.5 fold lower risk of death (HR =0.22, 95% CI: 0.09-0.53). Our findings will help to guide future clinical trial design in immunotherapy based on PD-L1 expression in tonsillar cancer.

Epigenetic regulation of OAS2 shows disease-specific DNA methylation profiles at individual CpG sites.

Epigenetic modifications are essential regulators of biological processes. Decreased DNA methylation of OAS2 (2'-5'-Oligoadenylate Synthetase 2), encoding an antiviral protein, has been seen in psoriasis. To provide further insight into the epigenetic regulation of OAS2, we performed pyrosequencing to detect OAS2 DNA methylation status at 11 promoter and first exon located CpG sites in psoriasis (n = 12) and two common subtypes of squamous cell carcinoma (SCC) of the head and neck: tongue (n = 12) and tonsillar (n = 11). Compared to corresponding controls, a general hypomethylation was seen in psoriasis. In tongue and tonsillar SCC, hypomethylation was found at only two CpG sites, the same two sites that were least demethylated in psoriasis. Despite differences in the specific residues targeted for methylation/demethylation, OAS2 expression was upregulated in all conditions and correlations between methylation and expression were seen in psoriasis and tongue SCC. Distinctive methylation status at four successively located CpG sites within a genomic area of 63 bp reveals a delicately integrated epigenetic program and indicates that detailed analysis of individual CpGs provides additional information into the mechanisms of epigenetic regulation in specific disease states. Methylation analyses as clinical biomarkers need to be tailored according to disease-specific sites.

Double positivity for HPV DNA/p16 in tonsillar and base of tongue cancer improves prognostication: Insights from a large population-based study.

The aim was to explore the overall survival (OS) for palatine tonsillar squamous cell carcinoma (TSCC), subdivided, according to certainty of tonsillar tumour origin, into specified tonsillar squamous cell carcinomas (STSCCs) and nonspecified tonsillar squamous cell carcinomas (NSTSCCs), and base of tongue squamous cell carcinoma (BSCC) when stratifying for HPV DNA status, p16 expression and combined HPV/p16 status. We included all patients (n = 797) diagnosed with TSCCs and BSCCs in Eastern Denmark as registered in the Danish Head and Neck Cancer Group (DAHANCA) database and the Danish Pathology Databank, 2000-2010. Patients were treated according to national guidelines (radiotherapy +/- concomitant cisplatin). All specimens were analysed using HPV DNA PCR and p16 immunohistochemistry. Clinical information was retrieved from the DAHANCA database and the Danish National Patient Registry. Information on vital status was obtained from the Danish Civil Registration System. We observed improved OS for HPV+/p16+ BSCCs compared to HPV-/p16- (hazard ratio for death [HR], 0.15; 95% CI, 0.09-0.24). Among STSCCs, HPV+/p16+ showed the lowest HR (0.19, 95% CI, 0.13-0.29); whereas, HPV-/p16+ showed an intermediate HR (0.39; 95% CI, 0.22-0.70). For NSTSCCs, HPV+/p16+ and HPV-/p16+ showed similar OS (HRs, 0.39; 95% CI, 0.26-0.59; and 0.48; 95% CI, 0.24-0.95, respectively). Combined HPV+/p16+ was a significantly better prognostic marker in BSCCs and STSCCs than HPV DNA and p16, alone (all p-values < 0.05). Whereas, combined testing in NSTSCC was not better than p16 (p = 0.53), alone. In conclusion, double positivity for HPV/p16 in conjunction with the certainty of tumour site improved prognosis.

Small Cell Lung Cancer Accompanied by Tonsillar Metastasis and Anti-Hu Antibody-Associated Paraneoplastic Neuropathy: A Rare Case Report With Long-Term Survival.

Tonsillar metastatic small cell lung cancer (SCLC) is rare, while anti-Hu antibodies are frequently found in SCLC. A 66-year-old man was admitted to our hospital with painful dysesthesia and muscle weakness in the distal extremities for over 1 year, progressive dysphagia for over 1 month, and severe cough and dyspnea for over 1 week. He was diagnosed with SCLC accompanied by tonsillar metastasis and anti-Hu antibody-associated paraneoplastic sensory neuropathy (PSN). The patient tolerated 6 cycles of sequential chemoradiotherapy and gradually recovered. The patient's disease remained in remission 2 years after the diagnosis with a remarkable reduction of tumor burden and a persisting high titer of anti-Hu antibodies. To our knowledge, this is the first case of tonsillar metastatic SCLC accompanied by anti-Hu antibody-associated PSN, whereby the anticancer immune response was presumed to play a vital role in disease control. Unilateral tonsillar metastasis of SCLC accompanied by anti-Hu antibody-associated PSN can occur and in certain circumstances, may have a favorable prognosis.

Composition of inflammatory cells regulating the response to concurrent chemoradiation therapy for HPV (+) tonsil cancer.

BACKGROUND: Human papillomavirus (HPV) (+) tonsil squamous cell carcinoma (TSCC) responds well to concurrent chemoradiation therapy (CCRT) and demonstrates a favorable prognosis. However, cases of HPV (+) TSCC-related death remain unresolved. We evaluated the distribution and prognostic value of inflammatory cells in HPV (+) TSCC. METHODS: We reviewed the medical records of 53 patients who were diagnosed with TSCC. HPV (+) TSCC was confirmed using HPV DNA PCR and immunohistochemical p16 overexpression. The numbers of CD4 (+), CD8 (+), and CD68 (+) stained cells were used to evaluate peritumoral lymphocyte infiltration. Patients were divided into two groups according to the mean numbers of stained cells and the mean ratios of each cell type. RESULTS: HPV (+) was noted in 39 patients. During the follow-up period, 27 patients had no evidence of disease, 2 patients showed disease, and 10 patients died of disease. In this group, advanced T and N stages were not related to overall or disease-specific survival outcomes. The overall survival rate was affected by a high CD68 (+) (HR=19.8; P=0.040) and low CD8/CD4 ratio (HR=7.7, P=0.025). The disease-specific survival rate was affected by a high number of CD68 (+) cells (HR=15.2; P=0.03) and low CD8 (+)/CD4 (+) ratio (HR=3.3; P=0.04). CONCLUSIONS: The number of CD68 (+) cells and the distribution of cytotoxic or immunosuppressive T lymphocytes could be determining factors for CCRT outcomes in HPV (+) TSCC patients.

A model for predicting clinical outcome in patients with human papillomavirus-positive tonsillar and base of tongue cancer.

AIM: To combine clinical and molecular markers into an algorithm for predicting outcome for individual patients with human papillomavirus (HPV) DNA/p16(INK4a) positive tonsillar and base of tongue squamous cell carcinoma (TSCC and BOTSCC). BACKGROUND: Head-neck cancer treatment has become more intensified, comprising not only surgery and radiotherapy, but also induction/concomitant chemotherapy and targeted therapy. With less treatment, 3-year disease free survival (DFS) is 80% for HPV-positive TSCC and BOTSCC. An 85-100% 3-year DFS is observed for HPV(+) TSCC and BOTSCC with absence of HLA class I, or CD44 expression, or high CD8(+) tumour-infiltrating lymphocyte (TIL) counts suggesting that therapy could be tapered for many if patients could be identified individually. PATIENTS AND METHODS: Patients treated curatively, with HPV DNA/p16(INK4a) positive tumours examined for HLA class I and II, CD44 and CD8(+)TILs, were included. An L1-regularised logistic regression was used to evaluate the effect of the biomarker data, age, stage, diagnosis, smoking and treatment on 3-year risk of death or relapse on a training cohort of 197 patients diagnosed 2000-2007 and validated on a cohort of 118 patients diagnosed 2008-2011. RESULTS: The variables finally included in the model were HLA class I, CD8(+) TILs, age, stage and diagnosis (TSCC or BOTSCC). The model showed acceptable discrimination and calibration. The discriminative ability of the model did not diminish after validation (AUC=0.77). CONCLUSION: To our knowledge, this is the first model to utilise information from several markers to predict an individual probability of clinical outcome for patients with HPV DNA/p16(INK4a) positive tumours.

[Clinical features and expressions of p16, p53 protein of human papillomavirus-related tonsillar carcinoma].

OBJECTIVE: To analyze the clinical characteristics, prognosis and molecular biological changes of tonsillar squamous cell carcinoma (TSCC). METHODS: Retrospective analysis of 61 TSCC cases treated from January 1999 to December 2012. Demographic data and clinical charts, including histologic grade of tumor, treatment and outcome of the patients, were reviewed.Human papillomavirus (HPV)-DNA were detected using SPF10-DNA enzyme immunoassay and LiPA genotyping method. Expressions of p16 and p53 proteins were examinated by immunohistochemistry. Survival rate was calculated with SPSS 19.0 software using the Kaplan-Meier method. RESULTS: There were 55 males and 6 females, with a median age of 57 years. Of the 61 TSCC, 21 were with well differentiation, 19 with moderate differentiation and 21 with poor differentiation, including 7 patients at stage II, 10 at stage III and 44 at stage IV. HPV-positive rate of TSCC was 29.5% (18/61) and high-risk HPV-16 subtype accounted for 72.2% (13/18). The percentage of famel patients in HPV-positive TSCC was higher than HPV-negative TSCC (22.2% vs 4.7%).HPV-positive TSCC was more common in non-smoking patients (50.0% vs 79.1%, χ(2) = 5, 155, P = 0.023) and non-drinking patients (27.8% vs 51.2%, χ(2) = 4.346, P = 0.037). HPV-positive TSCC mostly presented with high expression of p16 protein (88.9% vs 16.3%, χ(2) = 28.481, P = 0.000), and low expression of p53 protein (72.7% vs 46.5%, χ(2) = 5.028, P = 0.025). The prognosis of patients with HPV-associated TSCC was significantly better than non-HPV-associated TSCC, and The 3-year and 5-year overall survival rates of patients with HPV-positive TSCC were higher than those of patients with HPV-negative TSCC (87.7% vs 49.5% and 78.9% vs 33.0%, respectively). CONCLUSION: HPV-associated TSCC had unique clinicopathological and molecular biological features, showing better prognosis compared to HPV-negative TSCC.

TNF-α evaluation in tonsil cancer.

Squamous cell tonsil carcinoma is the most frequent form of oropharyngeal cancer, representing 70-80% of the total of head and neck malignant tumors. Poor clinical symptoms make that 60-80% of patients with squamous cell tonsil carcinoma have a late diagnosis, in the third and fourth stages, when the tumor exceeds the organ limits, invading the pharyngeal wall or the tongue base, being associated with metastases in the laterocervical lymphatic ganglions. The tumor necrosis factor alpha (TNF-α) represents an important inflammation mediator associated to carcinogenesis and even to tumor progression. We evaluated the seric values of TNF-α in a group of patients with tonsil cancer in comparison to a group of patients with chronic tonsillitis, as well as the reaction of mastocytes and macrophages in the two types of tonsil lesions. Seric levels of TNF-α in squamous cell tonsil carcinoma were quite high, varying from 1000 to 2000 pg÷mL, and in four patients, with poorly differentiated tonsil carcinoma in the fourth stage, the TNF-α values varied from 2000 to 4000 pg÷mL. In the patients undergoing radiotherapy, the TNF-α seric levels were within normal limits. In chronic tonsillitis, the TNF-α seric level varied from 10 to 200 pg÷mL. There were not observed any significant differences between the two types of tonsil lesions, regarding the macrophages and mast cells density on the surface unit.

Analysis of the intensity of immune cell infiltration and immunoreactivity of RCAS1 in diffuse large B-cell lymphoma of the palatine tonsil and its microenvironment.

Non-Hodgkin lymphoma of Waldeyer's ring constitutes a small percentage of cases of palatine tonsil malignancies and its precise etiology remains unknown. RCAS1 (receptor cancer-binding antigen expressed on SiSo cells) has been demonstrated to be associated with poor prognosis, the development of lymph node metastases and participation in tumor microenvironment remodeling. Our aim is to analyze the potential role of RCAS1 expression in the tumor and tumor microenvironment in the development of early-stage palatine tonsil B-cell lymphomas. We selected 20 patients and analyzed tissue samples from the lymphoma and tumor microenvironment of each patient and from a reference group of 20 patients with chronic tonsillitis. The presence of RCAS1 protein immunoreactivity was demonstrated in 65% of the examined tissue samples of diffuse large B-cell lymphoma and in 25% of the analyzed stromata in which it was exhibited by CD68-positive cells identified as macrophages and dispersed throughout the stroma. RCAS1 immunoreactivity in the lymphoma tissue samples remained at a level comparable with that of the reference and was significantly higher in these samples than in those from the stroma. Chronic inflammation of the palatine tonsils thus results in intensive infiltration by various types of immune system cells and in excessive RCAS1 immunoreactivity, both of which confirm the important regulatory role of RCAS1 in the immune response in the mucosa-associated lymphatic tissue of Waldeyer's ring. RCAS1 seems to be involved in creating tumor-induced inflammation in the tumor and its microenvironment.

Prevalence and prognostic value of human papillomavirus genotypes in tonsillar squamous cell carcinoma: a Korean multicenter study.

BACKGROUND: This study was aimed at investigating the change in the prevalence of human papillomavirus (HPV) genotypes in tonsillar squamous cell carcinoma (TSCC) and the association of the HPV genotype with the prognosis. METHODS: This multicenter study included 175 patients with TSCC from 3 general hospitals between 1991 and 2009. HPV DNA was detected in paraffin-embedded tissues with genotyping chips. A survival analysis that considered clinicopathological factors, the HPV genotype, and the expression of p53, retinoblastoma protein, p16, and epidermal growth factor receptor (assessed with immunohistochemistry) was performed with Cox regression analysis. RESULTS: High-risk HPV types were found in 23.4% of the cases. The prevalence of HPV-18 (10.3%) was as high as that of HPV-16 (10.3%). The proportion of high-risk HPV-positive tumors increased from 5.9% in 1991 to 31.6% in 2009. HPV-16 positivity was associated with an advanced stage and lymph node metastasis, whereas HPV-18 positivity was associated with old age and an advanced T stage. The survival analysis showed that old age and T classification were poor prognostic factors, whereas the expressions of various biomarkers were not associated with prognosis. HPV-18-positive cases had a poorer prognosis than HPV-16-positive cases and non-HPV-related TSCC cases. A multivariate analysis revealed that HPV-18 positivity, old age, and an advanced T stage were independent prognostic factors for predicting poor outcomes for patients with TSCC. CONCLUSIONS: The proportion of HPV-positive tonsillar cancer cases has increased during the last 20 years in the Republic of Korea. The presence of HPV-18 may serve as a biomarker for a poor prognosis.