Heterogeneous nuclear ribonucleoprotein B1 as early cancer biomarker for occult cancer of human lungs and bronchial dysplasia

Heterogeneous nuclear ribonucleoprotein (hnRNP) B1 is a RNA-binding protein of Mr 37,000. We previously reported that hnRNP B1 was specifically overexpressed in the nuclei of human lung cancer cells, particularly in squamous cell carcinoma (E. Sueoka et al., Cancer Res., 59: 1404-1407, 1999). We extended this study to determine whether hnRNP BL was overexpressed in roentgenographically occult cancers of the lungs and premalignant lesions of squamous cell carcinomas, such as bronchial dysplasia. The additional object of our study was to examine the usefulness of hnRNP B1 as a potential diagnostic marker for squamous cell carcinoma of various organs, such as the oral cavity and esophagus in humans. Surgically resected specimens of bronchial dysplasia, lung cancers, and various human squamous cell carcinomas, collected at two hospitals in Japan, were subjected to immunohistochemical staining with anti-hnRNP B1 antibody. Overexpression of hnRNP B1 protein was observed in 100% of stage I lung cancer tissues, but it was not found in normal bronchial epithelium. Squamous cell carcinoma of the lungs showed stronger staining than other histological types, and elevation of hnRNP B1 was found in both roentgenographically occult lung cancers and bronchial dysplasia. Furthermore, cytological examination with anti-hnRNP B1 antibody detected cancer cells in sputum, suggesting the potential of hnRNP B1 protein as a new biomarker for the very early stage of lung cancer in humans. Because strong staining of hnRNP B1 was also observed in various squamous cell carcinomas of oral and esophageal tissues as shown in our recent reports, overexpression of hnRNP B1 seems to be a common event in the carcinogenic processes of squamous cell carcinoma. These results suggest that hnRNP B1 protein could be a useful diagnostic biomarker for both the very early stages of lung cancer and various squamous cell carcinomas in humans.     

Molecular aspects of oral cancer

Squamous cell carcinoma of the oral cavity is the sixth most frequent cancer in the world with approximately 30,000 new cases diagnosed annually in the United States. The overall 5-year survival rate for patients with oral squamous cell carcinoma is among the lowest for major cancers and has not changed during the past two decades. Despite therapeutic and diagnostic progress in oncology during the past decades, the prognosis of intraoral squamous cell carcinoma remains poor. Thus it seems that finding a biological tumor marker or tumor markers which will increase the early diagnosis and treatment monitoring rates, is of paramount importance in respect to improving prognosis. The latest studies pertaining to tumor markers and their role in the detection, diagnosis and treatment monitoring of oral squamous cell carcinoma are reviewed. The importance of cell surface markers including blood antigens, and growth factors and receptors, and intercellular markers including cytokeratins and AgNORs are discussed. Particular attention is paid to quantitative DNA (aneuploidy) and oncogenes. The pivotal tumor suppressor gene, p53, is dealt with in depth.     

The role of selective neck dissection (I-III) in the treatment of node negative (N0) neck in oral cancer

It is now possible to limit the extent of selective neck dissection for mucosal squamous cell carcinoma of the head and neck by sparing selected lymphatic levels thereby reducing the morbidity. This has been brought about by our improved understanding of the metastasis behavior of these cancers. Studies have demonstrated similar rates of neck recurrences and survival after selective neck dissection compared to modified radical neck dissection. The purpose of this study was to evaluate the efficacy of selective neck dissection (SND) in managing the N0 neck in oral cavity carcinomas. A retrospective analysis of Squamous cell carcinoma of oral cavity with N0 neck from 1998 to 2004 was performed. Statistical analysis was done using SPSS software. The chi-square test was used to compare the various proportions. The overall and disease-free survival were estimated using the Kaplan–Meier method and statistical significant difference in survival was tested by log rank test. Out of the 219 cases, 84% were in the early stage and 16% were in the late stages. Seventy two percent of the patients had primary tumors in the anterior two-thirds of the tongue. One hundred and sixty one patients were pathologically node negative. There was no statistically significant difference in the regional recurrence between the pN0 and pN+ patients. There was no difference in the regional recurrence inside and outside the surgical field. The pathological node positive patients had a worse disease-free survival (DFS) compared to the node negative patients, and the patients with nodal recurrence had a significantly worse DFS compared to patients without nodal recurrence. SND (I–III) is a sound and effective procedure in the management of clinically negative neck in squamous cell carcinoma of the oral cavity. Clinically N0 neck but pathologically N+ neck requires adjuvant radiation therapy. It probably has a therapeutic role in the selected cases of squamous cell carcinoma of the oral cavity with N1 neck, and in these cases an extension of dissection to levels IV and V is beneficial.     

Overexpression of CRKII increases migration and invasive potential in oral squamous cell carcinoma

CT10 regulator of kinase (CRK) was originally identified as an oncogene product of v-CRK in a CT10 chicken retrovirus system. Overexpression of CRKII has been reported in several human cancers. CRKII regulates cell migration, morphogenesis, invasion, phagocytosis, and survival; however, the underlying mechanisms are not well understood. In the present study, we evaluated the possibility of CRKII as an appropriate molecular target for cancer gene therapy. The expression of CRKII in 71 primary oral squamous cell carcinomas and 10 normal oral mucosal specimens was determined immunohistochemically, and the correlation of CRKII overexpression with clinicopathological factors was evaluated. Overexpression of CRKII was detected in 41 of 70 oral squamous cell carcinomas, the frequency being more significant than in normal oral mucosa. In addition, CRKII overexpression was more frequent in higher-grade cancers according to the T classification, N classification, and invasive pattern. Moreover, RNAi-mediated suppression of CRKII expression reduced the migration and invasion potential of an oral squamous cell carcinoma cell line, OSC20. Downregulation of CRKII expression also reduced the expression of Dock180, p130Cas, and Rac1, and the actin-associated scaffolding protein cortactin. These results indicate that the overexpression of CRKII is tightly associated with an aggressive phenotype of oral squamous cell carcinoma. Therefore, we propose that CRKII could be a potential molecular target of gene therapy by RNAi-targeting in oral squamous cell carcinoma.     

Expression profiles of viral responsive genes in oral and oropharyngeal cancers

The association between Human Papillomavirus (HPV) DNA and oropharyngeal squamous cell carcinoma (SCC) has been supported by numerous studies strongly implicating HPV infection as a factor in the development of this cancer. In contrast, squamous cell carcinoma of the oral cavity has not been associated with HPV DNA, suggesting alternate aetiologic factors. The possibility that viral agents other than HPV could contribute to the development of oral cavity SCC should be given consideration, especially given the association of Epstein-Barr virus (EBV) with nasopharyngeal cancer. We used quantitative polymerase chain reaction (qPCR) studies to compare the expression levels of genes that may act as indicators of persistent stimulation by viral antigen in both oral cavity and oropharyngeal squamous cell cancers. Our results demonstrate that HPV-positive oropharyngeal tumours displayed gene expression patterns indicative of a viral signature and that HPV-negative oropharyngeal tumours do not display similar expression patterns. In contrast, we saw no evidence of either a viral or bacterial signature in the oral tumours examined. This would suggest that either an as of yet unidentified virus present in the oral tumour samples is not eliciting a typical immune response, or that there are no novel viral sequences or viruses present in the oral tumours examined.     

Hypoxia-induced up-regulation of apelin is associated with a poor prognosis in oral squamous cell carcinoma patients

Recently, apelin has been shown to be a novel angiogenic factor in various cancers including lung, breast and brain cancer. However, there is limited information regarding the expression and role of apelin in oral cavity cancer. In this study, we determined that apelin expression was localized in the cytoplasm of oral squamous cell carcinoma at various intensities. Strong apelin expression significantly correlated with tumor recurrence and disease-free survival. Using a multivariate analysis, we demonstrated that apelin was an independent prognostic factor for on disease-free survival, age, lymph node metastasis and CA9 expression. Moreover, apelin expression was up-regulated under hypoxic conditions, and exogenous apelin enhanced the proliferation and migration of oral cancer cells. Based on these results, we propose that the presence of hypoxia-induced apelin is a new prognostic factor and potential therapeutic target for oral squamous cell carcinoma.     

Radiotherapy and verrucous carcinoma of the oral cavity. A study of 107 cases.

One hundred and seven cases of oral verrucous carcinoma treated primarily with radiotherapy at Kasturba Hospital, Manipal, India between 1977 and 1987 were analysed concerning location within the oral cavity, clinical extent, and effectiveness of radiotherapy. The most common site was the buccal mucosa followed by the buccogingival sulcus. Only 13.2% of the patients presented with T1 or T2 tumours and 32.7% had clinically negative nodes. Biopsy had to be repeated more than once in 22 patients to get confirmation of invasive carcinoma. The 5-year survival rate was 35% for stage III and 26% for stage IV. The treatment results with radiotherapy were comparable with those for ordinary squamous cell carcinoma of the oral cavity. It is felt that the treatment policy for verrucous carcinoma can be the same as for ordinary squamous cell carcinoma. In order to prevent delay in diagnosis and treatment, proper cooperation between the treating oncologist and the pathologist is essential.     

High EGFR expression predicts poor prognosis in patients with squamous cell carcinoma of the oral cavity and oropharynx: a TMA-based immunohistochemical analysis

This retrospective study was designed to investigate the prognostic significance of EGFR overexpression in human oral squamous cell carcinoma on a long-term follow-up. EGFR expression was examined immunohistochemically on a tissue microarray (TMA) of paraffin embedded tissue specimens from 109 patients who underwent surgical treatment for squamous cell carcinoma of the oral cavity and oropharynx in the period between 1980 and 1997. High EGFR expression was found in 80 (73.42%) of the tumour samples. Kaplan-Meier curves showed that EGFR overexpression was significantly related to decreased overall survival (p=0.05). Multivariate analysis showed that EGFR overexpression is an independent prognostic marker in these patients (p=0.02, RR 3.6). These results confirm that EGFR overexpression is an independent prognostic marker in patients with squamous cell carcinoma of the oral cavity and oropharynx. The EGFR antigen represents an attractive target for targeted therapies with monoclonal antibodies or specific tyrosine-kinase inhibitors in these patients.     

Squamous cell carcinoma of the oral cavity, maxillary antrum and lip in a Zimbabwean population: a descriptive epidemiological study

Squamous cell carcinoma accounts for approximately 90% of oral malignancies. The objective of this study was to document the gender, age, sub-site distribution and histologic differentiation of squamous cell carcinoma of the oral cavity, maxillary antrum and lip in a Zimbabwean population. Hospital records of patients with a histologic diagnosis of squamous cell carcinoma of the oral cavity, maxillary antrum and lip seen at Harare Central Hospital and Parirenyatwa Hospital in Zimbabwe during the period January 1982-December 1991 were reviewed. 20.8% (n = 358/1723) were squamous cell carcinoma of the oral cavity, maxillary antrum and lip. Age ranged from 3 to 70years with a 2:1 male:female ratio. Peak incidence in both sexes were in the 41-50 and 51-60years age groups. Sub-site distribution was mandibular gingiva 18.4%, tongue 17.9%, floor of the mouth 16.2%, maxillary gingiva 9.2%, buccal mucosa 9.2%, maxillary antrum 12.6%, hard palate 7.8%, soft palate 4.8%, lower lip 2.8% and upper lip 1.1%. 64.8% were well differentiated, 24.8% moderately differentiated and 10.4% poorly differentiated. The mandibular gingiva, floor of the mouth and tongue were most commonly affected. Lip squamous cell carcinoma was uncommon. Well-differentiated squamous cell carcinoma was most common in the 41-60 years age group.     

Outpatient surgical treatment with CO2 laser in oral cancer: immediate and long-term results

The immediate and long-term results of excising squamous cell carcinoma of the oral cavity or lip by CO2 laser are analysed in 51 consecutive subjects treated as out-patients. From January 1982 to December 1989, 39 cases of T1 and 12 cases of small (less than 2.5 cm) non-infiltrating recurrences of squamous cell carcinoma were treated at the Istituto Nazionale Tumori in Milan. Complete removal was obtained in 44 instances, while in 7 cases cancerous margins were observed on the specimen; 5 of these underwent another wider treatment and 2 refused further therapy. Two of 39 T1 patients developed local relapses and 6/12 recurrent cancers relapsed again. Long term results are complicated by second primary cancers in 19 instances. Out-patient laser therapy is well accepted by patients and its use involves lowered direct and indirect health organisation and social costs.     

Serum immunoglobulins in squamous cell carcinoma of the oral cavity

Serum immunoglobulins (IgG, IgA, and IgM) have been studied in 70 patients with squamous cell carcinoma of oral cavity and in 40 age-matched normal controls. The results were correlated with clinical stage, tumor size, lymph node status, tumor differentiation, and treatment modalities. There was a significant rise in serum IgM and IgA in oral cancer patients as compared to controls. It was further raised in advanced clinical stage, but tumor size and histological differentiation and treatment modalities (surgery and chemotherapy) do not seem to affect serum immunoglobulin levels. The observations implies that the extension and dissemination of tumor mass is the important factor for the change in serum immunoglobulin level in squamous cell carcinoma of the oral cavity.     

Cell surface antigens in squamous cell carcinoma of the oral cavity

The ABH isoantigen was investigated in 80 patients with squamous cell carcinoma of the oral cavity and in their 46 affected lymph nodes. Isoantigen deletion shows a characteristic pattern of benign to malignant transformation of oral cancer. Total loss of isoantigen was found in anaplastic tumours, in metastatic lymph nodes and in the majority of advanced stage tumours. Total loss of isoantigen in metastatic lymph nodes indicates a frequent discharge of isoantigen-negative metastatic cells from the primary tumours to the lymph nodes and the regional organs. It seems that with the recent techniques a prospective observation of ABH isoantigen added to other pathological and clinical findings could be of prognostic significance in patients with squamous cell carcinoma of the oral cavity.     

A phase II study of (2'R)-4'-O-tetrahydropyranyladriamycin (THP) in patients with head and neck cancer

A phase II study of a new anthracycline, (2"R)-4'-O-tetrahydropyranyladriamycin (THP), was conducted in 110 patients with various head and neck cancers in a multi-institutional cooperative study. The response rate was 20.3% (PR 12) in an intravenously injected group and 52.3% (CR 8, PR 15) in an intraarterially injected group. In the former cases, the response rate according to primary sites was 19.2 to 27.3% for the maxilla, pharynx, oral cavity and larynx. In the latter cases, it was 40.9 to 64.3% for the maxilla, pharynx and oral cavity, and 100% for the external auditory meatus (CR 1, PR 1). According to histology, the response rate was 37.5 % in squamous cell carcinoma. Partial response was observed in two cases of undifferentiated carcinoma. The predominant toxicity was myelosuppression. Leukocytopenia (less than 3,000/mm3) was noted in 44 cases (41.9%). Loss of hair and stomatitis were observed in 13 (12.6%) and 12 (11.7%) respectively. However, these were mild and recovered quickly on discontinuation of THP. We concluded that THP therapy was markedly effective for various head and neck cancers.     

p53 expression in oral cancer: observations of a South Indian study

Oral cancers constitute a significant proportion of hospital admissions among cancer patients in India. The aim of this study was to elucidate the role of tumour suppressor gene p53 in the pathogenesis of oral squamous cell carcinoma by immunohistochemistry. Though extensive studies on p53 alterations in oral cancers have been done in Western countries and some Asian countries, only a few studies have emerged from India, especially the Southern states. This study would therefore be helpful in providing an Indian perspective, with particular reference to South Indian states. A total of 110 cases of oral squamous cell carcinoma, 35 dysplastic lesions, 15 hyperplastic lesions, and 50 samples of normal mucosa were assessed for p53 expression. Out of 110 cases of oral carcinoma, 40 (36%) were p53 positive. Among 35 cases of dysplastic lesions studied, 6 (17%) showed p53 positive staining. None of the hyperplastic lesions and normal oral lesions showed any evidence of p53 positivity. However, in 9 out of 40 (23%) cases of positive infiltrating squamous cell carcinomas, the adjacent or overlying non-tumourous epithelium demonstrated focal areas of p53 positive staining in the basal and parabasal layers of the epithelium. In addition, in 7 out of 110 (6%) cases, cytoplasmic staining was observed. In these samples, nuclei were not stained. Our results indicate that p53 over-expression may be involved in only a certain proportion of oral carcinomas. The fact that 6% of the dysplastic lesions were p53 positive, and adjacent non-tumourous epithelium of 23% infiltrating squamous cell carcinomas showed positive staining for p53 in the progenitor compartment of the epithelium indicates that p53 immunoreactivity could be used to detect early tumours as well.     

Evaluation of Mucosamin Effect on Treating Radiation Induced Oral Mucositis during and after Radiotherapy amongst Patients with Oral Cavity Squamous Cell Carcinoma

Background: Oral mucositis is a serious complication radiation therapy for cancer. This is a major complication during radiation therapy of the head and neck tumors in approximately all patients. Therefore, this study was conducted to evaluate the effect of Mucosamin on treatment of radiation induced oral mucositis during and after radiotherapy amongst patients with oral cavity squamous cell carcinoma. Materials and Methods: In this prospective clinical trial, eligible patients who referred to radiation oncology department of Namazi Hospital, Shiraz, Iran from Jan 2018 till Jan 2019 were evaluated. The cases with confirmed pathologic diagnosis of squamous cell carcinoma of the oral cavity underwent 6,000 cGy radiation therapy and were randomly divided into two groups: 1- Intervention group; Mucosamin spray for 3-4 times a day (n = 40); 2 - Control group; standard medications (3 times a day) (n = 40). Oral mucositis was evaluated weekly based on RTOG scoring scale. Grade of mucositis was recorded during treatment and after radiation therapy. Results: A total of 80 patients were divided in two groups of Mucosamin and control. From week 3 until the end of radiotherapy (week 6) and after radiotherapy (week 8), there was a significant difference in the severity of oral mucositis between the Mucosamin and the control groups (P <0.05). Conclusion: The results of this study showed that Mucosamin spray was able to significantly improved radiation-induced oral mucositis in patients with oral squamous cell carcinoma.     

Human papillomavirus type 16 and squamous cell carcinoma of the head and neck.

PURPOSE: Human papillomavirus (HPV) has previously been reported to be associated with squamous cell carcinoma of the head and neck. Our objective was to investigate the presence and type of HPV infection in head and neck tumors and determine whether infection was associated with individual tumor characteristics, patients' pattern of tobacco and alcohol exposure, or with clinical outcome. Experimental Design: Using a case series design, fresh tumor samples were obtained from a series of 89 head and neck squamous cell carcinoma patients, including 64 men and 25 women. The majority of tumors were located in the oral cavity, followed by the oropharynx. A PCR-based technique with restriction fragment length polymorphism analysis was used to detect and type HPV. RESULTS: Of the 89 patients, 18 (20%) had detectable HPV 16 in their tumor samples. HPV 16 was detected in 64% of tonsil tumors, 52% oropharyngeal tumors, and 5% oral cavity tumors. The mean age of subjects with HPV 16-positive tumors was younger than the patients with HPV-negative tumors. Also, this group consumed less alcohol on a weekly basis and had a better clinical outcome compared with the HPV-negative group. Smoking, clinical stage, tumor grade, and tumor-node-metastasis status were not associated with HPV 16 presence. CONCLUSIONS: Our study supports the previous reports that suggest HPV 16 is associated with squamous cell cancers located in the oropharynx and oral cavity. The fact that HPV-positive tumors were observed in younger, lighter alcohol-consuming individuals with a better overall and disease-specific survival suggests a distinct disease process in these patients.     

Squamous cell carcinoma of the oral cavity in young adults

The 12 patients less than 35 years of age treated for squamous cell carcinoma of the oral cavity at the American Oncologic Hospital between 1954-1979 are examined. Group A (eight patients) had involvement of the tongue; Group B (4 patients) had carcinoma of other oral sites. Mean “T” stage for Group A and Group B was 1 and 1.5, respectively. Treatment was surgical in the majority of cases. Seventy-one percent of Group A and 25% of Group B developed metastatic disease to the neck. The 2-year survival rate was 57% (A) and 75% (B) — 75% combined. The collective results of this and other studies suggest lower control rates than those reported for older patients with similar initial presentations. The implications of this observation are discussed in relation to the management of the younger patient with squamous cell carcinoma of the oral cavity.     

Diagnostic accuracy of magnetic resonance imaging (MRI) in the assessment of tumor invasion depth in oral/oropharyngeal cancer

The purpose of the present study was to evaluate the diagnostic value of MRI for measuring invasion depth in oral/oropharyngeal carcinoma. We retrospectively reviewed pathologic specimens and MRI findings of 114 patients who were diagnosed with squamous cell carcinoma of the oral cavity and oropharynx. Invasion depths were evaluated in pathologic specimens and by MRI. The mean histologic and MRI invasion depths were 13.57 ± 8.476 and 15.24 ± 10.700 mm, respectively. The overall Pearson's correlation coefficient for histologic and MRI (T1W-MRI) invasion depths was 0.825, which was statistically significant (P<0.001). Pearson's correlation coefficients for histologic and MRI invasion depths in oral tongue, tongue base, and tonsil cancers were 0.949, 0.941, and 0.578, respectively. The MRI invasion depth was significantly different according to nodal status in cancers of the oral tongue (P=0.001(?)) and tongue base (P=0.003(?)). With MRI, the invasion depth cutoff values for determining positive nodes were 9.5 and 14.5mm in cancers of the oral tongue and tongue base, respectively. Preoperative MRI is an accurate method for measuring tumor invasion depth in oral tongue and tongue base cancers. Furthermore, it has predictive value for nodal metastasis in the oral tongue and tongue base.     

Identification of human papillomaviruses in tumors of the oral cavity in an Indian community

Oral cancers and other squamous cell cancers of the head and neck are common cancers in India, primarily due to tobacco chewing/smoking and alcohol consumption. Recent reports indicate involvement of human papillomavirus (HPV), HPV 16, in a subset of squamous cell carcinoma of head and neck (SCCHN) cases. To investigate the types of HPVs present in 83 oral cancers and 19 other head and neck tumors, degenerate primers directed to consensus regions in the HPV L1 open reading frame (ORF) were employed to amplify genomic DNA from tumor and when available, the adjacent normal mucosa. PCR-amplified products were cloned and sequenced. Similar studies were done on exfoliated buccal cells of 102 individuals visiting a dental hospital for dental complaints. HPV was detected in 32 out of 102 patients (31%), in either the tumor or the adjacent normal mucosa, while 5% (5/102) of the comparative group were found to be HPV-positive. Sequence analysis revealed a number of cutaneous HPVs, predominantly HPV types of the genus Beta-Papillomavirus, in the oral cavity. Multiple HPV infections were also commonly observed in patients (14/102; 14%). HPV 16 and 18 were each detected in 6 patients (6/102; 6%). Neither high-risk HPVs nor multiple infections were observed in the mouthwash samples of the comparative group. We report that the oral cavity harbors a variety of different HPVs. These viruses, in conjunction with the carcinogens present in tobacco could contribute to carcinogenesis.     

PLCE1在口腔鳞状细胞癌中的表达及其临床意义

目的:探讨磷脂酶Cε1（phospholipase C epsilon－1,PLCE1)在口腔鳞状细胞癌(OSCC)组织中的表达及其与临床病理特征和患者预后的关系。方法:应用免疫组织化学方法检测PLCE1在83例OSCC组织和20例正常口腔黏膜组织中的表达,并分析 PLCE1表达与OSCC临床病理特征的关系;采用Kaplan-Meier法进行生存分析,Cox 风险比例回归模型分析影响OSCC患者预后的独立因素。结果:PLCE1在OSCC组织与口腔正常黏膜组织中高表达率分别为53.01%和15.00%,差异有统计学意义（P=0.002）。PLCE1的表达与患者年龄、性别、吸烟无相关性,而与肿瘤分化程度、T分期、临床分期、N分期有密切关系。单变量分析显示临床分期、PLCE1、T分期、N分期是影响OSCC预后的因素,双变量分析显示PLCE1是其独立预后因素。结论:PLCE1过表达与OSCC的发生、发展密切相关,可作为判断OSCC恶性程度和不良预后的参考指标。