Oral Oncology

Editorial Board/Aims & Scope

2012-05-01

Ras oncogenes in oral cancer: The past 20 years

Avaniyapuram Kannan Murugan, Arasambattu Kannan Munirajan, Nobuo Tsuchida — 2012-01-12

Summary: Oral squamous cell carcinoma (OSCC) of head and neck is associated with high morbidity and mortality in both Western and Asian countries. Several risk factors for the development of oral cancer are very well established, including tobacco chewing, betel quid, smoking, alcohol drinking and human papilloma virus (HPV) infection. Apart from these risk factors, many genetic factors such as oncogenes, tumor suppressor genes and regulatory genes are identified to involve in oral carcinogenesis with these risk factors dependent and independent manner. Ras is one of the most frequently genetically deregulated oncogene in oral cancer. In this review, we analyze the past 22years of literature on genetic alterations such as mutations and amplifications of the isoforms of the ras oncogene in oral cancer. Further, we addressed the isoform-specific role of the ras in oral carcinogenesis. We also discussed how targeting the Akt and MEK, downstream effectors of the PI3K/Akt and MAPK pathways, respectively, would probably pave the possible molecular therapeutic target for the ras driven tumorigenesis in oral cancer. Analysis of these ras isoforms may critically enlighten specific role of a particular ras isoform in oral carcinogenesis, enhance prognosis and pave the way for isoform-specific molecular targeted therapy in OSCC.

Review of drug treatment of oral submucous fibrosis

2011-12-29

Summary: This study undertook a review of the literature on drug treatment of oral submucous fibrosis. An electronic search was carried out for articles published between January 1960 to November 2011. Studies with high level of evidence were included. The levels of evidence of the articles were classified after the guidelines of the Oxford Centre for Evidence-Based Medicine. The main outcome measures used were improvement in oral ulceration, burning sensation, blanching and trismus. Only 13 publications showed a high level of evidence (3 randomized controlled trials and 10 clinical trials/controlled clinical trials), with a total of 1157 patients. Drugs like steroids, hyaluronidase, human placenta extracts, chymotrypsin and collagenase, pentoxifylline, nylidrin hydrochloride, iron and multivitamin supplements including lycopene, have been used. Only systemic agents were associated with few adverse effects like gastritis, gastric irritation and peripheral flushing with pentoxifylline, and flushingly warm skin with nylidrin hydrochloride; all other side-effects were mild and mainly local. Few studies with high levels of evidence were found. The drug treatment that is currently available for oral submucous fibrosis is clearly inadequate. There is a need for high-quality randomized controlled trials with carefully selected and standardized outcome measures.

Primary malignant melanoma, of head and neck: A comprehensive review of literature

A.K. Vikey, Deepali Vikey — 2012-01-20

Summary: Malignant melanoma; since long time is considered as deadly disease, but risk factor is minimized due to new technologies, substantial literatures, and promising treatments. The diverse etiopathogenesis; including physical carcinogens, bio-molecules, biological behavior, anatomical locations, and negligence; contribute to complexity of disease. So even after advanced medical technology, malignant melanoma is the challenge to doctors as well as common public. There is increase in incidence rate day by day, which directly attributes to recent concept of sun beds or tanning beds and global climate. After considering its severity, different researches are carried out in the field of radiology and biotechnology. But again these are not sufficient to control the disease. However; to reduce the mortality there is need of general public awareness regarding causative factors and preventive measures. Many literatures recently advocate for long time survival of malignant melanoma, after its early detection and treatment.

Association between the rs2910164 polymorphism in pre-mir-146a and oral carcinoma progression

2011-12-19

Summary: MicroRNAs are short non-coding RNAs that regulate gene expression by RNA interference. Oral squamous cell carcinoma (OSCC) is a prevalent malignancy worldwide. miR-146a has been reported to regulate Toll-like receptors and cytokine signaling, which are both crucial for inflammation and oncogenesis. This study identifies that areca nut extract, TNFα and TGFβ up-regulates miR-146a in OSCC cells. The increased expression of miR-146a enhanced the oncogenicity of OSCC cells. In addition, a G to C polymorphism (rs2910164), which is located in the pre-miR-146a and has been associated with functional alterations in miR-146a, was significantly more prevalent among OSCC patients having more advanced nodal involvement. Our analysis also suggested a higher miR-146a expression in OSCC tissues of patients carrying C polymorphism. The present study concluded a higher prevalence of the pre-mir-146a C-variant was associated with OSCC progression in patients with this disease.

HMGB1 is overexpressed in tumor cells and promotes activity of regulatory T cells in patients with head and neck cancer

2012-01-24

Summary: HMGB1 has gained a prominent role in cancer development and is implicated in tumor escape phenomena. To date, only few data are available on effects of HMGB1 on regulatory T cells (Treg) in cancer patients. This study evaluates the prevalence of HMGB1 and its effects on Treg in patients with head and neck squamous cell carcinoma (HNSCC). Sixty-seven patients with HNSCC and seventeen healthy donors were included in this study. Tumor tissues of patients were analyzed for expression of HMGB1 employing immunofluorescence and qRT-PCR. HMGB1 serum levels were assessed using ELISA. Tumor-infiltration and Treg from peripheral blood were phenotyped with flow cytometry and immunofluorescence microscopy. Migration and suppressive function of Treg upon HMGB1 stimulation was analyzed in chemotaxis assays and CFSE assays. HMGB1 is overexpressed in tumor cells of HNSCC, and serum levels are significantly elevated. Tumor-infiltrating Treg express HMGB1-recognizing receptors, TLR4 and RAGE. HMGB1 is a chemoattractant for Treg and promotes their suppressive function. Our data provide new aspects how the HMGB1 tumor-derived danger signal augments function of Treg in patients with HNSCC.

Tumor-associated carbonic anhydrase XII is linked to the growth of primary oral squamous cell carcinoma and its poor prognosis

2011-12-15

Summary: The pattern of protein expression in tumors is under the influence of nutrient stress, hypoxia, and low pH, which determines the survival of neoplastic cells and the development of tumors. Carbonic anhydrase (CA) XII is a transmembrane enzyme that catalyzes the reversible hydration of cell-generated carbon dioxide into protons and bicarbonate. Hypoxic conditions activate its transcription and translation, and enhanced expression is often present in several types of tumors. However, CA XII expression in oral squamous cell carcinoma (OSCC) and its correlation with patients’ prognosis have not been investigated so far. In this study, we detected the expression of CA XII in 264 patients with OSCC using tissue microarrays (TMAs), and evaluated its correlation with clinicopathologic factors and disease prognosis. CA XII expression was present in 185/264 (70%) cases and was associated with more-advanced clinical stages (p=0.003), a larger tumor size (p<0.001), and postoperative recurrence (p=0.047), but was not associated with positive lymph node metastasis or distal metastasis. Importantly, CA XII expression was correlated with a poorer patient prognosis in a univariate (p=0.034, log-rank test) survival analysis. According to our results, the expression of CA XII in OSCC samples can predict the progression of OSCC and survival of OSCC patients.

Increased serum placenta growth factor level is significantly associated with progression, recurrence and poor prognosis of oral squamous cell carcinoma

2012-01-16

Summary: We recently found that the expression of placenta growth factor (PlGF) in oral squamous cell carcinoma (OSCC) specimens is correlated with the progression and prognosis of OSCC. In this study, serum samples were obtained from 72 OSCC patients before and 3months after surgical cancer excision and from 30 normal controls. Serum PlGF levels were determined by enzyme-linked immunosorbent assay (ELISA). The mean serum PlGF levels were significantly higher in pre-surgery OSCC patients than in normal controls (19.1±10.7 vs. 10.1±4.5, P<0.001). Serum PlGF levels dropped to near the normal control levels after surgical cancer removal. Higher pre-surgery serum PlGF levels were significantly associated with larger tumor size (P=0.015), positive lymph node metastasis (P=0.001), more advanced clinical stages (P=0.002), and loco-regional recurrence (P=0.037). The serum PlGF level was identified as an independent unfavorable prognosis factor by multivariate Cox regression analyses (P=0.014). Kaplan–Meier curve showed that OSCC patients with a higher serum PlGF level had a significantly poorer cumulative recurrence-free survival than those with a lower serum PlGF level (log-rank test, P=0.009). When we used the serum PlGF level of 19.1pg/ml (mean normal control value plus 2 standard deviations) as a cutoff point, the sensitivity, specificity, and positive predictive value for tumor recurrence was 80%, 56% and 78%, respectively. We conclude that the serum PlGF level may be a valuable biomarker for prediction of therapeutic effect, progression, recurrence and prognosis of OSCC.

The prognostic value of histological typing in nasopharyngeal carcinoma

Florence Cheung, Oscar Chan, Wai Tong Ng, Lucy Chan, Anne Lee, Siu Wah Pang — 2011-12-19

Summary: We analyzed the relation of histological typing in late stage nasopharyngeal carcinoma (NPC) with clinical outcome and excision repair cross complementation group 1 protein (ERCC1) expression. The biopsy specimens of 259 patients with NPC were reviewed by two pathologists for classification according to 2005 WHO subtypes. The patients were of stage III to IVB and treated with radiotherapy (RT) alone or concurrent–adjuvant chemoradiotherapy (CRT). Expression of ERCC1 protein detected by immunohistochemistry on paraffin sections was correlated with the histological subtypes. There were 10 cases (3.9%) of differentiated non-keratinizing carcinoma compared with 249 cases of conventional undifferentiated carcinoma. The former exhibited more advanced squamous differentiation with 3 cases belonging to the papillary variant. The degree of ERCC1 expression was generally high compared with the median of the cohort. Clinically, the differentiated group fared poorly compared with the undifferentiated group with respect to loco-regional failure-free rate, distant failure-free rate, disease-free survival and overall survival (p⩽0.05). Treatment modality of the 10 patients (5 RT, 5 CRT) was similar to the whole cohort. Contrary to general acceptance that differentiation of non-keratinizing NPC had little bearing on prognosis, we demonstrated that in endemic area differentiation in fact conferred a worse prognosis in stage III to IVB patients. There was positive correlation of differentiation with ERCC1 expression. We advocate precise histological typing of NPC in pathology report for prognostic purpose and outcome correlation.

Enteral feeding outcomes after chemoradiotherapy for oropharynx cancer: A role for a prophylactic gastrostomy?

2011-12-30

Summary: To determine the outcomes of patients managed with different routes of enteral feeding during chemoradiotherapy for oropharynx cancer. The hospital and dietetic records of consecutive patients with oropharynx squamous cell carcinoma treated between January 2007 and June 2009 with concurrent chemoradiotherapy were reviewed retrospectively. One hundred and four patients were analysed. Seventy-one received a prophylactic gastrostomy, 21 were managed with a strategy of NG tube as required and 12 received a therapeutic gastrostomy. Patients with a prophylactic gastrostomy commenced enteral feeding a median of 24days after commencing radiotherapy, compared with a median of 41days (p<0.001) for the NG as required group. Comparing prophylactic gastrostomy, NG as required and therapeutic gastrostomy, median number of unplanned inpatient days were 6, 14 and 7, respectively (p<0.01 for prophylactic gastrostomy vs. NG as required). Mean percentage weight loss at the end of treatment (6.1% vs. 7.1% vs. 5.2%, respectively) and at 6months post-radiotherapy (11.7%, 14.3% and 8.9%) were similar in all groups (p=0.23). There was no significant difference in type of diet post-radiotherapy between prophylactic gastrostomy and NG as required groups (p=0.22). Median duration of enteral feeding was 181, 64 and 644days, respectively (p<0.01 for prophylactic gastrostomy vs. NG as required). Use of a prophylactic gastrostomy (p<0.01) and higher T stage (p<0.01) were associated with increased duration of enteral feeding on a multivariate analysis. These data reinforce concerns regarding the detrimental impact of prophylactic gastrostomy placement upon long-term enteral feed dependence.

A phase II study of pemetrexed combined with cisplatin in patients with recurrent or metastatic nanopharyngeal carcinoma

T.K. Yau, T. Shum, A.W.M. Lee, M.W. Yeung, W.T. Ng, L. Chan — 2011-12-29

Summary: Pemetrexed is a novel chemotherapy agent with good efficacy and toxicity profiles. This phase II study aimed at evaluating its use in combination with cisplatin for recurrent or metastatic nasopharyngeal carcinoma (NPC). All participating patients had metastatic or recurrent NPC with prior treatment by platinum-based chemotherapy. The study regimen comprised of pemetrexed 500mg/m2 and cisplatin 75mg/m2, repeated 3-weekly for 4 cycles. Efficacy evaluation was based on both radiological and biochemical responses. Patients with no progressive disease and good tolerance were given another 2–4 cycles. Fifteen patients were treated for a total of 4–8 cycles (median, 6 cycles); 9 had distant metastases and 6 had loco-regional recurrences only. Reduction of DNA copies of EB virus by ⩾50% was observed in 93% accessible patients, with 21% of them being biochemical complete response (CR). Radiologically, 1 (7%) patient achieved CR, 2 (13%) achieved partial response and 8 (53%) had stable diseases. The median time to progression was 30weeks. Treatment was well tolerated with only 1 (7%) patient developing grade 4 toxicity (of anemia). The most common grade 3 toxicities were neutropenia (27%) and anemia (20%). The baseline mean total QOL scores (as measured with FACT-H&N version 4) was 100.4 and showed no significant change after the fourth cycle (95.6, p=0.20) and sixth cycle (91.9, p=0.15). Pemetrexed in combination with cisplatin is a well tolerated regimen with encouraging efficacy for metastatic and recurrent NPC. Further evaluation of its role in the management of NPC is warranted.

Treatment outcomes and prognostic features in adenoid cystic carcinoma originated from the head and neck

Chunying Shen, Tingting Xu, Caiping Huang, Chaosu Hu, Shaoqin He — 2012-01-03

Summary: Surgery is the main treatment modality for adenoid cystic carcinoma (ACC) originated from the head and neck. However, the extensive local infiltrative and perineural spread related to this malignancy often cause difficulty to achieve high tumor control. The aim of this study is to evaluate the efficacy of postoperative radiotherapy (RT) in ACC, and to identify prognostic variables associated with treatment outcomes. A retrospective review of 101 patients diagnosed with ACC in the head and neck region was performed. T stage distribution was T1, 25; T2, 35; T3, 18; and T4, 23 patients. All patients were grouped into two arms: surgery alone or combined with postoperative radiotherapy. The 5-year local–regional control (LRC), overall survival (OS) and disease-free survival (DFS) rates for all the patients were 70.5%, 91.7% and 63.2%, respectively. On univariant analysis, postoperative radiotherapy did improve the 5-year LRC and DFS compared to surgery alone (81.0% vs. 53.4%, p=0.0003 and 71.3% vs. 50.0%, p=0.0052, respectively). And patients with T1–T2 lesions achieved better treatment outcomes, whereas stage T3–T4 was associated with high local failure and poor disease-free survival. Furthermore, multivariate analysis revealed that the addition of radiotherapy and early lesions were both favorite predictors for local control and survival rates. The prognosis for ACC of the head and neck was excellent. Surgery combined with postoperative radiotherapy significantly reduced the local failure, and further improved disease-free survival. Nevertheless, the relatively high distant metastasis was an obstacle of curing the ACC patients.

Diagnostic value of CT and MRI in the detection of paratracheal lymph node metastasis

2012-01-06

Summary: The presence of paratracheal lymph node (PTLN) metastasis harbours a worse prognosis. Uniform guidelines on PTLN dissection are missing, mainly because of the value of diagnostic techniques for the detection of PTLN metastasis are not clear. This study is performed to identify CT and MRI criteria for detection of PTLN metastasis. 149 patients who underwent laryngectomy and a PTLN dissection between 1990 and 2010 were included. Patient, tumour, treatment and follow up data were collected. On computed tomography (CT) and magnetic resonance imaging (MRI) different test criteria were examined. Considering PTLN with a maximal axial diameter of ⩾5mm as positive predicts PTLN metastasis best: sensitivity and specificity 70% and 36% (CT) and 50% and 71% (MRI). Other risk factors for PTLN metastasis were subglottic extension of the tumour (sensitivity is 45%) and clinical positive neck status (sensitivity is 59%). When atleast one of these risk factors was present and the status of PTLN was considered positive, a high sensitivity (90% for CT and 100% for MRI) and a lower specificity (19% for CT and 32% for MRI) was found. If atleast one of the risk factors such as subglottic extension, clinical positive neck and PTLN with a maximal axial diameter of ⩾5mm is present, sensitivity and negative predictive value for the prediction of PTLN metastasis are high, but the specificity is low. These risk factors can be used to select laryngectomy patients for PTLN dissection.

Long-term treatment outcome of minor salivary gland carcinoma of the hard palate

2012-01-16

Summary: Minor salivary gland carcinoma of the hard palate is rare, and its long-term survival rate is high, making it difficult to evaluate the prognostic factors and the efficacy of treatment. This study was designed to evaluate the treatment outcome of minor salivary gland carcinoma of the hard palate. 103 cases of minor salivary gland carcinoma of the hard palate treated with surgery alone or underwent surgery combined with post-operative radiotherapy hospitalized in Cancer Center, Sun Yet-Sen University, from 1968 to 2008 were reviewed retrospectively. The most common histologic types were adenoid cystic carcinoma in 48 patients(46.6%), mucoepidermoid carcinoma in 37(35.92%), malignant mixed tumor in 15(14.56%), and acinic cell carcinoma in 3(2.91%). The median follow-up time was 74.83months (range 0.9–356.57months). Overall outcomes at 5 and 10years were overall survival (OS), 77.9% and 65.7%; recurrence-free survival (RFS), 64.4% and 53.2%; and disease specific survival (DSS), 77.9% and 67.7%, respectively. There was no significant difference in overall survival (P=0.52), recurrence-free survival (P=0.762) and disease specific survival (P=0.449) between patients who underwent surgery alone and those who underwent surgery plus post-operative radiotherapy. Surgery has been accepted as the primary treatment for minor salivary gland carcinoma of hard palate. Sufficient surgical excision with adequate margins is essential for a favorable outcome. We advocate using radiotherapy in the post-operative context for patients with poorly differentiated, cervical lymph node metastasis, positive or close margins, and large primary lesions.

Electron beam radiotherapy for tongue cancer using an intra-oral cone

2012-01-12

Summary: To explain the adaptation technique using an intra-oral cone (IOC) for radiation therapy, and to determine the optimal schedule resulting in a high local control rate and an acceptable complication rate using direct electron beam radiation for the treatment of tongue cancer. Thirty patients with the tongue cancer (T1:T2:T3=16:11:3) were treated with 6–15MeV electron radiation using an IOC. Twenty-six patients were treated with electron radiation using an IOC with or without an excisional biopsy. The other four patients were treated with a combination of the external beam radiation and electron radiation using the IOC. In order to formulate a safe and effective treatment program, we calculated the biologically effective dose (BED). The two- and five-year local control rates for all patients were 63% and 52%, respectively. The two- and five-year overall survival rates for all patients were 73% and 69%, respectively. Local control was achieved in 12 of 15 patients who were irradiated with a BED of 90.9Gy10 or more, whereas it was not achieved in nine of the 15 patients who were treated with less than a BED of 90.9Gy10 (p=0.03). The application of electron radiation using an IOC for the treatment of tongue cancer provides acceptable local control and adverse effect rates, especially for elderly patients considered to be high risk for complications from anesthesia. The optimum BED10 value for the treatment of early tongue cancer using the IOC technique appears to be at least 90.9Gy10.

Platelet-rich therapies in the treatment of intravenous bisphosphonate-related osteonecrosis of the jaw: A report of 32 cases

Marco Mozzati, Giorgia Gallesio, Valentina Arata, Renato Pol, Matteo Scoletta — 2012-01-20

Summary: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is an important complication in cancer patients taking intravenous BPs (BPs). In most cases, BRONJ is associated with an oral surgery procedure involving jaw bone. Currently, BRONJ management remains controversial, and there is no definitive standard of care for this disease. In fact, several articles in the recent literature discuss treatments that range from topical to surgical treatment, without definitive conclusion about treatment. A clinical study was conducted on 32 patients treated with i.v BPs for oncologic pathologies affected by BRONJ. The patients were treated by resection of the necrotic bone with primary closure of the mucosa over the bony defect using plasma rich in growth factors (PRGF). Orthopanoramic and computed tomography were performed before and after surgery. No intraoperative complications were observed, and all 32 cases were treated successfully. Our data on the use of PRGF demonstrate positive results for this surgical treatment. PRGF may enhance vascularization and regeneration of osseous and epithelial tissues.

Comment on “Chole RH et al. Review of drug treatment of oral submucous fibrosis. Oral Oncol 2012; 48(5):393–398”

Samapika Routray, Anagha Shete Motgi, Aparajita Sunkavalli — 2012-03-21

We would like to congratulate Chole RH et al. for their article in press- “Review of drug treatment of oral submucous fibrosis”. They have extensively presented a review of all treatment modalities that were found to have high level of evidence in the past to treat oral submucous fibrosis. Oral submucous fibrosis being a common potentially malignant disorder in the Indian scenario needed a full revision of the drug treatment for the knowledge enhancement in the present day. After reading the ayurvedic therapy section we feel that use of turmeric or Curcuma longa Linn and tea polyphenols were very wisely described.