Management of locally advanced HPV-related oropharyngeal squamous cell carcinoma: where are we?

HPV-related (HPV+) oropharyngeal cancer (OPC) has a better prognosis compared to HPV unrelated (HPV-) OPC. This review summarizes and discusses several of the controversies regarding the management of HPV+ OPC, including the mechanism of its treatment sensitivity, modern surgical techniques, chemotherapy regimens, and treatment de-intensification protocols. We also discuss and reconsider potential adverse prognostic factors such as tumor EGFR expression, tumor hypoxia, and patient smoking history, as well as the significance of retropharyngeal adenopathy. Finally, we discuss elective nodal treatment of uninvolved lymph node stations. While this review does not exhaust all controversies related to the management of HPV+ OPC, it aims to highlight some of the most clinically relevant ones.

Are females predisposed to complications in head and neck cancer free flap reconstruction?

PURPOSE: To investigate gender and other possible factors affecting the frequency and severity of postoperative complications in head and neck cancer free flap reconstruction. MATERIALS AND METHODS: A prospective longitudinal cohort study was conducted at the Greek Anticancer Institute, St. Savvas Hospital in head and neck cancer free flap reconstruction concerning postoperative complications. We documented the patients' demographic characteristics, social habits, and perioperative factors (ie, duration of general anesthesia), reconstructive techniques, neoadjuvant radiotherapy, and physical status. Initially, univariate statistical analysis was performed to confirm which predictor variables might influence the presence and severity of complications. Next, multivariate statistical analysis was performed using logistical regression and including the factors that were statistically significant on univariate analysis. RESULTS: From 1999 to 2009, we assessed 95 patients who had undergone surgery for head and neck cancer. Of the 95 patients, 24 were women and 71 were men. The patient age range was 20 to 87 years (mean 52, median 55). A total of 55 complications occurred in 49 patients (51.57%). Of the 55 complications, 12 (12.63%) were of major severity, 21 (22.10%) of median severity, and 22 (23.15%) of low severity. The statistical analysis revealed that the factors associated with complications were preoperative radiotherapy, female gender, and operation time. The factors associated with severe complications were female gender and alcohol use. CONCLUSIONS: Multivariate analysis of the data revealed that the factor associated with an increased incidence of postoperative complications was preoperative radiotherapy. Moreover, the variable that remained statistically significant and correlated with an increased incidence and severity of free flap reconstruction complications was female gender. Identifying the etiology of these findings is an intriguing field for additional research.

Functional results of speech and swallowing after oral microvascular free flap reconstruction.

PURPOSE: To study speech and swallowing in patients who underwent microvascular free flap reconstruction after major surgery of the oral cavity. PATIENTS AND METHODS: Twenty patients, 17 men and 3 women, with a mean age of 58.5 years (range 27-79 years) were included in the study. Squamous cell carcinoma was the most common malignancy. Swallowing assessment was performed through videofluoroscopy, using three consistencies of barium meal. The recorded swallows were assessed for the ability to hold the bolus during the oral phase, lip seal, tongue movement, residue in the floor of the mouth, laryngeal penetration and aspiration. Speech function regarding intelligibility and articulation was objectively assessed. RESULTS: Fifteen out of 20 patients (75%) had a good lip seal. Fourteen patients (73.6%) had adequate control of bolus, while in 89.4% the neotongue motility was satisfactory. Vallecular residue was noted in 25% of patients, laryngeal penetration in two (10%), while three patients (15%) continued to have significant aspiration, which necessitated continuous feeding through a gastrostomy. Postoperative speech intelligibility and articulation was satisfactory in 75 and 62.5% of the patients, respectively. CONCLUSIONS: Microvascular free flap reconstruction of major defects after oral resections rehabilitates the functions of swallowing and speech in acceptable levels, improving quality of life in these patients.

Contemporary management of cancer of the oral cavity.

Oral cancer represents a common entity comprising a third of all head and neck malignant tumors. The options for curative treatment of oral cavity cancer have not changed significantly in the last three decades; however, the work up, the approach to surveillance, and the options for reconstruction have evolved significantly. Because of the profound functional and cosmetic importance of the oral cavity, management of oral cavity cancers requires a thorough understanding of disease progression, approaches to management and options for reconstruction. The purpose of this review is to discuss the most current management options for oral cavity cancers.

Free microvascular tissue transfer for the reconstruction of midfacial defects in oncological patients.

This study reviews our experience with free microvascular tissue transfer for the repair of midfacial defects in surgical oncology. From 2000 to 2008, eight patients with maxillectomy defects were immediately reconstructed using free flaps. Their clinical charts were retrospectively reviewed to record demographic data, ablative and reconstructive procedures, complications and outcome. Free tissue transfer was successful in all patients, giving an overall success rate of 100%. The mean follow-up time was 4 to 101 months (mr: 43.8). Three patients died from the disease giving a patient mortality of 30%, while five patients are alive, free of disease and back to their normal daily activities. The restoration of function and improvement of patients' quality of life was a common feature in all our reconstructions. The development of free tissue transfer has made surgical treatment of oncological patients with maxillectomy defects previously considered inoperable possible, improving at the same time their quality of life.

Infected lingual osseous choristoma. Report of a case and review of the literature.

Osseous choristoma is a rare, benign lesion of the oral cavity occurring usually in the tongue. It appears as a tumorous mass of normal bony structure with mature cells in an ectopic position. The case of a 72 years Caucasian male is presented and analyzed along with 52 similar cases reported in the English literature between 1967 and 2007. Lingual choristoma shows a female predilection, whereas the commonest anatomic location is the posterior third of the tongue, occurring at or close to the foramen caecum and the circumvallate papillae. Histologically the lesions show signs of a well-circumscribed mass of vital bone located under the surface oral epithelium. Some lesions represent developmental malformations, whereas others may be reactive lesions after trauma or chronic irritation. Treatment of lingual osseous choristoma consists of simple excision.

Overcoming wound complications in head and neck salvage surgery.

BACKGROUND: Loco-regional treatment failure after radiotherapy with or without chemotherapy and/or prior surgery represents a significant portion of head and neck cancer patients. Due to a wide array of biological interactions, these patients have a significantly increased risk of complications related to wound healing. METHODS: Review of the current literature was performed for wound healing pathophysiology, head and neck salvage surgery, and wound therapy. RESULTS: The biology of altered wound healing in the face of previous surgery and chemoradiotherapy is well described in the literature. This is reflected in multiple clinical studies demonstrating increased rates of wound healing complications in salvage surgery, most commonly in the context of previous irradiation. Despite these disadvantages, multiple studies have described strategies to optimize healing outcomes. The literature supports preoperative optimization of known wound healing factors, adjunctive wound care modalities, and microvascular free tissue transfer for salvage surgery defects and wounds. CONCLUSION: Previously treated head and neck patients requiring salvage surgery have had a variety of disadvantages related to wound healing. Recognition and treatment of these factors can help to reverse adverse tissue conditions. A well-informed approach to salvage surgery with utilization of free vascularized or pedicled tissue transfer as well as optimizing wound healing factors is essential to obtaining favorable outcomes.

Mucoepidermoid carcinoma of the salivary glands. Review of the literature and clinicopathological analysis of 18 patients.

Salivary gland carcinomas are a rare and clinically diverse group of neoplasms among which mucoepidermoid carcinomas (MEC) are reported to be the most frequently encountered. During the years 1994-2004 18 patients with MEC were treated in our Department. All patients underwent surgery with a curative intent, and in 11 of them treatment was supplemented by radiotherapy. Follow up ranged from 6 to 120 months. Twelve (66.6%) MECs originated from the major salivary glands with the majority located in the parotid. Histologically, 50% of tumors were classified as low grade, 28% as intermediate and 22% as high-grade MECs. Positive surgical margins were documented in six cases (33%) and all in tumors of high or intermediate histological grade. All these patients received adjuvant radiotherapy and one developed local recurrence. Local recurrence occurred in two more patients with histologically free margins. Both received postoperative radiotherapy. Distant metastases were documented in four patients all between 14 and 24 months after surgical treatment. An association between local recurrence and distant metastasis might be suggested since all patients with local recurrences subsequently developed distant metastases. The 5-year overall disease specific survival rate was 85%. Statistical multivariate analysis demonstrated that the factor that significantly correlated with overall survival was the histological grade of tumors (Log Rank test: p=0.013). A trend towards poorer survival was observed in patients aged over 50 years. Our results also suggested a potential benefit of postoperative radiotherapy for patients with positive margins.

Induction chemotherapy followed by concurrent chemoradiation in advanced squamous cell carcinoma of the head and neck: final results from a phase II study with docetaxel, cisplatin and 5-fluorouracil with a four-year follow-up.

Encouraging results have recently been reported in patients (pts) with locally advanced unresectable squamous cell carcinoma of the head and neck (SCCHN) when induction chemotherapy (IC) is used and followed by radiotherapy (RT). The present study assessed the therapeutic response of an aggressive regimen consisting of docetaxel (TXT), cisplatin (CDDP) and 5-fluorouracil (5-Fu) as IC and concurrent with RT in pts with locally advanced (stages III and IV) SCCHN. 42 pts (35 male and 7 female) with a mean age of 58 years suffering from stages III and IV (Mo) SCCHN were included to this organ preservation phase II clinical trial. The site of the primary tumors was the anterior mouth in 9 pts, base of tongue and oropharynx in 12, middle third of the face in 8 and larynx in 13. The performance status of the pts was 0-1 according to WHO and above 80% according to Karnofsky classification. IC consisted of TXT (40 mg/m2), CDDP (40 mg/m2) and 5-Fu (350 mg/m2) every two weeks (wks) for a total of four courses and repeated, coupled with RT (66-68 cGys total dose fractionated at 200 Gy per day, 5 days a week), for up to seven wks. In total, pts received eight courses of chemotherapy (CT) at the end of RT treatment. Pts were evaluated at the end of IC, after RT and every six wks thereafter. 41 pts were eligible for evaluation after IC (one died from myocardial infarction) and 39 after completion of treatment (two died during RT). Statistical multivariate analysis was performed using SPSS (11) package. Complications from IC and RT were evaluated according to WHO criteria and included mucositis Grade (Gr) IV in 10% of the pts, Gr III in 50%, Gr II in 20%. Anemia presented in 40% of the pts with Gr II, 40% with Gr I, neutropenia 17% with Gr IV, 20% with Gr III, 30% with Gr II, thrombocytopenia 3% with Gr III, 10% with Gr I and xerostomia up to Gr II in 70% of the pts. The response rate (RR) after IC was complete response (CR) for 10 pts (24.4%), partial response (PR) for 22 (53.7%) and no response (NR) for 9 (21.9%). At the end of the treatment the RR in the intention-to-treat population were CR for 25 pts (64.1%), and PR for 14 (35.9%). Follow up ranges from 18 to 56 months (mts). 14 pts died during follow-up time. The mean survival time is 41 mts and the median 40. 2 pts with CR developed local recurrence and two distant metastases, whereas all pts with PR developed progressive disease (PD) and all but two are dead from disease. It is evident from this phase II study that TXT-CDDP-5Fu based IC followed by the same regimen coupled with RT improves local control. Pts that showed CR after IC continued to maintain disease status during RT (P-value=0.0181). In pts with SD concurrent RT did not alter dramatically disease outcome. Patients who showed complete response after both IC and RT presented a four-year survival rate of 74% compared to a 30% to partial responders (P-value=0.0001). Results are encouraging and further study of the toxicity and follow-up is needed to validate treatment effectiveness.

Adenoid cystic carcinoma of the head and neck. Clinicopathological analysis of 23 patients and review of the literature.

Adenoid cystic carcinoma (ACC) is a rare epithelial tumor with a distinct natural history characterized by an indolent but persistent growth, late onset of distant metastases and eventual death of patients. Between 1991 and 2003, 23 patients with ACC were treated in our Department. Surgery with a curative intent followed by radiotherapy (RT) was applied in 22 patients. Complete resection was achieved in 72.73% of patients. Local recurrence occurred in 26% of patients. Positive margins emerged as the only statistically significant parameter (p < 0.0001) influencing the development of local recurrence. Distant metastasis (DM) occurred in 47.8% of patients. In 54.5% of the patients developing DM, this occurred between 5 and 10 years after the initial treatment. DM was influenced by perineural invasion (p = 0.04) and was disassociated from local control of the tumor. The mean overall survival of our patients was 70.58 months and the mean disease free survival 61.85 months. Perineural invasion (p = 0.048) and DM (p = 0.001) had a statistically significant impact on final patients' outcome. The most important factor influencing survival was DM. Its late onset, irrespectively of local control, supports the hypothesis that ACC has a potential to develop DM in the very early phases of tumor growth.

Molecular events in relapsed oral squamous cell carcinoma: Recurrence vs. secondary primary tumor.

Relapses have a great impact on both the morbidity and mortality rates of oral squamous cell carcinoma (OSCC) patients. Current classification criteria are imprecise and need improvements. Recent advances in understanding of OSCC relapses on a molecular level provide new possibilities to better classify true recurrences and second primary tumors. This review discusses the limitations of the current OSCC relapse classification method and presents possible alternatives to improve this classification based on molecular techniques. Moreover, these molecular techniques add to the further understanding of these lesions and may provide tools for clinical management.

Malignant orbital and orbitomaxillary tumors: surgical considerations.

Malignant tumors of the orbit and the orbitomaxillary region constitute 4-8% of head and neck malignancies. The lesions can be primary orbital malignant tumors or can invade the orbit from the eyelids, the eyeball or the paranasal sinuses, especially the maxillary sinus and ethmoids. The commonest primary malignant tumors of the orbit are lymphomas, rhabdomyosarcomas and lacrimal gland epithelial tumors. These tumors are excluded from the present study since their management differs from that of metastatic tumors. Our experience is based on a series of 48 patients operated during the last five years. There was an equal distribution according to both age and sex, with two-thirds of the patients being over 60 years of age. Histologically, the basal cell carcinomas (B.C.C.) prevailed with 19 cases, followed by squamous cell carcinomas (Sq.C.C.) in 12, adenocarcinomas (AdenoCa) in 10 and orbital melanomas (O.M.) in 7. In 13 cases the maxilla was also affected. Surgical treatment varied from exenteration to wide cran iofacial resections; immediate reconstruction followed in all cases. Only 10 patients were treated with surgery alone. In the remaining 38 patients radiotherapy was given, alone or in combination with chemotherapy. The surgical techniques included exente ration with split-thickness skin grafting in 19 cases, exenteration with coverage with median forehead flap in 16, and maxillectomy with forehead and temporalis flaps in 7 cases. The tumors recurred in 12 patients, all of them in the first postoperative year. Ten patients died from intracranial involvement or distant metastases. In six of these patients the lesions were Sq.C.C., in two AdenoCa and in two O.M. It is concluded that the surgical treatment of orbital and orbitomaxillary malignancies, although subject to broad guidelines that determine the operability of the tumors, should be individualized according to the extent of the lesion and the experience of the surgeon.

Development of the Greek version of the University of Washington quality of life questionnaire for patients with head and neck cancer.

The University of Washington quality of life (UW-QOL) questionnaire, created in 1993 to evaluate health related quality of life, has been widely used in English-speaking populations and translated and validated in other languages. The aim of the present study was to carefully translate and psychometrically validate the UW-QOL questionnaire in Greek. The revised version of the questionnaire was obtained by forward and backward translation of the original English version, according to internationally accepted guidelines. Validation was performed in 120 patients with head and neck cancer treated in a Greek Anticancer Institute in Athens, during their follow-up visits. Eligible patients completed the Greek version of the questionnaire and two other previously validated quality of life questionnaires (EORTC QLQ H&N35 and C-30). Related data and the patients' demographics were extracted from the patient's notes. Strong internal consistency (mean Cronbach α value of 0.83) was shown, with good construct validity. Statistically significant differences were noted between tumour staging and treatment modality and global quality of life. Strong correlation was shown between previously validated EORTC questionnaires and the translated UW-QOL questionnaire. In conclusion, the Greek version of the UW-QOL questionnaire appears to be culturally appropriate and psychometrically valid.

Publication bias in oral and maxillofacial surgery journals: an observation on published controlled trials.

BACKGROUND: Publication bias (PB) diminishes the full distribution of research, distorts and discredits the scientific record, and thus compromises evidence-based practice. The objective of this study was to analyse published controlled trials with regard to PB in leading oral and maxillofacial surgery (OMS) journals. METHODS: All controlled trials published in the International Journal of Oral and Maxillofacial Surgery, Journal of Cranio-Maxillofacial Surgery, Journal of Oral and Maxillofacial Surgery, and British Journal of Oral and Maxillofacial Surgery in 2008 were analysed for a primary outcome, country of authors, sample size, gender of the first author, funding source and location of the study. RESULTS: Of 952 published articles, 53 controlled trials (5.7%) were identified. The OMS journals preferentially published controlled trials with a positive outcome (77.4%) and from high-income countries (73.6%). Single-centred trials (86.8%) with low sample size (n<100; 69.8%) were published more frequently. The majority of the first authors were male (75.5%). Funding source disclosure was missing in most studies (73.6%) [corrected]. CONCLUSIONS: Our results suggest the possible existence of PB in the OMS literature. Hence, it should be borne in mind that the published articles may not be representative of all scientific works, especially when systematic reviews and meta-analyses are conducted or read. In the meantime, journals should establish measures to eliminate PB to uphold scientific integrity. However, this study was an observation based on the published articles. An analysis of all submitted manuscripts would provide more accurate estimates of PB. Ethical considerations on PB are also discussed.

Endoscope-assisted submandibular sialadenectomy: a review of outcomes, complications, and ethical concerns.

OBJECTIVES: To review outcomes and complications of endoscope-assisted submandibular sialadenectomy (EASS) and to analyze this innovative technique with regard to ethical issues. METHODS: We used a systematic review study design to identify clinical studies on EASS, published in English, French, German, and Thai. The last electronic search was conducted in September 2009. We checked the bibliographies of the identified articles, relevant local journals, and congress abstracts. Publications were further assessed and assigned their respective levels of evidence. We also investigated reporting on human subject protection, conflicts of interest, funding support, and commercial relationships. RESULTS: Five case series reporting a total of 28 patients met the inclusion criteria. There was no need of recourse to open surgery. All of the authors claimed satisfactory cosmetic results. Complications were uncommon. However, no controlled trial was available, and outcome measures varied between studies. Human subject protection and funding sources were mentioned in only 2 articles. Commercial relationships and conflicts of interest could not be identified. CONCLUSIONS: All of the reports favor outcomes of EASS. However, their level of evidence is low, and the superiority of this procedure over the conventional surgery remains unknown. The success of this procedure should not be overemphasized in information for consent and mislead surgeons to begin it without adequate training and elaborate environment. The lack of ethical documentation creates a high degree of suspicion of the studies.

Immunotherapy of head and neck cancer: current and future considerations.

Patients with head and neck squamous cell carcinoma (HNSCC) are at considerable risk for death, with 5-year relative survival rates of approximately 60%. The profound multifaceted deficiencies in cell-mediated immunity that persist in most patients after treatment may be related to the high rates of treatment failure and second primary malignancies. Radiotherapy and chemoradiotherapy commonly have severe acute and long-term side effects on immune responses. The development of immunotherapies reflects growing awareness that certain immune system deficiencies specific to HNSCC and some other cancers may contribute to the poor long-term outcomes. Systemic cell-mediated immunotherapy is intended to activate the entire immune system and mount a systemic and/or locoregional antitumor response. The delivery of cytokines, either by single cytokines, for example, interleukin-2, interleukin-12, interferon-gamma, interferon-alpha, or by a biologic mix of multiple cytokines, such as IRX-2, may result in tumor rejection and durable immune responses. Targeted immunotherapy makes use of monoclonal antibodies or vaccines. All immunotherapies for HNSCC except cetuximab remain investigational, but a number of agents whose efficacy and tolerability are promising have entered phase 2 or phase 3 development.

VEGF and ki 67 expression in squamous cell carcinoma of the tongue: An immunohistochemical and computerized image analysis study.

Over-expression of ki 67 and vascular endothelial growth factor (VEGF) is a frequent finding in squamous cell carcinoma (SCC) of the oral mucosa. The expression of VEGF and ki 67 proteins was studied in a cohort of 87 patients with primary, previously untreated SCC of the tongue, using computerized image analysis (CIA) in order to determine the potential prognostic significance of these factors. Immunohistochemical analysis was performed with monoclonal anti-ki 67 (MIB 1) and anti-VEGF antibodies. A digital image analysis assay was applied for the evaluation of the results. Using CIA, VEGF over-expression was observed in 24/87 (27.5%) of the examined cases and this finding correlated to the stage of the disease (p=0.05). ki 67 was over-expressed in 49/87 (56.3%) of the cases and correlated to the size of the tumors (p=0.05). Cox regression analysis showed that there was no prognostic significance associating VEGF protein expression to survival status of the examined patients (p=0.77), whereas ki 67 over-expression was strongly correlated to poor prognosis (p=0.017). The size of the primary tumors was also strongly correlated to survival status of the patients (p=0.024), whereas stage of disease showed a borderline statistical significance (p=0.091).

Giant Basal cell carcinoma: clinicopathological analysis of 51 cases and review of the literature.

BACKGROUND: Giant basal cell carcinoma (GBCC) is an aggressive malignant neoplasm. Because of the rarity of the tumor and its recognized high risk of recurrence, there are no guidelines for its treatment. PATIENTS AND METHODS: Published articles in PubMed Central were carefully reviewed. Data from 48 patients obtained from 30 individual articles were added to our 3 cases, producing a total number of 51 cases of GBCC. A clinical database was established in order to define the behavior of this tumor, prognostic factors and optimal treatment. RESULTS: GBCC mostly occurs in elderly male patients, with a peak incidence in the seventh decade of life. It develops as long-standing dermal tumor with mean disease duration of 14.5 years and is most commonly located on the back, followed by the face and upper extremity. The most common histological subtype is nodular. The average size at presentation is 14.77 cm in its largest diameter. The presence of metastasis at the time of presentation represents the most significant adverse prognostic factor. Local recurrence or metastasis develops in 38.3% of patients despite optimal therapy. The overall reported cure rate is 61.7% by a mean follow-up of 2 years. Wide local excision of the tumor with or without postoperative radiochemotherapy represents the optimal treatment. CONCLUSION: Optimal management of GBCC consists of wide local excision with histologically confirmed tumor-free margins, frequently followed by adjuvant therapy. In cases of lymphatic spread, a regional lymphadenectomy is also necessary. In addition, consideration should be given to a close and long-term follow-up because of the high rate of locoregional recurrence.