Image-guided surgery in head and neck cancer: current practice and future directions of optical imaging.

A key aspect for the postoperative prognosis of patients with head and neck cancer is complete tumor resection. In current practice, the intraoperative assessment of the tumor-free margin is dependent on visual appearance and palpation of the tumor. Optical imaging has the potential of traversing the gap between radiology and surgery by providing real-time visualization of the tumor, thereby allowing for image-guided surgery. The use of the near-infrared light spectrum offers 2 essential advantages: increased tissue penetration of light and an increased signal-to-background ratio of contrast agents. In this review, the current practice and limitations of image-guided surgery by optical imaging using intrinsic fluorescence or contrast agents are described. Furthermore, we provide an overview of the various molecular contrast agents targeting specific hallmarks of cancer that have been used in other fields of oncologic surgery, and we describe perspectives on its future use in head and neck cancer surgery.

Dysphagia after an L-shaped reconstruction technique of the free jejunum graft.

BACKGROUND: The free jejunum graft is a well-established reconstruction technique after total laryngopharyngectomy. However, besides necrosis of the jejunum graft, the two most important complications are pharyngocutaneous fistula formation and dysphagia due to stricture formation. OBJECTIVES: This study aims to develop an L-shaped reconstruction technique of the free jejunum graft to decrease pharyngocutaneous fistula formation and long-term stricture formation after total laryngopharyngectomy. METHODS: An L-shaped side-to-end anastomosis was performed at the proximal end of the jejunum graft in six patients treated for piriform sinus carcinoma. Patient and operation characteristics and follow-up were recorded. RESULTS: A successful jejunum transfer was performed in all six patients. No pharyngocutaneous fistula or stricture formation occurred during a median follow-up of 23 months (range: 18-30 months). Swallowing rehabilitation started at the median 12th postoperative day (range: 5-150 days). Four patients developed dysphagia at a median of 2 months (range: 1-6 months) after oral intake was started. X-barium swallow revealed a redundant pouch of the transferred jejunum graft, which resulted in compression on the jejunum interposition during swallowing. In three patients, an operation was required to resolve these problems. After the revision operation, no dysphagia occurred during a median follow-up of 12 months (range: 7-13 months). CONCLUSIONS: Because of dysphagia complaints in the majority of our patients, we cannot recommend the described technique and should find other means to improve direct postoperative results and long-term quality of life in this difficult-to-treat group of patients.

Selective neck dissection for N0 and N1 oral cavity and oropharyngeal cancer: are skip metastases a real danger?

OBJECTIVES: To contribute to insight in therapeutic safety of selective neck dissections for oral cavity and oropharyngeal cancer with a special focus on the risk of skip metastases. DESIGN: Retrospective data analysis. SETTING: Tertiary referral centre. PARTICIPANTS: A total of 291 patients operated for oral cavity or oropharyngeal squamous cell cancer between 1999 and 2004. MAIN OUTCOME MEASURES: Incidence of skip metastases in both pathologically N0 and N+ necks for oral cavity and oropharyngeal cancer. RESULTS: Of all neck dissections (n = 226) performed for oral cavity cancer, skip metastases to level III or level IV occurred in 14 cases (6%). Ten skip metastases occurred in level III only (10/226 = 4%). Thus, four necks had metastases in level IV, which would not have been removed in case of a Selective neck dissection level I-III (supraomohyoid neck dissection). In case of oropharyngeal cancer, skip metastases to level III or level IV occurred in six of 92 cases (7%). Five skip metastases occurred in level III only (5/92 = 5%). This means that of the necks containing skip metastases, only one neck (1%): had metastases in level IV, which would not have been removed in case of a Selective neck dissection level I-III (Supraomohyoid neck dissection). CONCLUSIONS: The question whether level IV should be included in the treatment of N0 and even N1 necks of patients with cancer of the oral cavity and oropharynx cannot be answered by all data available to us now. The fear of skip metastases including level IV does not seem to be justified.

Reliability of interpretation of CT examination of the larynx in patients with glottic laryngeal carcinoma.

INTRODUCTION: Reports in literature suggest that tumor volume, cartilage invasion, and cartilage sclerosis are independent prognostic factors for tumor control in radiotherapy as primary treatment of laryngeal carcinomas. OBJECTIVE: Assessment of the interobserver variability and prognostic value in the measurement of tumor volume, cartilage invasion, and sclerosis. MATERIALS AND METHODS: Retrospective analysis of 55 CT scans by three independent observers. Volume measurements and determination of cartilage invasion, cartilage sclerosis, and tumor localization were calculated. Correlation between the prognostic factors and radiotherapy was calculated for each observer. RESULTS: Values for interobserver agreement varied substantially; cartilage invasion (kappa value: -0.02 to 0.66), cartilage sclerosis (kappa value: 0.13 to 0.57), tumor localization of subsites (kappa value: 0.03 to 0.60), and tumor volume (correlation: 0.34 to 0.73). The found interobserver variation makes it impossible to establish accurate prognostic factors. CONCLUSION: Determination of tumor volume, cartilage invasion, and cartilage sclerosis on the basis of CT imaging shows considerable interobserver variation; clinical significance appears to be limited. EBM RATING: B-3a.

Treatment of hypopharyngeal carcinoma: analysis of nationwide study in the Netherlands over a 10-year period.

OBJECTIVE: To analyse different treatment strategies and treatment results of hypopharyngeal carcinoma in the Netherlands. DESIGN: Retrospective study. SETTING: Eight head and neck centres in the Netherlands. PARTICIPANTS: A total of 893 patients were treated between 1985 and 1994. Patients were mostly treated with radiotherapy alone, combined surgery and radiotherapy and surgery alone. RESULTS: The 5-year survival for the whole group was 26%. The 5-year survival for patients treated with curative intention was 32% and treated with palliative intention was 5%. The 5-year disease-free survival after radiotherapy alone was 37%, after surgery alone 41% and after combined therapy 47%. The role of chemotherapy could not be investigated because of a small number of patients treated with chemotherapy in this period. CONCLUSION: Combined therapy with surgery and radiotherapy has a better survival for patients with a hypopharyngeal carcinoma in comparison with radiotherapy alone. The N-stage is more important for the prognosis than the T-stage.

Squamous carcinoma of the external auditory canal: a different approach.

Squamous carcinoma of the external ear canal is a rare disease and a challenge to treat. Some controversy exists regarding the best options for treatment. Reported 5-year survival varies between 35% and 63%. Since 1976, we have adopted a conservative approach to these tumours, with patients undergoing a specific protocol of meticulous tumour debulking followed by a course of repeated topical 5-fluoro-uracil (5-FU) cream application and necrotectomy. Data was collected prospectively. From 1976 to 1998, 23 patients underwent primary treatment according to our protocol. Nine patients had T1 disease whereas six had T2 and eight had T3 disease. The 5- and 10-year overall survivals were 74% and 60% respectively. These results compare very favourably with those in the literature and surgical debulking with topical 5-FU and necrotectomy remains our primary treatment of choice for squamous cell carcinoma of the external auditory canal.

CO2-laser treatment of recurrent glottic carcinoma.

BACKGROUND: Evaluation of the results of CO2 laser treatment of recurrent glottic carcinoma after radiotherapy. METHODS: Records of all patients treated in the University Hospital Rotterdam and the Dr. Daniel den Hoed Cancer Center between 1980 and 1996 by CO2 laser for recurrent glottic carcinoma were studied. RESULTS: Forty patients were treated by laser surgery. Average follow-up was 77 months. Twenty-three patients (58%) had another recurrence develop after laser surgery. Three were cured by a second laser procedure. Therefore, 20 patients (50%) were successfully treated with laser surgery. In 23 patients the recurrence did not extend into the anterior commissure; in 57% a total laryngectomy could be avoided. In 17 patients the recurrence did extend into the anterior commissure; in 41% a total laryngectomy was avoided. CONCLUSION: Most patients with recurrent carcinoma of the larynx after radiotherapy can be cured by laser surgery if the tumor does not extend into the anterior commissure.

Lymphoid cell infiltration into Epstein-Barr virus-positive nasopharyngeal carcinomas.

OBJECTIVES: A pilot study was designed to analyze lymphoid cell infiltration in Epstein-Barr virus-positive (EBV+) nasopharyngeal carcinomas (NPCs) and to determine whether this pattern of infiltration is consistent with non-EBV+ head and neck carcinomas or with solid EBV+ tumors in other locations. STUDY DESIGN: We performed a retrospective analysis of archived NPCs and oral cavity carcinomas. METHODS: Immunohistochemical staining of the archive material for various markers (CD3, CD8, UCHL-1, S-100, and intercellular adhesion molecule) was performed. Polymerase chain reaction techniques to establish the presence of the EBV genome were used. Cells in different locations were counted under a light microscope by 2 of the authors. RESULTS: The infiltration pattern of NPCs was different from that of oral cavity carcinomas. Stromal infiltration was significantly denser in oral cavity carcinomas. Tumor nest infiltration was more pronounced in NPCs. The pattern of infiltration was comparable with what has been described for other solid EBV+ tumors. CONCLUSIONS: The immune response to NPCs is likely to be strongly influenced by the presence of the EBV genome. The pattern of infiltration is similar to that of other non-head and neck EBV+ solid tumors and different from that of EBV- head and neck carcinomas.

Nasopharyngeal brush biopsies and detection of nasopharyngeal cancer in a high-risk population.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is an important tumor in many countries. Ethnic and regional factors strongly influence disease risk. NPC is usually diagnosed late in disease development, and 10-year survival rates are as low as 10%. Epstein-Barr virus (EBV), a possibly causative agent, is present in all cells of essentially all undifferentiated NPCs. We wished to determine the following: 1) whether an ambulatory nasopharyngeal brush biopsy could provide sufficient tumor cell DNA for the detection of EBV and 2) whether the detection of EBV in this locale reflects the presence of tumor cells or simply EBV carrier status. METHODS: We collected nasopharyngeal tissue via ambulatory brush biopsies from 21 patients with newly diagnosed NPC and from 157 subjects with other otolaryngologic complaints. The majority of study subjects were from high-risk populations. Sample DNA was analyzed for the presence of EBV genomic sequences by use of the polymerase chain reaction (PCR). RESULTS: Ninety-six percent of samples yielded sufficient DNA for PCR amplification. Nineteen of 21 patients with NPC brushed positive for EBV DNA, while all but two (1.3%) of 149 informative control subjects were negative for EBV (two-sided P<.0001). One of the EBV-positive control subjects had an EBV-positive inverted sinonasal papilloma; the other EBV-positive control subject exhibited no overt clinical disease. CONCLUSION: Demonstration of EBV DNA in nasopharyngeal brush biopsy specimens detects NPC with a sensitivity of at least 90% (95% confidence interval = 89.63%-91.32%) and a specificity of approximately 99% (95% confidence interval = 98.64%-98.68%). This technique merits further testing as a possible ambulatory screening strategy in high-risk populations.

Supraomohyoid neck dissection. Is it diagnostic or therapeutic?

BACKGROUND: The supraomohyoid neck dissection (SOHND) is often performed in patients with cancer of the oral cavity, where there is no clinical or radiologic evidence of regional metastases. When on pathologic examination positive neck nodes are found, however, some consider it a curative operation, whereas others regard it as a staging procedure only. METHODS: We retrospectively reviewed 43 patients with cancer of the oral cavity who had a SOHND during the period from 1991 to 1994. All patients were staged as having N0 disease and had a total of 48 SOHNDs (38 unilateral, 5 bilateral). The follow-up period was at least 2 years. RESULTS: Seven of 48 N0-staged necks showed occult metastasis (15%). Two of these patients received postoperative radiotherapy. One of 7 (14%) patients with pathologic node-positive disease on the SOHND side developed recurrent ipsilateral neck disease during the follow-up period, whereas 4 (10%) recurrences developed in 41 necks that were pathologically staged as N0. Survival was 88% for patients with pathologically N0 necks versus 86% for patients with pathologically N+; disease. CONCLUSION: Supraomohyoid neck dissection is an effective staging procedure; however, in this group of patients, neck recurrence and patient survival after SOHND appear not to be related to pathology N stage. Also, SOHND with or without adjuvant radiotherapy appears to control the neck in the majority of patients, attesting to therapeutic efficacy. A prospective study is needed, however, to see if a "wait and see" policy does not achieve similar long-term outcome.

Facial nerve reconstruction: outcome and failures.

OBJECTIVE: Our study was conducted to assess the outcome of reconstruction of the facial nerve after various resections for parotid neoplasms. METHOD: A 10-year retrospective analysis of 350 primary parotid neoplasms (of which 70 were malignant) and 10 recurrent benign neoplasms involving facial nerve resection in 19 and 2 patients, respectively. Four patients had total resection of the facial nerve and reconstruction with a five-branch assemblage using standard microtechniques. Four patients had reconstruction of the orbital branch only. Twelve patients, of whom three also had a midface branch reconstructed, had reconstruction of the ramus mandibularis. One patient had a direct anastomosis of a partial resection of the main trunk of the nerve. Objective assessment of muscle activity was carried out in the distribution of the reconstructed nerve with a minimum of 18 months follow-up. RESULTS: All four patients with total facial nerve reconstruction had excellent tone in repose. None had purposeful focused movement, and all had mass movement; however, all had good eye closure. None of the patients with mandibular branch grafting alone had useful return of function, but those who had concomitant midface grafting had good return of function of the reconstructed branches. All patients who had orbital grafting had appropriate eye closure. CONCLUSIONS: Facial nerve grafting is effective to rehabilitate gaps in the pes anserinus, even if patients undergo postoperative radiotherapy. Total nerve grafting provides good tone in repose and eye closure, which justifies the procedure. Single-branch grafting is mandatory for the orbital branch, but one can question the use of a single-branch graft for the mandibular branch.

The physiologic reservoir of Epstein-Barr virus does not map to upper aerodigestive tissues.

The human Epstein-Barr herpesvirus (EBV) has distinct oncogenic potential, but with over 90% of the adult world population infected, malignancy is a rare outcome of carrier status. However, EBV's association with over half of Hodgkin's and non-Hodgkin's lymphomas as well as several solid tumors, notably nasopharyngeal carcinoma, makes EBV-linked malignancies one of the largest single cancer entities. EBV is a B-lymphotropic virus, well controlled by surveillant T cells in immunocompetent hosts. To determine the presence and site of principal virus reservoirs is a likely prerequisite for understanding the etiology of EBV-associated tumors. Its near 100% association with nasopharyngeal carcinoma led to postulates that the upper aerodigestive tract tissue may be common sites of persistent latent or low-grade replicating infection. Using a protocol designed to avoid viral crosscontamination, the authors employed polymerase chain reaction to detect genomic EBV DNA sequences in 231 biopsies from different mucosal sites in the upper aerodigestive tract, as well as from salivary gland tissue and neck nodes in individuals not suspected to have EBV-related malignancy. Only two samples, one from oral cavity mucosa and one from parotid gland tissue, were positive for EBV. The observation that oropharyngeal tissue is not the principal EBV reservoir has mechanistic implications for the development of EBV-positive tumors in that locale.

The effects of thymostimulin on immunological function in patients with head and neck cancer.

Patients with head and neck carcinoma show deficits of cellular immunity, probably due to low molecular mass factors (LMMFs) released by the tumour. Thymostimulin (TP1) restores the defective monocyte chemotaxis and dendritic cell clustering capability in the presence of the tumour when administered pre-operatively. In the present study we investigated these immune parameters in 39 patients treated with TP1 for 10 days pre- and 6 months post-operatively and in 22 patients who were not treated with TP1 for 6 months after operation. Removal of the tumour in non-TP1-treated patients also resulted in a restoration of monocyte and dendritic cell functions, while TP1 treatment gave no additional effect. LMMF levels in the blood of both TP1-treated and non-TP1-treated patients remained elevated even after removal of the tumour, and it is therefore concluded that it is unlikely that depression of cellular immunity is a direct effect of these LMMFS.

Thymostimulin enhancement of T-cell infiltration into head and neck squamous cell carcinoma.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) produces immunosuppressive low-molecular-mass factors (LMMFs) responsible for defects in the cell-mediated immune system. These defects include impaired monocyte chemotaxis and an impaired capability of dendritic cells (DC) to form cellular clusters. It has been shown previously that the immunomodulating drug thymostimulin (TP1) restores these defects in vitro. METHODS: An immunohistochemical study was performed on tumors of 18 patients with HNSCC who had preoperatively been treated with TP1 in one of three dosages (0.5 mg/kg, 1.0 mg/kg, 2.0 mg/kg body weight). Additionally, tumors of 4 patients who had been treated with a placebo and 12 patients who had not received any preoperative treatment were studied. A relative surface area of infiltration, meaning the percentage of stromal or epithelial tissue covered by infiltrating cells in histological sections, was calculated using an image analysis system (VIDAS RT) for CD3+ T-cells, CD14+/CD68+ monocytes/macrophages and L25+/CD1a+ dendritic cells for each tumor. RESULTS: A highly significant, denser T-cell infiltration into the stromal tissue area of tumors of patients who had been treated with TP1 when compared with tumors of non-TP1-treated patients was observed for all three dosages. None of the other tumor-infiltrating cell types was affected by TP1. In addition, a correlation was found between the tumor T-cell infiltration and capability of DCs in the peripheral blood to form clusters with T-cells. No correlation existed between CD3+ T-cell numbers in peripheral blood and T-cell infiltration into the tumor; nor were monocyte chemotactic functions in peripheral blood correlated with tumor infiltration by monocytes or monocyte-derived macrophages and DCs. CONCLUSIONS: Preoperative treatment of HNSCC patients with TP1 appears to strongly enhance tumor--T-cell infiltration. The number of tumor-infiltrating DCs was not affected by TP1, but a positive correlation between tumor--T-cell infiltration and DC clustering capability suggests that the functional status of DCs is important in improved cell-mediated immunity.

If functional sinus surgery fails: a radical approach to sinus surgery.

Radical surgery of the nose and paranasal sinuses was performed in 56 patients as a last resort for severe recurrent treatment-resistant rhinosinusitis. Surgery consists of removal of all walls between the nasal fossa and the paranasal sinuses, creating one cavity. All patients were permanently relieved of sinusitis and nasal obstruction, and other symptoms were greatly reduced. Morbidity is low in relation to preoperative symptoms. We conclude that radical sinus surgery is an effective last resort if functional sinus surgery repeatedly falls.

In vivo effects of thymostimulin treatment on monocyte polarization, dendritic cell clustering and serum p15E-like trans-membrane factors in operable head and neck squamous cell carcinoma patients.

Head and neck squamous cell carcinoma patients have been characterized by impairments in their cell-mediated immune system, particularly by decreased chemotactic function of monocytes and impairments in the function of the monocyte-derived dendritic cells (viz, a decreased capability to form cell "clusters"). These impairments are thought to be due to immunosuppressive factors of low molecular mass released by tumor, the so-called p15E-like factors. These suppressive effects of p15-like factors can be neutralized in vitro by thymic peptides, such as thymostimulin (TP1). In a randomized double-blind, placebo-controlled multicenter trial in the Netherlands, 41 patients with operable head and neck squamous cell carcinomas (HNSCC) were treated for 10 days prior to surgery with intramuscular TP1 in one of three dosages (0.5 mg/kg; 1.0 mg/kg or 2.0 mg/kg body weight) or treated with placebo. Assessment of monocyte chemotaxis, the capability of dendritic cells to form clusters and the presence of p15E-like low-molecular-mass factors (LMMFs) in serum was performed before TP1 treatment and on the day of surgery. Findings demonstrated that TP1 in a dose of 1.0 mg/kg and 2.0 mg/kg resulted in normalization of impaired monocyte chemotactic capability. Although the cluster capability of dendritic cells after TP1 treatment improved, values only reached statistical significance for the 0.5 mg/kg group. Serum p15E-like LMMF levels were not affected by TP1 treatment in any of the patient groups. Contrary to expectations we found no correlation between elevated immunosuppressive LMMFs and defective monocyte chemotaxis or cluster capability of dendritic cells. We conclude that treatment with TP1 can improve monocyte chemotaxis in HNSCC patients but an effect on the production of p15E-like factors by carcinoma cells could not be demonstrated.

Macrophage and dendritic cell infiltration in head and neck squamous-cell carcinoma; an immunohistochemical study.

A study was undertaken to help us reach a better understanding of the tumor-infiltrating pattern of lymphoid cells and in particular of monocyte-derived cells, namely the CD68+, acid-phosphatase-expressing scavenger macrophages and the MHC-class-II- and S100-antigen-presenting dendritic cells in head and neck squamous-cell carcinoma. In the stroma of the tumors distinctive small fields of lymphocytes were found, the T cell areas of these fields being intermingled with dendritic cells. Intra-epithelial dendritic cell infiltration was low. The infiltrative pattern of macrophages was similar to patterns described in earlier studies with substantial stromal invasion and inconsistent intra-epithelial invasion, but small granuloma-like structures of CD68+ macrophage-like cells, found in the stroma of tumors, have not been reported before. The histochemical localization of the tumor-infiltrated dendritic cells and macrophages supports the view that the former cells are involved in the sensitization to tumor antigens, whereas the latter cells are involved in tumor cytotoxicity/scavenging of tumor cell debris. Although it has been shown in the past that transmembranal (TM) factors (p15E-like factors) present in the serum and tumor of patients with cancer of the head and neck have suppressive effects on monocyte/macrophage/dendritic cell function, a relationship between the intensity of epithelial staining for TM factors and the infiltrative pattern of monocytes/macrophages/dendritic cells could not be demonstrated.

Nasal and paranasal disease in adult cystic fibrosis patients.

Children with cystic fibrosis frequently have nasal polyps and sinusitis. This study addresses (para-) nasal disease in 39 adult cystic fibrosis patients. Fifteen patients (39%) had recently had serious nasal symptoms and 26% sinusitis. Seventeen (44%) had nasal polyposis. Almost all sinus radiographs taken showed opacification, which was unrelated to symptoms. Polypectomies and antral irrigations were usually ineffective, whilst more extensive surgery generally gave better results. It is concluded that a substantial number of adult cystic fibrosis patients frequently have upper airway symptoms. Sinus radiographs have little or no diagnostic value. Treatment of (para-) nasal disease in cystic fibrosis patients can be difficult; a guideline for treatment is suggested, calling for simple interventions coupled with intranasal steroids and nasal irrigation in early disease and for endoscopic to radical sinus surgery in recurrent advanced disease.