Improved survival in patients with head and neck cancer in the 1990s

It is generally felt amongst the medical profession and the lay public that cancer is being treated more successfully than in the past. This is certainly true for childhood malignancies and leukaemia but evidence that significantly improved survival is occurring in the common solid tumours is lacking. Since 1963 the University of Liverpool Department of Otolaryngology/Head and Neck Surgery has collected data on all patients with head and neck tumours presenting to the department. The present study investigates patients with histologically proven squamous cell carcinoma of the four main sites: larynx, hypopharynx, oral cavity and orophyarnx. From 1963 until the end of 1989, 2738 patients were seen by the department and from 1990 a further 717 patients have been seen. Since 1990 patients have tended to be in better general physical condition but, on the other hand, have tended to have more advanced disease at the primary site. The department has latterly tended to see fewer laryngeal cancers and more cancers of the oropharynx. Significantly fewer patients have presented with neck node metastases. Multiple logistic regression suggests that the most significant difference between the two groups is the great reduction in neck node recurrence rates in the group of patients seen since 1990 (P = 0.0001). The recurrence of tumours at the primary site since 1990 has been 35% compared with 41% before 1990, and recurrence in the neck nodes since 1990 has been 12%, compared with 15% before 1990. These differences are significant (P = 0.0141 and P = 0.0494, respectively). When studying survival in the 1960s, 1970s and 1980s, the 5-year cure rate was 50%, whereas since 1990 the figure has risen to 60% tumour-specific 5-year survival—a significant difference. A similar effect was noted in observed survival. This improvement in cure rate occurred for all four main sites. The results were confirmed by Cox’s proportional hazards model where year of treatment was highly significantly associated with improved survival (P = 0.0001). It has been demonstrated that locoregional recurrence has improved since 1990 and this is reflected in improved survival figures. Although there are differences in the parameters of tumours referred before 1990 and since 1990, multivariate analysis suggests that the improvement in neck node recurrence rates may be responsible for this improved survival rate. Multivariate analysis for survival also suggests that the improvement in cure rates is independent of compounding variables and dependent on the year of presentation of the tumour. This improved survival may be related to factors, such as the administration of radical postoperative radiotherapy.     

A contemporary review of indications for primary surgical care of patients with squamous cell carcinoma of the head and neck

The success of organ preservation protocols in laryngeal cancer has led to an increase in the use of primary chemoradiation in both laryngeal and extralaryngeal sites, despite a paucity of randomized controlled clinical trial data comparing nonoperative treatment to the gold standard of surgery followed by postoperative radiation for adverse pathologic features for head and neck cancer, and an increasing recognition that the high surgical salvage rates enjoyed by laryngeal cancer patients do not translate to extralaryngeal sites. These data suggest that there is a need to apply more rigorous standards to the use of organ preservation strategies and offer an opportunity to review the role of primary surgery in head and neck cancer. Laryngoscope, 2009     

Association of BMI-1 and p16 as prognostic factors for head and neck carcinomas

Conclusions BMI-1 is an upstream repressor of tumor suppressor p16 and their inverse expression patterns have been linked with patient survival in OPSCC. In this material only p16 remained a relevant prognostic marker in OPSCC.

Objectives HNSCC tumors carry variable phenotypes and clinical outcomes depending on their anatomical location. In OPSCC, expression of tumor suppressor p16 is used as a surrogate marker of HPV infection and has prognostic value. There are no good prognostic biomarkers for HNSCC tumors of other anatomical locations.

Aim To study the expression patterns of p16 and BMI-1 in not only oropharyngeal but also oral, hypopharyngeal, and laryngeal squamous cell carcinomas and to clarify their putative connections with clinical parameters, survival, and each other.

Method Hospital records on 130 patients (59 OPSCC, 18 OSCC, 20 HPSCC, and 33 LSCC) diagnosed between 1997–2008 at the Helsinki University Hospital, Finland, were reviewed. BMI-1 and p16 expressions were studied by immunohistochemistry.

Results Sixty-eight per cent of OPSCC expressed p16 and expression correlated with lower age, lower T- and higher N-category, and with improved OS and DFS. BMI-1 expression was most prevalent in OPSCC and LSCC, but had no clinical correlations. No correlation between p16 and BMI-1 expression was found.     

Perifacial lymph node metastasis in the submandibular triangle of patients with oral and oropharyngeal squamous cell carcinoma with clinically node-positive neck

OBJECTIVES: The objectives of this retrospective chart review were to investigate the rate of metastasis to the perifacial lymph node, which was defined as the nodal pads that lie anterior or posterior to the anterior facial vein on top of the facial artery in the submandibular triangle, and to identify its risk factors in patients with oral and oropharyngeal squamous cell carcinoma (OOSCC) with clinically node-positive neck. METHODS: Beginning in July 1999, we routinely removed the perifacial lymph node pads of the submandibular triangle (level Ib) from the main therapeutic comprehensive neck dissection (level I-V) specimen for evaluation of metastatic rate to this nodal group in patients with OOSCC with clinically node-positive neck. This study is a retrospective analysis of patients undergoing perifacial node sampling from July 1999 to March 2006. A total of 66 patients (17 patients with oral cavity cancer and 49 with oropharyngeal cancer) underwent perifacial lymph node dissections. Of these, three (two with oral cavity tumors and one with an oropharynx tumor) had clinically positive node in level I. RESULTS: The incidence rate of metastasis to the perifacial lymph node was 35% in oral cavity carcinoma (six of 17) and 8% in oropharynx carcinoma (four of 49). In addition, in patients without clinically positive level I node, the occult metastasis rate of the perifacial node was 27% in oral cavity carcinoma (four of 15) and 6% in oropharynx carcinoma (three of 48). Clinical or pathologic nodal staging above the N2b advanced lesion had a statistically significant association with perifacial lymph node metastasis (P < .05). CONCLUSION: Our data suggest that these nodal pads should be removed thoroughly for the treatment of node-positive neck in patients with oral cavity carcinoma. In contrast, however, complete removal may be unnecessary in comprehensive neck dissection of patients with oropharyngeal carcinoma with clinically node-positive neck, especially below nodal stage N2a.     

Squamous cell carcinoma antigen in patients with cancer of the larynx

The purpose of this study was to evaluate the clinical usefulness of squamous cell carcinoma antigen (SCC Ag) in patients with squamous cell carcinoma of the larynx. Plasma specimens were obtained from 70 patients with cancer of the larynx before and after treatment and during follow-up. Disease status and the marker levels were determined blind to each other. Microparticle enzyme immunoassay (IMx SCC) was used to measure the SCC Ag level. Applying standard normal limits the sensitivity of the marker at diagnosis was 25.7%. SCC Ag levels were generally lower after therapy than before. Relapse occurred more often in patients with an abnormal pretreatment SCC Ag level, which was more frequent in those with nodal invasion. The marker level increased in 70% of the patients with relapse before the clinical detection of recurrence. SCC Ag is of limited usefulness in the primary diagnosis of cancer of the larynx, but is useful in detecting recurrence of cancer.     

Second primary squamous cell carcinoma arising in cutaneous flap reconstructions of two head and neck cancer patients

Early complications of myocutaneous flap transfers following surgical eradication of head and neck tumors have been extensively described. However, knowledge concerning long-term complications of these techniques remains limited. We report the cases of two patients with a prior history of squamous cell carcinoma of the head and neck (HNSCC), who developed a second primary SCC on the cutaneous surface of their flaps, years after reconstruction. Interestingly, it seems that the well-known risk of a second primary SCC in patients with previous head and neck carcinoma also applies to foreign tissues implanted within the area at risk. Given the important expansion of these interventions, this type of complication may become more frequent in the future. Therefore, long-term follow-up of patients previously treated for HNSCC not only requires careful evaluation of the normal mucosa of the upper aero-digestive tract, but also of the cutaneous surface of the flap used for reconstruction.     

The influence of lymph node metastasis in the treatment of squamous cell carcinoma of the oral cavity, oropharynx, larynx, and hypopharynx: N0 versus N+

OBJECTIVES/HYPOTHESIS: Management of the N0 neck is a continuing controversy. The study compares the influence of N0 and N+ disease on the results of treating squamous cell carcinoma (SCCA) of the oral cavity (OC), oropharynx (OP), larynx (LX), and hypopharynx (HP) with five different treatment modalities. The study also compares the results of four different approaches to the treatment of the N0 neck. STUDY DESIGN: A retrospective study of 3887 patients. METHODS: Patients in the Tumor Research Project of the Department of Otolaryngology-Head and Neck Surgery of the Washington University School of Medicine (St. Louis, MO) with biopsy-proven previously untreated SCCA of one of the four above-mentioned regions who were treated with curative intent by one of five modalities and who were eligible for 5-year follow-up were included in the study. The treatment modalities included local resection of primary alone (LR), composite resection (primary with neck dissection) (CR), radiation therapy alone (RT), local resection with radiation therapy (LR/RT), and composite resection with radiation therapy (CR/RT). The N0 neck was treated with one of four approaches: observation with close follow-up reserving treatment only for subsequent neck disease, neck dissection, RT to the neck region, and a combination of neck dissection with RT. Multiple diagnostic, treatment, and follow-up parameters were studied using standard statistical analyses to determine statistical significance. RESULTS: The 5-year disease-specific survival (DSS) for the all-sites group (ASG) was 59%. The DSS for the subsites included the following: OC, 53%; OP, 47%; LX, 70%; and HP, 42%. Patients with N0 disease had significantly better DSS than patients with N+ disease at all sites. Occult neck disease in N0 patients was low with 4% pN1 for ASG, OC, and LX and with 11% pN1 for OP and HP. There was 3% pN2 for LX, 4% pN2 for ASG and OC, and 6% pN2 for OP and HP. The DSS for patients with occult neck disease was statistically similar to that of N+ patients. Prognostic survival indicators included age, decade of treatment, T stage, N stage, TN stage, treatment modality, and recurrence. Patients over 65 years of age had poorer DSS than younger patients. Staging T, N, and TN affected survival at all sites. Local resection produced better DSS for ASG, OC, LX, and HP patients. Local resection with radiation therapy produced increased DSS for ASG and OC patients. There was no survival advantage for HP patients related to treatment modality. Treatment of the N0 neck with observation and later treatment for subsequent neck disease produced a survival advantage for patients in the ASG. This advantage was specific for ASG and LX patients staged T1N0. For patients staged T2N0, T3N0, and T4N0 at all four subsites there was no survival advantage for any of the four neck approaches. CONCLUSION: Lymph node metastasis significantly and negatively affects DSS in patients with SCCA of the OC, OP, LX and HP. The rate of occult neck disease (pN+) in N0 patients receiving meticulous workup is low. When present, it produces DSS rates similar to those found in N+ patients. In the study series, there was decreased survival in patients older than 65 years of age, in patients with advanced tumor (T, N, TN), and in patients with recurrent disease. None of the four current approaches to treatment of the N0 neck produces a significant survival advantage. Close observation with later treatment reserved for subsequent neck disease produces statistically similar survival (DSS) to the three elective (prophylactic) treatments and is a valid form of treatment. It may preclude unnecessary treatment of the neck with its attendant risks and complications.     

Prognostic significance of lymph node reactivity in patients with laryngeal carcinoma

Apart from the presence or absence of metastases in patients with laryngeal carcinoma, there are changes of reactivity in cervical lymph nodes that are seen histologically as nonspecific reactive lymphadenitis. These changes are morphological manifestations of the regional lymphatic system reactivity in relation to tumor, and their presence may be of prognostic value. To test this hypothesis, 45 patients with laryngeal carcinoma were examined for the evidence of node reactivity. The classification applied by Tsakraklides et al. was used, defining patterns of lymphocyte predominance, germinal center appearance (indicating lymph node stimulation) and whether or not lymphocyte depletion had occurred. The presence of node reactivity was compared with long-term (5-year) survivals in the group of patients studied. By applying statistical analysis it was found that lymph node stimulation was a favorable prognostic factor, while its absence worsened prognosis.     

The clinical value of serum squamous cell carcinoma antigens 1 and 2 in head and neck squamous cell carcinoma

Objective

The usefulness of pretreatment measurement of SCC antigen in patients with head and neck SCC is still controversial. Our aim of this study was to evaluate the clinical usefulness of serum SCC antigen, SCCA1 and SCCA2 in the management of patients with head and neck SCC.

Prognostic factors for parotid metastasis of cutaneous squamous cell carcinoma of the head and neck

BackgroundCutaneous squamous cell carcinoma (CSCC) develops on the head in 80% of cases. Parotid metastasis (PM) is rare, but treatment, which associates surgery and radiation therapy, is heavy and prognosis poor.Material and methodsAll cases of parotidectomy for PM of CSCC of the head and neck between 2005 and 2015 were studied retrospectively. Epidemiologic, oncologic and therapeutic data were analyzed. Overall and specific survival were calculated following Kaplan-Meier. Log-rank and Cox models were used to identify prognostic factors for PM.ObjectivesThe principal study objective was to identify factors for survival in PM from CSCC of the head and neck.ResultsThirty-five patients were included. Mean time to onset of PM was 13 months. Overall 1-, 2- and 5-year survival was respectively 70, 66 and 59%. Independent prognostic factors comprised immunodepression, age at treatment, positive CSCC margins, macroscopic facial nerve involvement, and metastatic cervical adenopathies.ConclusionThe study confirmed an association of several independent prognostic factors at the stage of parotid lymph-node metastasis, related to patient, primary CSCC and PM. Complete primary resection is essential to reduce the risk of PM. Intensified radiologic and clinical surveillance should enable early diagnosis.     

Circulating fragments of cytokeratin 19 in patients with head and neck squamous cell carcinoma

In head and neck squamous cell carcinoma a reliable serum marker of carcinogenesis should be of predictive value for the development of recurrent disease or a second primary tumour. At the moment, such a tumour marker is not available. Recently, elevated levels of cytokeratin 19-fragments (Cyfra 21-1) have been detected in the serum of patients with lung cancer, in particular with squamous cell carcinoma. Cytokeratin 19 is an intermediate cell filament protein expressed in simple epithelia and their malignant counterparts. Therefore, in this prospective study, a standardized sandwich enzyme-linked immunosorbent assay for soluble cytokeratin 19 fragments was tested in the serum of 20 patients with a previously untreated head and neck squamous cell carcinoma. The results were compared with that of 20 control individuals. Our results showed significantly higher Cyfra 21-1 concentrations in the serum of patients with cancer (10.21 ± 3.03 ng/ml) than the controls (7.2 ± 2.63 ng/ml). After radical treatment the marker levels dropped significantly to 1.65+ 1.07 ng/ml. Cyfra 21-1 appears to be of value as a circulating tumour marker for head and neck squamous cell carcinoma especially in monitoring disease control.     

Prognostic significance of nodal ratio in cutaneous squamous cell carcinoma of the head and neck

The TNM classification is not specific for head and neck skin cancer and makes no allowance for disease extent. Studies have shown that the relative number of metastatic-to-examined lymph nodes, termed the Nodal ratio, is a reliable independent prognosticator in several types of cancer. The study was designed as a retrospective analysis in a university affiliated tertiary care center setting. The files of all patients (n = 71) with cutaneous head and neck squamous cell carcinoma and regional lymph node metastasis who attended a tertiary medical center between 1990 and 2008 were reviewed for clinical variables and outcome, and Nodal ratio was calculated. Data were analyzed for impact on survival. On multivariate analysis Nodal ratio and age were found to be significant predictors of overall survival. The N-ratio was the only significant predictor of disease-specific survival. Age, type of treatment (selective/modified neck dissection), pathologic N stage, and radiotherapy had no effect. The Nodal ratio is a potentially valuable prognostic index in cutaneous squamous cell carcinoma. The minimal number of nodes that need to be excised has to be determined.     

Elective neck dissection and survival in patients with squamous cell carcinoma of the oral cavity and oropharynx

OBJECTIVE/HYPOTHESIS: The utility of elective neck dissection in the management of patients with oral cavity and oropharyngeal cancer who present without neck metastases remains controversial. The study addressed the question of whether elective neck dissection improves regional control and survival in patients with squamous cell carcinoma of the oral cavity and oropharynx presenting with T1/T2 node-negative disease. STUDY DESIGN: A nonrandomized, uncontrolled retrospective chart review. METHODS: A nonrandomized, uncontrolled retrospective chart review was performed. Resection of the primary tumor was performed in all patients. The neck was observed in one group, and elective neck dissection was performed for patients in another group. RESULTS: The study data indicated that elective neck dissection significantly improves regional control and regional recurrence-free survival. Elective neck dissection when compared with observation of the neck did not improve overall survival. CONCLUSION: Elective neck dissection reduces regional recurrence and may extend disease-free survival.     

Galectin-3 upregulation during tumor progression in head and neck cancer

Objectives/Hypothesis: To examine the level of expression of galectin-3 in relation to neoplastic progression of hypopharyngeal squamous cell carcinomas (HSCCs) and laryngeal squamous cell carcinomas (LSCCs). Study Design: Retrospective study. Methods: Using a polyclonal antibody against galectin-3 without cross-reactivity to other galectins, we analyzed the presence of galectin-3 using quantitative immunohistochemistry in i) a series of 79 HSCCs compared with 16 normal epithelia, 20 low-grade dysplasia (Low_D) and 25 high-grade dysplasia (High_D) and in ii) a series of 58 LSCCs compared with 34 normal epithelia, 12 Low_D, and 18 High_D. In parallel, galectin-3 expression was studied using Western blotting on a series of 19 fresh biopsies from patients presenting a head and neck tumor. Results: Western blotting excluded a notable degree of proteolytic truncation of galectin-3 in situ. Immunohistochemical galectin-3 positivity expressed as percentage of cells was significantly higher in LSCCs and HSCCs than in Low_D (P = .01) or High_D (P = .0002), respectively. Increased expression of galectin-3 in HSCCs was accompanied by a shift from the cytoplasmic compartment to the nucleus (P = .007). In intertumor-type comparison, laryngeal carcinomas presented nuclear presence of galectin-3 only rarely (1 of 58 cases in laryngeal cancer vs. 27 of 79 cases in hypopharyngeal cancer, P = .00006) and a comparatively low labeling index (P < 10⁻⁶). Conclusions: Our data reveal an association between level of presence of galectin-3 and neoplastic progression of HSCCs and LSCCs.