The effect of P53 expression and smoking/alcohol in P16(+) and P16(-) oropharyngeal carcinoma and risk classification: the Turkish Society of Radiation Oncology Head & Neck Study Group 01-002.

OBJECTIVE: The aim of this study is to categorize the risk groups of patients with oropharyngeal carcinoma (OPC) according to p16 and p53 status, smoking/alcohol consumption history, and other prognostic factors. STUDY DESIGN: The immunostaining of p16 and p53 of 290 patients was retrospectively evaluated. The history of smoking/alcohol consumption of each patient was noted. p16 and p53 staining patterns were reviewed. The results were compared with demographic findings and prognostic factors. Risk groups have been classified for the p16 status of patients. RESULTS: The median follow-up was 47 months (range 6-240). Five-year disease-free survival (DFS) rates for patients with p16 (+) and (-) were 76% and 36%, and overall survival rates were 83% vs 40%, respectively (HR = 0.34 [0.21-0.57], P < .0001), HR = 0.22 [0.12-0.40] P < .0001, respectively). p16(-), p53(+), heavy smoking/alcohol consumption, performance status; advanced T and N stages in patients with p16(-), and continuing smoking/alcohol consumption after treatment were found to be unfavorable risk factors. Five-year overall survival rates were 95%, 78%, and 36% for low, intermediate, and high-risk groups, respectively. CONCLUSIONS: The results of our study have shown that p16 negativity in patients with oropharyngeal cancer was found to be an important prognostic factor, especially for those with lower p53 expression and not smoking/consuming alcohol.

A multicenter retrospective analysis of patients with nasopharyngeal carcinoma treated in IMRT era from a nonendemic population: Turkish Society for Radiation Oncology Head and Neck Cancer Group Study (TROD 01-001).

BACKGROUND: We aimed to evaluate patients with nasopharyngeal carcinoma (NPC) in a nonendemic population. METHODS: In a national, retrospective, multicenteric study, 563 patients treated with intensity modulated radiotherapy at 22 centers between 2015 and 2020 were analyzed. RESULTS: Median age was 48 (9-83), age distribution was bimodal, 74.1% were male, and 78.7% were stage III-IVA. Keratinizing and undifferentiated carcinoma rates were 3.9% and 81.2%. Patients were treated with concomitant chemoradiotherapy (48.9%), or radiotherapy combined with induction chemotherapy (25%) or adjuvant chemotherapy (19.5%). After 34 (6-78) months follow-up, 8.2% locoregional and 8% distant relapse were observed. Three-year overall survival was 89.5% and was lower in patients with age ≥50, male sex, keratinizing histology, T4, N3 and advanced stage (III-IVA). CONCLUSIONS: Patients with NPC in Turkey have mixed clinical features of both east and west. Survival outcomes are comparable to other reported series; however, the rate of distant metastases seems to be lower.

Outcomes of carotid sparing intensity-modulated radiotherapy for early stage glottic cancer in 201 patients: Multicenter study of Turkish Radiation Oncology Society/TROD-01-007.

BACKGROUND: To assess and report clinical outcomes after carotid sparing intensity-modulated radiotherapy for early stage laryngeal cancer. METHODS: We retrospectively analyzed 201 patients with early stage glottic laryngeal cancer treated with carotid sparing intensity-modulated radiotherapy (IMRT)/volumetric modulated arc therapy (VMAT) techniques in six TROD centers. RESULTS: After a median follow-up of 31 months the actuarial 1- and 3-year local and locoregional control rates were 99.4% and 94.7%, 98.4% and 93%, respectively. T classification, anterior commissure involvement, IMRT technique, and type of fractionation were not found to be prognostic for local control. Overall, eight patients had lost their organ function due to recurrence or toxicity. Grade 3 and 4 acute laryngeal edema was seen in eight (4%) and one (0.5%) of patients, respectively. Grade 3 and 4 late laryngeal edema developed in two (1%) and one patient (0.5%), respectively. CONCLUSION: Oncologic outcomes of patients treated with carotid sparing IMRT were excellent; comparable with historical series, with acceptable side effects. Longer follow-up is needed to estimate long term effect on stroke.

Outcome of Early-Stage Glottic Laryngeal Carcinoma Patients Treated with Radical Radiotherapy Using Different Techniques.

PURPOSE: The aim was to evaluate the treatment outcomes and prognostic characteristics of patients with early-stage glottic laryngeal carcinoma who underwent radical radiotherapy (RT) with different techniques. PATIENTS AND METHODS: Radiotherapy was applied using the 2D conventional technique between 1991 and 2004 (130 patients), 3DCRT until 2014 (125 patients), and by VMAT until January 2017 (44 patients). Clinical T stages were 38 (12.7%) for Tis, 209 (69.9%) for T1, and 52 (17.4%) for T2. Radiotherapy technique and energy, anterior commissure involvement, and stage were analyzed as prognostic factors. RESULTS: The median total dose was 66 (50-70) Gy, and median follow-up time was 72 (3-288) months; 5-year disease-specific survival (DSS) rates were 95.8%, 95.5%, and 88.6%, respectively, in Tis, T1, and T2 stages. In multivariate analyses, anterior commissure involvement was found significant for all survival and local control rates. The patients treated with VMAT technique had better local control and DSS rates. However, these results were not statistically significant. CONCLUSION: In early-stage laryngeal carcinomas, radical RT is a function sparing and effective treatment modality, regardless of treatment techniques.

Evaluation of Lateral Temporal Bone Resection in Locally Advanced Tumours of the Parotid Gland.

This study evaluated the effects of lateral temporal bone resection (LTBR) on local tumour control in patients with locally advanced parotid gland tumours. The medical records of seven patients treated with radical parotidectomy combined with LTBR for locally advanced primary parotid tumour at the Otolaryngology Department of Dokuz Eylul University between January 1995 and December 2016 were retrospectively evaluated. Demographic variables, tumour characteristics, treatment properties, postoperative complications, follow-up durations and local, regional and distant recurrences were analysed. Before referral to our clinic, four patients had de novo primary parotid tumours, and three patients had a recurrence of primary parotid tumours. The histopathologic diagnoses were squamous cell carcinoma in two patients, and adenosquamous carcinoma, malignant myoepithelial carcinoma, adenocarcinoma, adenoid cystic carcinoma and spindle cell sarcoma in the other patients. During the follow-up period, one patient died due to postoperative pulmonary embolism in the first month, and four patients died due to distant metastasis without local or regional recurrences. LTBR combined with radical parotidectomy in locally advanced primary malignant parotid gland tumours is a feasible surgical technique for local tumour control. However, the most common cause of death in these cases is distant metastases, despite appropriate resection.

Tumor deposits in salivary gland tumors.

Tumor deposits (TDs), identified in different types of carcinomas are associated with poor prognosis. Salivary gland tumors were evaluated for the first time for TDs in this series. Pathological and clinical features of 25 salivary gland carcinomas primarily treated surgically including neck dissection were determined and all cases were evaluated for TDs in dissection specimens. Seven patients (28%) had TDs. There was no difference for TDs when histological type, tumor grade, tumor localization, pT, pN stage, surgical margin, lymphovascular, perineural invasion, local recurrence, distant metastatic disease and overall survival were considered. Disease-free survival rates at 12 and 24 months were 52.5%, 28.6% and 73.3%, 57.1%, for cases with and without TDs (P = 0.463). Overall survival rates at 12 and 24 months for these groups were 85.7% and 57.1 versus 86.7% and 66.7% respectively (P = 0.916). Mean estimated recurrence-free survival time for all cases, TD negative and TD positive cases were: 171.86, 182.72 and 82.42 months, respectively. Mean estimated overall survival time for these groups were 175.80, 186.489 and 89.70 months, respectively. TDs were described in salivary gland tumors for the first time in this series and seem to be associated with poor prognosis requiring further evaluation in larger series.

Tumor deposits in head and neck carcinomas.

BACKGROUND: Tumor deposits, nodules in the peritumoral adipose tissue with no architectural residue of lymph node, have previously been described in colorectal adenocarcinomas. To date, however, there has been no examination of tumor deposits in head and neck squamous cell carcinoma (HNSCC). METHODS: Neck dissection specimens of 140 patients with HNSCC were reevaluated for tumor deposits. RESULTS: Tumor deposits were detected in 24 cases (17%). Cases with tumor deposits had more lymphatic invasion (p = .007), higher pathological N classification (p = .00), and more frequently showed distant metastasis (p = .003). Disease-free and overall survival were significantly shorter for tumor deposit positive cases (p = .016 and p = .005, respectively). Only tumor deposits were significant for overall survival. Tumor deposits increased the risk of recurrent disease 2294 times. Tumor deposits and pericapsular invasion were identified as independent prognostic markers; tumor deposits increased the risk of death from disease 3.4 times, whereas pericapsular invasion was associated with a 2.2-fold increase in the risk of death. CONCLUSION: These results highlight the existence of tumor deposits in neck dissection specimens of HNSCC and their association with poor prognosis. © 2015 Wiley Periodicals, Inc. Head Neck 38: E256-E260, 2016.

Undifferentiated Laryngeal Carcinoma with Pagetoid Spread.

Pagetoid spread, is used to define intraepithelial spread of cancer cells, when a massive carcinoma is identified beneath the basal membrane. There are only few reports of pagetoid spread at the head and neck region. Herein a 74 year old male patient with bilateral transglottic laryngeal high grade malignant epithelial tumor with pagetoid spread is presented. The tumor was located at the submucosa and there was spread of the CK7 and CK19 positive tumor cells into the non neoplastic mucosa, which was CK5/6 positive, sparing the basement membrane, creating a typical pagetoid pattern. Radiographic and positron emission tomography scan examination of the patient was unremarkable at presentation other than the laryngeal and neck lesions; but extensive systemic metastasis developed at 6 months following operation. To the best of our knowledge no epithelial malignancy with pagetoid spread was described at the larynx. Pagetoid spread may be a hallmark of very aggressive behavior in laryngeal carcinoma.

Pediatric laryngeal cancer with 5-year follow up: case report.

Larynx cancer is the commonest malignancy of upper aerodigestive tract. However, laryngeal cancer is extremely rare in childhood since these tumors are generally not suspected in the differential diagnosis of hoarseness, dysphagia and/or progressive airway obstruction in children; diagnosis can be made relatively late. In this report we would like to present a case of advanced stage pediatric laryngeal carcinoma who was treated with chemoradiotherapy and remained well on her 5-year follow-up.

The prognostic value of tumor-stroma proportion in laryngeal squamous cell carcinoma.

OBJECTIVE: Tumor-stroma proportion of tumor has been presented as a prognostic factor in some types of adenocarcinomas, but there is no information about squamous cell carcinomas and laryngeal carcinomas. MATERIAL AND METHOD: Five digital images of the tumor sections were obtained from 85 laryngeal carcinomas. Proportion of epithelial tumor component and stroma were measured by a software tool, allowing the pathologists to mark 205.6 µm2 blocks on areas as carcinomatous/stromal, by clicking at the image. Totally, 3.451 mm2 tumor areas have been marked to 16.785 small square blocks for each case. RESULTS: Median follow up was 48 months (range 3-194). The mean tumor-stroma proportion was 48.63+18.18. There was no difference for tumor-stroma proportion when tumor location, grade, stage and perinodal invasion were considered. Although the following results were statistically insignificant, the mean tumor-stroma proportion was the lowest (37.46±12.49) for subglottic carcinomas, and it was 52.41±37.47, 50.86+19.84 and 44.56±16.91 for supraglottic, transglottic and glottic cases. The tumor-stroma proportion was lowest in cases with perinodal invasion and the highest in cases without lymph node metastasis (44.72±20.23, 47.77±17.37, 50.05±17.34). Tumor-stroma proportion was higher in the basaloid subtype compared with the classical squamous cell carcinoma (53.76±14.70 and 48.63±18.38 respectively). The overall and disease-free survival analysis did not reveal significance for tumor-stroma proportion (p=0.08, p=0.38). Only pathological stage was an independent factor for overall survival (p=0.008). CONCLUSION: This is the first series investigating tumor-stroma proportion as a prognostic marker in laryngeal carcinomas proposing a new method, but the findings do not support tumor-stroma proportion as a prognostic marker.

T4N0M0 nasopharyngeal carcinoma patients: do they have a distinct tumor biology?

OBJECTIVES: To investigate the clinical manifestations and treatment outcomes of non-metastatic T4N0 nasopharyngeal cancer patients, and to compare them with other stage IVA subgroups of patients. PATIENTS AND METHODS: A retrospective analysis of 775 non-metastatic nasopharyngeal cancer patients, treated in four radiotherapy centers between 1990 and 2005, was undertaken. Among 197 stage IVA patients, 90 (11.6%) patients were staged as T4N0, 32 (4.1%) as T4N1, and 75 (9.7%) as T4N2. T4N0 patients constituted 40.8% of all T4 cases (median age 53 years; range 15 to 76 years). Cranial nerve involvement was detected in 59 (65.5%) of these cases. RESULTS: The median follow-up period was 38 months. There were only nine (10%) patients younger than 30 years of age with T4N0 tumors, for patients with diseases other than T4N0, 27.1% of the patients were under 30. Survival rates for five-year loco-regional progression free survival, distant failure free survival, and disease specific survival were 65.9%, 94%, and 71.4%, respectively. Distant failure free survival of T4N0 patients was more probable than for stage T4N1 (p=0.06) and T4N2 (p=0.008) patients. CONCLUSION: Non-metastatic T4N0 tumors have some distinct features, including a unimodal age distribution and a better distant failure free survival than the other subgroups of stage IVA. Therefore, it may be better to include T4N0 patients in stage III instead of stage IVA.

Tumor budding as a prognostic marker in laryngeal carcinoma.

Tumor budding is recognized as an adverse prognostic factor for a few carcinoma types. We evaluated the importance of this finding in 64 laryngeal carcinoma patients treated with surgery and radiotheraphy, with a median follow up of 53 (6-181) months. Budding was determined by re-evaluating hematoxylin-eosin (H&E) stained tumor sections, and classified as mild, moderate, and marked. Budding was not identified in 14 (21.88%) cases. Mild, moderate, and marked budding was observed in 21 (32.81%), 15 (23.44%), and 14 (21.88%) cases, respectively. Only when cases with marked budding were compared with the others, statistically significant results were obtained. In patients with and without marked budding, local disease-free survival, metastatic disease-free survival, and overall survival were 71% and 97% (p=0.72), 77% and 93% (p=0.038), and 77% and 75% (p=0.71), respectively. Marked budding was identified as a prognostic factor by univariate analysis for distant metastasis-free survival. Multi-variate analysis, by which well-recognized prognostic histopathologic parameters were evaluated, revealed that only the number of metastatic lymph nodes and budding were significantly associated with distant metastasis (p=0.02 and p=0.044), respectively. These results suggest that budding might be a valuable prognostic factor, particularly for distant metastasis in laryngeal carcinomas.

Importance of patient, tumour and treatment related factors on quality of life in head and neck cancer patients after definitive treatment.

The purpose of this study is to assess patient, tumour and treatment related factors on quality of life (QoL) outcomes of patients who received definitive or postoperative radiotherapy +/- chemotherapy for head and neck (H&N) cancer. In this cross-sectional study, 110 H&N cancer patients were evaluated in follow-up visit and were asked to fill out the European Organisation for Research and Treatment of Cancer QoL Core Questionnaire (QLQ-C-30) and H&N Module (QLQ-H&N35). Patients were also graded for their late side effects using EORTC/RTOG scoring system. The QLQ C-30 and QLQ-H&N35 mean scores were compared using ANOVA analysis for these variables: age, gender, occupation, educational status, social security status, place of residence, tumour localization, clinical stage, comorbidity, Karnofsky performance score, treatment modality and side effects. Median follow-up was 29 (4-155) months. Tumour localization was significant factor affecting physical (P = 0.03), social (P = 0.01), cognitive (P = 0.002) functioning. Treatment modality had significant impact on the physical (P = 0.02) and cognitive scores (P = 0.008). Global QoL was affected significantly by disease stage (P = 0.01) and occupation (P = 0.01). The QLQ-H&N35 scores were found significantly higher in patients with moderate/severe late morbidity. Tumour localization and the treatment modality are the most important factors affecting the QoL of H&N cancer patients treated definitively.

Assessment of treatment-related thyroid dysfunction in patients with head and neck cancer.

OBJECTIVE: To assess thyroid dysfunction in head and neck cancer patients who have received external beam radiotherapy according to radiotherapy fields and dose, tumor site and other local or systemic treatments retrospectively and prospectively and propose a follow-up schedule. MATERIAL AND METHODS: A total of 378 patients was classified into two groups. Group I (n = 345) consisted of surgically treated 153 laryngeal, 80 nasopharyngeal and 112 oral cavity/oropharyngeal carcinoma patients; these patients were evaluated retrospectively for treatment-related thyroid dysfunction using their data files. Group II included 33 patients with head and neck cancer who were evaluated prospectively. Thyroid function tests were performed at the beginning of the radiotherapy and every three months after the radiotherapy course, and thyroid dysfunction regarding surgery, radiotherapy and chemotherapy was evaluated. RESULTS: In Group I, the median follow-up for 153 operated laryngeal carcinoma patients was 44 months. Four (2.6%) of them were found to have clinically apparent hypothyroidism. After a median follow-up of 36 months, none of the 80 nasopharyngeal carcinoma patients showed signs of hypothyroidism. Clinically apparent hypothyroidism was detected in only 1 (0.8%) of the oral cavity/oropharyngeal carcinoma patients after a median follow-up of 25 months. In Group II, 1 (3%) patient was found to have thyroid dysfunction postoperatively prior to radiotherapy. At the time of analysis, 29 (87.8%) patients were euthyroidic, 2 (6.1%) patients had subclinical and 2 (6.1%) patients had clinical hypothyroidism. All patients with thyroid dysfunction have had combined surgery and radiotherapy, and none of the patients treated with radical radiotherapy has experienced hypothyroidism. CONCLUSIONS: Even after a short follow-up, the incidence of thyroid dysfunction was 12.2% in head and neck cancer patients treated with combined surgery and radiotherapy. We recommend thyroid function tests in these patients prior to and once every 3-6 months after the radiotherapy course.

The impact of treatment center on the outcome of patients with laryngeal cancer treated with surgery and radiotherapy.

For laryngeal cancer, surgical excision of the primary tumor should be undertaken with the aim of achieving tumor-free margins. Adequate pathological assessment of the specimen and the competency of the treatment center play a crucial role in achieving cure. The present study aimed to analyze the significance of place of surgery on the outcome of patients with laryngeal cancer who underwent surgical operation in other centers and were subsequently referred to Doküz Eylul University Head and Neck Tumour Group (DEHNTG) for postoperative irradiation. Patients were divided into three groups according to their place of surgery. The first group (Group I) consisted of patients who had their surgical operation at DEUH. Patients in the second group (Group II) were referred from centers with oncological surgical experience. The third group (Group III) consisted of patients referred from hospitals with no surgical teams experienced in head and neck cancer treatment. The clinical and pathological features of patients in these three groups were analyzed to assess the impact of place of surgery on clinical outcome as well as the prognostic factors for survival. The study population consisted of 253 patients who were treated between 1991 and 2006 with locally advanced laryngeal cancer according to the protocol of DEHNTG. The median follow-up was 48 (3-181) months. The 5 years overall, loco-regional disease-free and distant disease-free survivals were 66, 88 and 91%, respectively. When patients' clinical and histopathological features were analyzed for the impact of place of surgery, surgical margin positivity rates were found to be higher in Group III (P = 0.032), although the other two groups had more advanced clinical and pathological N stage disease (P = 0.012, P = 0.001). In multivariate analysis, older age (P < 0.0001), presence of perinodal invasion (P = 0.012), time interval between surgery and radiotherapy longer than 6 weeks (P = 0.003) and tumor grade (P = 0.049) were the most significant factors. For loco-regional failure-free survival, advanced clinical stage (P = 0.002), place of surgery (P = 0.031) and presence of clinical subglottic invasion (P = 0.029) were shown to be important prognostic factors. For distant metastasis-free survival, only pathological (+) lymph node status (P = 0.046) was a significant factor in multivariate analysis. The significance of place of surgery as well as other well-known prognostic factors underlines the importance of an experienced multidisciplinary treatment team if best results are to be obtained for the patient.

Treatment results of 165 pediatric patients with non-metastatic nasopharyngeal carcinoma: a Rare Cancer Network study.

PURPOSE: This Rare Cancer Network (RCN) study was performed in pediatric nasopharyngeal carcinoma (PNPC) patients to evaluate the optimal dose of radiotherapy and to determine prognostic factors. PATIENTS AND METHODS: The study included 165 patients with the diagnosis of PNPC treated between 1978 and 2003. The median age was 14 years. There were 3 (1.8%) patients with stage I, 1 (0.6%) with IIA, 10 (6.1%) with IIB, 60 (36.4%) with III, 44 (26.7%) with IVA, and 47 (29%) with IVB disease. While 21 (12.7%) patients were treated with radiotherapy (RT) alone, 144 (87.3%) received chemotherapy and RT. The median follow-up time was 48 months. RESULTS: The actuarial 5-year overall survival (OS) was 77.4% (95% CI: 70.06-84.72), whereas the actuarial 5-year disease-free survival (DFS) rate was 68.8% (95% CI: 61.33-76.31). In multivariate analysis, unfavorable factors were age >14 years for LRC (p=0.04); male gender for DMFS (p=0.03); T3/T4 disease for LRFS (p=0.01); and N3 disease for DFS (p=0.002) and OS (p=0.002); EBRT dose of less than 66 Gy for LRFS (p=0.02) and LRRFS (p=0.0028); and patients treated with RT alone for LRFS (p=0.0001), LRRFS (p=0.007) and DFS (p=0.02). CONCLUSION: Our results support the current practice of using combined radiation and chemotherapy for optimal treatment of NPC. However, research should be encouraged in an attempt to reduce the potential for long-term sequelae in pediatric patients given their relatively favorable prognosis and potential for longevity.

Validation of the Medical Research Council and a newly developed prognostic index in patients with malignant glioma: how useful are prognostic indices in routine clinical practice?

Although different prognostic indices for malignant gliomas have been developed, their validity outside of clinical trials has not been widely tested. The aim of this study was to determine whether the Medical Research Council (MRC) brain tumour prognostic index was able to stratify patients for survival managed in routine practice, and secondly to compare the results with our newly developed prognostic score which included tumour grade and only 3 prognostic groups. The MRC and the new prognostic index were calculated for a group of 119 adult patients with malignant glioma managed by surgical resection/biopsy and post-operative radiotherapy. For the MRC and new score, 6 and 3 prognostic groups were defined, respectively. For all patients median survival was 11 (2-66) months. The overall survival rate at 12 and 24 months were 43% and 18%, respectively. The MRC median and two-year survival rates were 14 months and 26% for a score of 1-10, 14 months and 27% for a score of 11-15, 13 months and 22% for a score of 16-20, 8 months and 10% for a score of 21-25, 8 months and 0% for those scoring 26-33. There was only one patient in the 34-38 group. For the new prognostic index, median and two-year survival rates were respectively 16 and 26%; 12 and 23%; 8 and 7% for the good, intermediate and poor prognostic groups. Both indices were significant factors for survival in univariate analysis (MRC index, p = 0.0089, new index p = 0.0002), but not in multivariate analysis. Both the MRC and our newly devised prognostic score were able to separate patients into good and poor prognostic groups, which may aid in treatment decisions, although there was less differentiation between the MRC groups especially over the first year. Both scores use routinely available factors. However, inclusion of tumour grade in the new score may be an advantage over the MRC index.