Radical Resection of Malignant Tumors of Major Salivary Glands: Is This Possible?

In primary therapy, a universally recognized surgical indication applies to all tumors of the salivary glands. According to the classic rule, radical resection of a head and neck tumor requires clean margins of at least 5 mm, although recent studies have shown that for certain locations, 1 mm may be sufficient. In the surgical resection of a tumor of the salivary glands, especially of the parotid gland, can these rules be respected? Owing to the complex branching and connections of the facial nerve within the parotid gland, even a medium-sized malignant tumor may be in contact with a branch of the nerve, thus raising the question of its preservation. The facial nerve is so important from a functional and aesthetic point of view that it is commonly believed that it should be preserved unless it is incorporated into the tumor. This is a compromise between an oncological resection, that is, the complete excision of the tumor with no residual cancer cells left behind, and quality of life. Almost all authors try to overcome this lack of radicality by indicating postoperative (chemo)radiotherapy. In this article, the pros and cons of nerve preservation will be analyzed by examining the published studies on this topic.

Adenoid cystic carcinoma. An indolent but aggressive tumour. Part A: from aetiopathogenesis to diagnosis.

Adenoid cystic carcinoma (ACC) is a relatively rare tumour of the minor and major salivary glands. It is uncommon in the parotid gland while it is much more frequent in the submandibular gland and in minor salivary and mucinous glands (oral cavity, oropharynx, and paranasal sinuses). ACC may also arise in secretory glands located in other tissues, such as in the tracheobronchial tree, oesophagus, breast, lungs, prostate, uterine cervix, lachrymal and Bartholin's glands, and skin. The natural history of ACC is characterised by an indolent growth rate, a relatively low probability of regional lymph node metastases and a high likelihood of haematogenous dissemination. ACC has been traditionally subdivided into three histological groups (cribriform, tubular, and solid) based on solid components of the tumour. Some studies have shown that tumours with a solid growth component have a rapid fatal course, compared to tumours without a solid growth component, but other studies have failed to correlate growth patterns with clinical course. The purpose of this review is to analyse the very large number of studies (sometimes contradictory) on ACC. In this first part, the aetiology, epidemiology, histopathology, clinical behaviour and diagnostic workup are examined.^ieng

Il carcinoma adenoide cistico (ACC) è un tumore relativamente raro ad origine dalle ghiandole salivari minori e maggiori. È poco frequente nella parotide mentre lo è molto di più nella ghiandola sottomandibolare, nelle ghiandole salivari minori e in quelle mucinose del cavo orale, orofaringe e seni paranasali. Esso può anche insorgere nelle ghiandole secretrici localizzate in altri tessuti come l'albero tracheo-bronchiale, l'esofago, la mammella, il polmone, la prostata, la cervice uterina, la cute, le ghiandole lacrimali e quelle del Bartolini. La sua storia naturale è caratterizzata da una lenta crescita, da rare metastasi linfonodali e da frequenti metastasi a distanza. Dal punto di vista istologico esso è stato tradizionalmente suddiviso in tre forme (cribriforme, tubulare e solido). Alcuni studi hanno dimostrato che i tumori con una prevalente componente solida hanno una prognosi peggiore rispetto a quelli con prevalente componente cribriforme o tubulare ma altri studi hanno contestato questa affermazione. Il proposito di questa review è quello di analizzare il grande numero di pubblicazioni (talvolta contraddittorie) sul carcinoma adenoide cistico. In questa prima parte saranno discusse l'eziologia, l'epidemiologia, l'istopatologia, la presentazione clinica e l'iter diagnostico.

Adenoid cystic carcinoma. An indolent but aggressive tumour. Part B: treatment and prognosis.

The purpose of this review is to analyse the very large number of studies (sometimes contradictory) on adenoid cystic carcinoma (ACC). This second part provides a critical analysis of various treatment described in the literature. Anywhere the primary tumour is located, the most common treatment for ACC is complete surgical resection, with or without post-operative radiotherapy (PORT), while conventional photon and/or electron radiotherapy alone and chemotherapy are commonly used in unresectable or metastatic disease. Fast neutron radiotherapy was used in the past with good local results, but the risk of late effects was high and tended to increase over time. Modern carbon-ion radiotherapy seems to be a valid option in selected cases. The quite universally accepted poor prognostic factors are advanced stage, perineural and intraneural invasion, involved margins, and initial presence or later development of neck metastases. The impact of histologic grade on prognosis is controversial. Owing to the long natural history of ACC, the follow-up for patients must be at least 10 years long.^ieng

Il proposito di questa review è quello di analizzare il grande numero di studi (talvolta contradittori) sul carcinoma adenoide cistico. Questa seconda parte presenta una analisi critica dei vari trattamenti descritti in letteratura. Ovunque il tumore primitivo sia localizzato il trattamento più indicato è una resezione radicale con o senza radioterapia postoperatoria. La radioterapia convenzionale con fotoni e/o elettroni e la chemioterapia sono comunemente riservate ai casi inoperabili o metastatici. La radioterapia con neutroni è stata ampiamente utilizzata in passato con buoni risultati locali, ma il rischio di effetti collaterali tardivi si è dimostrato alto e con tendenza ad aumentare nel tempo. Il moderno trattamento con ioni carbonio si sta dimostrando una valida alternativa in casi selezionati. I fattori prognostici negativi quasi universalmente accettati sono lo stadio avanzato, l'invasione perineurale e intraneurale, i margini positivi e le metastasi linfonodali alla presentazione o successive. Il valore prognostico del grading istologico è controverso. Stante la lunga storia naturale del carcinoma adenoide cistico il follow-up dei pazienti deve essere almeno di 10 anni.

Survival for ethmoid sinus adenocarcinoma in European populations.

BACKGROUND: Adenocarcinoma of the ethmoid sinus is rare. EUROCARE data provide a good opportunity to study the survival of this rare disease in a population of continental size. PATIENTS AND METHODS: A total of 204 cases, age 15 to 99 years, diagnosed with primary ethmoid sinus adenocarcinoma between 1983 and 1994, were analyzed. The data were contributed by 22 population-based cancer registries from the nine countries participating in EUROCARE. Relative survival by sex, age, period of diagnosis, region and stage, and adjusted relative excess risk (RER) of death, were estimated. RESULTS: Survival was 83%, 58% and 46%, 1, 3 and 5 years, respectively after diagnosis. Five-year survival was best (60%) in patients of 55-64 years and worst (33%) in the oldest age group (> or =65 years). Five-year survival differ between European population: in Norway (55%, 95% confidence interval 26.4-80.9) and western Europe that includes populations from Eindhoven, Saarland, Geneva, Italy and France (56%, 95%CI 41.3-68.9) was higher than in the UK (41%, 95% CI 30.8-51.8) and eastern Europe which includes Slovakia and Slovenia, (22%, 95% CI 3.5-54.4). Five-year survival did not improve over time. Due to the rarity of the disease, all the survival differences did not reach the statistical significance. CONCLUSIONS: Since no survival improvement with time was evident from this study, efforts should be made to improve early diagnosis. GPs and ENT specialists should be alerted to the disease and encouraged to take occupational histories in people with persistent nasal symptoms, which may lead to a reasonable suspicion of malignancy. Monitoring of exposed workers may also improve early diagnosis. Patients with suspected ethmoid cancer should be referred immediately a specialized diagnosis and treatment centre.

Autologous freeze-treated bone for mandibular reconstruction after malignant tumor resection: a study of 72 patients.

OBJECTIVE: The aim of the study was to assess the possibility of mandibular reconstruction with autologous freeze-treated bone after mandibular resection for malignant tumors. PATIENTS: The medical records of 72 consecutive patients surgically treated with segmental mandibular resection and reconstruction with autologous freeze-treated mandible were reviewed. RESULTS: All tumors were in stage T4a for deep infiltration of the mandible. Soft tissues were reconstructed with a direct mucosal closure (4 cases), with a pedicled pectoralis flap (17 cases), and with a forearm fasciocutaneous free flap without or with radial periosteum (18 and 33 cases). Four patients presented with a recurrence after previous surgery and radiotherapy, and 26 patients underwent postoperative radiotherapy. We resected the mental arch in 35 cases and the lateral mandible in 37 cases. Forty-one patients (56.9%) retained their autologous mandibular graft. In 31 cases, the bone graft was removed for mucosal dehiscence and bone infection. Lateral resections achieved a better success rate than anterior resections (75.7% vs 37.1%). The pedicled pectoralis flap achieved the worse success rate (35.3%) in comparison with forearm fasciocutaneous flap (66.7%). Postoperative radiotherapy decreased the success rate (40.0% vs 69.1%). CONCLUSIONS: Mandibular reconstruction with autologous frozen bone is an interesting alternative to more sophisticated methods for patients with oral cancer involving the bone. It is time and cost sparing in comparison to fibula or iliac crest flaps. However, in spite of any intraoral reconstruction, the success rate is not stirring. In our opinion, this type of mandibular reconstruction must be reserved to patients with lateral tumors, with poor prognosis, or severe comorbidities not allowing more complex bone reconstruction.

Effects of treatment intensification on acute local toxicity during radiotherapy for head and neck cancer: prospective observational study validating CTCAE, version 3.0, scoring system.

PURPOSE: To quantify the incidence and severity of acute local toxicity in head and neck cancer patients treated with radiotherapy (RT), with or without chemotherapy (CHT), using the Common Terminology Criteria for Adverse Events, version 3.0 (CTCAE v3.0), scoring system. METHODS AND MATERIALS: Between 2004 and 2006, 149 patients with head and neck cancer treated with RT at our center were prospectively evaluated for local toxicity during treatment. On a weekly basis, patients were monitored and eight toxicity items were recorded according to the CTCAE v3.0 scoring system. Of the 149 patients, 48 (32%) were treated with RT alone (conventional fractionation), 82 (55%) with concomitant CHT and conventional fractionation RT, and 20 (13%) with accelerated-fractionation RT and CHT. RESULTS: Severe (Grade 3-4) adverse events were recorded in 28% (mucositis), 33% (dysphagia), 40% (pain), and 12% (skin) of patients. Multivariate analysis showed CHT to be the most relevant factor independently predicting for worse toxicity (mucositis, dysphagia, weight loss, salivary changes). In contrast, previous surgery, RT acceleration and older age, female gender, and younger age, respectively, predicted for a worse outcome of mucositis, weight loss, pain, and dermatitis. The T-score method confirmed that conventional RT alone is in the "low-burden" class (T-score = 0.6) and suggests that concurrent CHT and conventional fractionation RT is in the "high-burden" class (T-score = 1.15). Combined CHT and accelerated-fractionation RT had the highest T-score at 1.9. CONCLUSIONS: The CTCAE v3.0 proved to be a reliable tool to quantify acute toxicity in head and neck cancer patients treated with various treatment intensities. The effect of CHT and RT acceleration on the acute toxicity burden was clinically relevant.

Lymph node metastases in malignant tumors of the paranasal sinuses: prognostic value and treatment.

OBJECTIVE: To assess the frequency of nodal involvement and its prognostic value in malignant tumors of the paranasal sinuses, particularly in maxillary sinus squamous cell carcinoma. DESIGN: Retrospective review. SETTING: Tertiary cancer center. PATIENTS: The medical records of 704 consecutive patients surgically treated for malignant tumors of the paranasal sinuses from January 1968 to March 2003 were reviewed. The tumors were staged according to American Joint Committee on Cancer-International Union Against Cancer 2002 classification. Only patients with clinically positive nodes underwent a neck dissection. MAIN OUTCOME MEASURES: Lymph node metastases (at presentation or during follow-up, occurring alone, or with concurrent local recurrence and/or distant metastasis). Also analyzed were local recurrence (occurring alone or with concurrent distant metastasis), distant metastasis (occurring alone), and overall survival. RESULTS: The tumor site was the ethmoid sinus in 305 cases and maxillary sinus in 399 cases. At baseline, 5 patients (1.6%) in the ethmoid sinus group and 33 (8.3%) in the maxillary sinus group presented with positive nodes (P < .001); during follow-up, nodal recurrences (alone or simultaneous with T and/or M recurrence) occurred in 15 and 51 patients, respectively, and the corresponding 5-year incidence estimates were 4.3% and 12.5% (P = .001). The highest incidence of node metastases was found in maxillary sinus squamous cell carcinoma, particularly in T2 tumors. Five-year overall survival estimates were 45.3% for patients with N0 tumors and 0% for those with N+ (N1, N2, or N3) ethmoid sinus tumors, and 50.6% and 16.8%, respectively, for patients with maxillary sinus tumors. CONCLUSIONS: Lymph node metastases are a poor prognostic factor for patients with malignant tumors of the paranasal sinuses. The incidence of these metastases is low, particularly in ethmoid sinus tumors. A prophylactic treatment of the neck in patients with N0 tumors (surgery or radiotherapy) might be considered in T2 squamous cell carcinoma of the maxillary sinus and in undifferentiated carcinoma of the ethmoid sinus.

Molecular and cytogenetic subgroups of oropharyngeal squamous cell carcinoma.

PURPOSE: The aim of this study was to acquire further insights into the pathogenetic pathways of head and neck squamous cell carcinomas (HNSCC) that may be useful for identifying new biomarkers instrumental in developing more specific treatment approaches. EXPERIMENTAL DESIGN: Cell cycle regulators and epidermal growth factor receptor (EGFR) and BRAF genes were analyzed in a series of 90 oropharyngeal SCCs of a cohort of surgically treated patients from a single institution, and the results were matched with the presence of high-risk human papillomavirus (HR-HPV) DNA and the TP53 status. RESULTS: At least four distinct groups of tumors were identified sharing a common histology but displaying different molecular/cytogenetic patterns: (a) 19% were HPV-positive SCCs whose lack of alterations of the investigated genes could explain their particular natural history, which requires less aggressive treatment; (b) 37% were HPV-negative SCCs carrying TP53 mutations, which may be more effectively treated by drugs acting through p53-independent apoptosis; (c) 34% were HPV-negative SCCs carrying wild-type TP53 and loss of 9p21 (p16INK4a and p15INK4b) and/or cyclin D1 overexpression that justify treatment with DNA-damaging drugs followed by cell cycle inhibitors; and (d) 10% were HPV-negative lacking tumor suppressor genes and cell cycle alterations. The second, third, and fourth groups also showed an increased copy number of EGFR and chromosome 7 (43%) that might justify the additional or alternative use of EGFR inhibitors. CONCLUSIONS: Our findings suggest that assessing HPV, TP53, 9p21, and EGFR status may be crucial to finding more tailored and beneficial treatments for oropharyngeal SCCs.

Postoperative radiotherapy for synovial sarcoma of the head and neck during pregnancy: clinical and technical management and fetal dose estimates.

AIMS AND BACKGROUND: In vivo and phantom dosimetry is reported to estimate the fetal dose and evaluate the effectiveness of a special shielding device to reduce fetal exposure in a woman undergoing postoperative radiation therapy for synovial oral cavity sarcoma at the 30th week of pregnancy. METHODS: In vivo measurements were performed by placing thermoluminescent dosimeters on 3 points for fetal dose estimation: uterine fundus, umbilicus and pubis. A Rando anthropomorphic phantom was used to simulate radiotherapy. We also performed off-axis dose measurements for wedged beams to estimate the dose contribution of this accessory used in the treatment. RESULTS: The special shielding device reduced the fetal dose by 70% on average, despite the presence of wedges, which increased the dose by a factor of about 2.5. Before delivery the patient received 48 Gy, and from the in vivo measurements a fetal dose of 8.5, 1.7 and 0.7 cGy was estimated to the uterine fundus, umbilicus and pubis, respectively. CONCLUSIONS: Pre-treatment simulation in the same irradiation conditions is the only reliable approach to predict the fetal dose. By using a special shielding device, radiotherapy can be optimized while keeping the fetal exposure below the risk of deterministic damage.

Lip-splitting in transmandibular resections: is it really necessary?

Mandibular resection approach (Commando or Composite resection) is one of the fundamental techniques for oral and oropharyngeal large tumour resection. We reviewed the charts of patients who underwent a transmandibular resection for an oral and/or oropharyngeal cancer between 1980 and 2002. Of 700 patients who underwent a mandibular resection for cancer, 332 had been operated without lower lip splitting. A mono or bilateral en-block neck dissection was always performed, except in cases of relapses after a prior surgical treatment with neck dissection. We repaired 307 patients with flaps (pedicled or free flaps, with or without bone). Unsplitting of the lip never complicated resection and reconstruction. Furthermore the procedure was time sparing, as we avoided haemostasis and suture of the lip. The cosmetic results were better than those obtained by traditional technique. We used a non-lip-splitting technique also for pull-through, marginal mandibulectomy and, sometimes, for mandibular-swing approaches. In the latter case, the technique has some advantages and disadvantages and must be applied according to circumstances. We can conclude that lip-splitting in transmandibular resection for oral and oropharyngeal tumours is not necessary.

Primary chemotherapy in resectable oral cavity squamous cell cancer: a randomized controlled trial.

PURPOSE: Prognosis of patients with advanced oral cavity cancer is worth improving. Chemotherapy has been reported to be especially active in oral cavity tumors. Here we repeat the results of a randomized, multicenter trial enrolling patients with a resectable, stage T2-T4 (> 3 cm), N0-N2, M0 untreated, squamous cell carcinoma of the oral cavity. PATIENTS AND METHODS: Patients were randomly assigned to three cycles of cisplatin and fluorouracil followed by surgery (chemotherapy arm) or surgery alone (control arm). In both arms, postoperative radiotherapy was reserved to high-risk patients, and surgery was modulated depending on the tumor's closeness to the mandible. Patients' accrual was opened in 1989 and closed in 1999. It included 195 patients. RESULTS: In the chemotherapy arm, three toxic deaths were recorded. No significant difference in overall survival was found. Five-year overall survival was, for both arms, 55%. Postoperative radiotherapy was administered in 33% of patients in the chemotherapy arm, versus 46% in the control arm. A mandible resection was performed in 52% of patients in the control arm, versus 31% in the chemotherapy arm. CONCLUSION: The addition of primary chemotherapy to standard surgery was unable to improve survival. However, in this study, primary chemotherapy seemed to play a role in reducing the number of patients who needed to undergo mandibulectomy and/or radiation therapy. Variations in the criteria used to select patients for these treatment options may make it difficult to generalize these results, but there appears to be room for using preoperative chemotherapy to spare destructive surgery or radiation therapy in patients with advanced, resectable oral cavity cancer.

Lung metastasectomy in adenoid cystic carcinoma (ACC) of salivary gland.

To define the role of surgical management of lung metastases in ACC. Twenty ACC patients referred to lung metastasectomy were retrospectively reviewed. Twenty-six operations were performed; at the first metastasectomy, a resection with clear margins (R0) was achieved in 11 patients (55%), 3 are alive and well. Four out of 9 patients with residual disease (R2) are still alive. Median survival after metastasectomy was 78 and 52 months for R0 and R2 (p=0.4); median freedom from progression (FFP) in R0 and R2 groups was 30 and 15 months (p=0.2), respectively. A better outcome was obtained for patients with a disease-free interval 36 months and 6 metastases and bilateral involvement were critical in achieving a R0 intervention. Lung metastasectomy provided a prolonged FFP in a high selected subset of patients with ACC. However, if this could be translated into a survival benefit, it is still to be demonstrated.

Improved outcome of nasopharyngeal carcinoma treated with conventional radiotherapy.

PURPOSE: To describe the outcome of patients with nonmetastatic nasopharyngeal carcinoma (NPC) treated with conventional radiotherapy at a single institution. METHODS AND MATERIALS: From 1990 to 1999, 171 consecutive patients with NPC were treated with conventional (two-dimensional) radiotherapy. Tumor histology was undifferentiated in 82% of cases. Tumor-node-metastasis Stage (American Joint Committee on Cancer/International Union Against Cancer 1997 system) was I in 6%, II in 36%, III in 22%, and IV in 36% of patients. Mean total radiation dose was 68.4 Gy. Chemotherapy was given to 62% of the patients. The median follow-up for surviving patients was 6.3 years (range, 3.1-13.1 years). RESULTS: The 5-year overall survival, disease-specific survival, and disease-free survival rates were 72%, 74%, and 62%, respectively. The 5-year local, regional, and distant control rates were 84%, 80%, and 83% respectively. Late effects of radiotherapy were prospectively recorded in 100 patients surviving without relapse; 44% of these patients had Grade 3 xerostomia, 33% had Grade 3 dental damage, and 11% had Grade 3 hearing loss. CONCLUSIONS: This analysis shows an improved outcome for patients treated from 1990 to 1999 compared with earlier retrospective series, despite the use of two-dimensional radiotherapy. Late toxicity, however, was substantial with conventional radiotherapy.

Regionally advanced nasopharyngeal carcinoma: long-term outcome after sequential chemotherapy and radiotherapy.

AIMS AND BACKGROUND: To evaluate the long-term clinical outcome of 61 patients with regionally advanced nasopharyngeal carcinoma treated with sequential chemotherapy and radiotherapy within a phase II trial. METHODS: The trial evaluated a combined modality regimen including 3 cycles of induction polychemotherapy (epirubicin 70 mg/m2 d1, and cisplatin 100 mg/m2 d1, both recycled every 3 weeks) followed by definitive radiotherapy to the primary site (64-70 Gy) and the neck (50-70 Gy). Patients included in the trial had pathologically confirmed nasopharyngeal carcinoma; stage (UICC 1987) T-any, N2-3, M0; ECOG performance status 0-1. Sixty-one patients were enrolled between 1990 and 1996; stage according to UICC 1997 was IIb in 8%, III in 36% and IV in 56% of the patients; histology was WHO type 1-2 in 11% and WHO type 3 in 89% of cases. Minimum follow-up of 33 surviving patients is 5.2 years. RESULTS: Clinical failure has been observed in 30 patients (49%): initial failure, observed within the third year of follow-up in all but one case, was local alone in 6 (20%), regional alone in 10 (33%), local and regional in 1 (3%), regional and distant in 1 (3%), and distant alone in 12 patients (40%). Seven patients received salvage surgery to the neck, 2 of them still disease-free at 10 and 11 years from salvage surgery; 4 patients with an isolated local relapse were re-irradiated, and one of them was alive and well at 6.5 years from salvage radiation. At 5-year local control, regional control and distant metastasis-free rates were 83%, 74% and 73%, respectively; overall and disease-free survival were 64% and 51%. Late effects of initial treatment, as evaluated in 30 patients surviving 5 years without relapse, were generally acceptable, but some degree of xerostomia, dental damage, trismus and hearing loss were reported by a significant proportion of patients (respectively 100%, 88%, 76% and 86%). CONCLUSIONS: In our experience, long-term clinical cure of regionally advanced nasopharyngeal carcinoma was obtained in 51% of cases treated with chemotherapy and radiotherapy. Salvage treatments (neck surgery, local re-irradiation) are worthy, as they increase the cure rate by approximately 10%, raising 5-year survival to over 60%. Late effects are significant, calling for refinements in radiation technique, better integration with chemotherapy to possibly decrease the need for higher radiation dose, and/or use of effective radioprotectants.

Tp53 status as guide for the management of ethmoid sinus intestinal-type adenocarcinoma.

OBJECTIVE: Intestinal-type adenocarcinoma (ITAC) of the ethmoid sinus is a rare, occupational-related tumor. Optimal treatment consists of surgery and radiotherapy, while chemotherapy is still investigational. The molecular profile of ITAC is characterized by the occurrence of TP53 mutations associated with genotoxic agents such as wood dust. We investigated the role of p53 functionality in relation to the primary treatment. MATERIALS AND METHODS: We retrospectively reviewed 100 medical charts of consecutive patients with a first diagnosis of ITAC treated at our Institute; 74 patients were evaluable for TP53 analysis. Thirty (41%) were treated from 1991 to 2006 with craniofacial resection followed by radiotherapy (Group A), compared with 44 patients (59%) treated from 1996 to 2006 with cisplatin-based induction chemotherapy (PFL) followed by standard treatment (Group B). RESULTS: Five-year OS in Group A was 42%, while in Group B it was 70% (p = 0.041); 5-year DFS in Group A was 40%, while in Group B it was 66%, (p = 0.009) (p = 0.061 and 0.003 at Cox multivariable OS and DFS analyses). Analyzing each group according to p53 functional status, only for Group B patients (who received preoperative chemotherapy) both OS and DFS were in favor of functional p53 (p = 0.023 and p = 0.010, respectively). No impact of p53 functional status as a biomarker was observed in Group A. CONCLUSIONS: Functional p53 may predict PFL-chemotherapy efficacy, offering a possible increase in survival when induction chemotherapy is given to a selected population. On the other hand, upcoming innovative approaches should be explored in the presence of non-functional p53.