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This review aimed to critically analyse data pertaining to the clinical presentation and treatment of neuroendocrine carcinomas of the larynx.
A PubMed search was performed using the term ‘neuroendocrine carcinoma’. English-language articles on neuroendocrine carcinoma of the larynx were reviewed in detail.
Results and conclusion
While many historical classifications have been proposed, in contemporary practice these tumours are sub-classified into four subtypes: carcinoid, atypical carcinoid, small cell neuroendocrine carcinoma and large cell neuroendocrine carcinoma. These tumours exhibit a wide range of biological behaviour, ranging from the extremely aggressive nature of small and large cell neuroendocrine carcinomas, which usually have a fatal prognosis, to the less aggressive course of carcinoid tumours. In small and large cell neuroendocrine carcinomas, a combination of irradiation and chemotherapy is indicated, while carcinoid and atypical carcinoid tumour management entails conservation surgery.
Positron emission tomography-computed tomography with fluorine-18 fluorodeoxy-D-glucose has a major role in the investigation of head and neck cancers. Fluorine-18 fluorodeoxy-D-glucose is not a tumour-specific tracer and can also accumulate in benign pathology. Therefore, positron emission tomography-computed tomography scan interpretation difficulties are common in the head and neck, which can produce false-positive results. This study aimed to investigate patients detected as having abnormal vocal fold uptake on fluorine-18 fluorodeoxy-D-glucose positron emission tomography-computed tomography.
Positron emission tomography-computed tomography scans were identified over a 15-month period where reports contained evidence of unilateral vocal fold uptake or vocal fold pathology. Patients’ notes and laryngoscopy results were analysed.
Forty-six patients were identified as having abnormal vocal fold uptake on positron emission tomography-computed tomography. Twenty-three patients underwent positron emission tomography-computed tomography and flexible laryngoscopy: 61 per cent of patients had true-positive positron emission tomography-computed tomography scans and 39 per cent had false-positive scan results.
Most patients referred to ENT for abnormal findings on positron emission tomography-computed tomography scans had true-positive findings. Asymmetrical fluorine-18 fluorodeoxy-D-glucose uptake should raise suspicion of vocal fold pathology, accepting a false-positive rate of approximately 40 per cent.
A public health campaign on laryngeal cancer was conducted in 2011 in the Humber and Yorkshire Coast Cancer Network. This study evaluated its subsequent impact (if any) upon the stage of laryngeal cancer at presentation.
Cases of laryngeal cancer diagnosed in the Humber and Yorkshire Coast Cancer Network from January 2009 to July 2014 were identified from cancer registries and were dichotomised into early (tumour stage T1–2) and late (T3–4) disease. Statistical analysis using segmented regression analysis of interrupted time series data was performed.
There were no statistically significant changes in laryngeal cancer cases immediately after the intervention for both early (p = 0.191) and late (p = 0.680) stage disease. There were also no significant changes to monthly detection rates in both groups on follow up.
Findings of the first public health campaign on laryngeal cancer in the UK are described. Such processes are complex; the implications for future study are discussed.
The optimal management of glottic carcinoma involving the anterior commissure is controversial.
A retrospective analysis was conducted of 76 patients with glottic squamous cell carcinoma treated by transoral carbon dioxide laser resection by a single surgeon.
Sixty-three patients (with tumour stage Tis–T3) were eligible for inclusion. Thirty patients had involvement of the anterior commissure; these patients were significantly more likely to have either uncertain or positive margins (63.3 vs 30.3 per cent, p = 0.012), and were also more likely to receive adjuvant radiotherapy (40 vs 3.2 per cent, p = 0.0005). The overall laryngeal preservation rate was 96.8 per cent; there was no statistically significant difference between those with and without anterior commissure involvement (96.7 and 96.9 per cent respectively).
Transoral laser resection with the use of adjuvant radiotherapy in a minority of patients with adverse pathological findings can be recommended for the primary treatment of anterior commissure glottic cancer from an oncological perspective; excellent local control and laryngeal preservation rates can be achieved.
To evaluate the clinical and histopathological factors affecting the prognosis of patients with squamous cell locoregional advanced laryngeal cancer.
A retrospective chart review was conducted of 121 patients with locoregional advanced laryngeal cancer, primarily treated with surgery from 2007 to 2011. Disease-free survival and overall survival rates were analysed as oncological outcomes. Prognostic variables, namely gender, pharyngeal invasion, pathological assessment of tumour and nodal stage, adjuvant therapy, margin status, nodal extracapsular extension, tumour differentiation, lymphovascular and perineural invasion, and predominant growth pattern, were also analysed.
One-year and three-year disease-free survival rates were 81.3 per cent and 63.5 per cent, respectively. One-year and three-year overall survival rates were 88.3 per cent and 61.4 per cent, respectively. Multivariate analysis showed that nodal extracapsular extension (p < 0.05) and an infiltrative growth pattern (p < 0.05) were associated with disease progression. Nodal extracapsular extension (p < 0.05) was associated with higher mortality.
Nodal extracapsular extension and an infiltrative growth pattern were the main prognostic factors in locoregional advanced laryngeal cancer. The presence of pharyngeal invasion, pathologically confirmed node-positive stage 2–3 disease, close or microscopic positive margins, and lymphovascular and perineural invasion have a negative impact on prognosis.
Genetic alteration of cyclin-dependent kinase inhibitors has been associated with carcinogenesis mechanisms in various organs.
This study aimed to evaluate the expression and mutational analysis of Cip/Kip family cyclin-dependent kinase inhibitors (p21CIP1/WAF1, p27KIP1 and p57KIP2) in early glottic cancer.
Expressions of Cip/Kip family and p53 were determined by quantitative reverse transcription polymerase chain reaction and densitometry. For the analysis of p21 inactivation, sequence alteration was assessed using single-strand conformational polymorphism polymerase chain reaction. Additionally, the inactivation mechanism of p27 and p57 were investigated using DNA methylation analysis.
Reduced expression of p27 and p57 were detected in all samples, whereas the expression of p21 was incompletely down-regulated in 6 of 11 samples. Additionally, single-strand conformational polymorphism polymerase chain reaction analysis showed the p53 mutation at exon 6. Methylation of p27 and p57 was detected by DNA methylation assay.
Our results suggest that the Cip/Kip family may have a role as a molecular mechanism of carcinogenesis in early glottic cancer.
A case of salvage supracricoid laryngectomy with cricohyoidoepiglottopexy after failed radiation therapy and vertical partial laryngectomy had successful oncological and functional outcomes. This is the first reported application of salvage supracricoid laryngectomy with cricohyoidoepiglottopexy after the failure of two major treatments.
A 65-year-old man was referred for salvage supracricoid laryngectomy with cricohyoidoepiglottopexy. The right recurrent hemilarynx was successfully resected. After pexis, the right lobe of the thyroid gland was repositioned to overlap and reinforce the pexis gap and fill the devoid portion of the strap muscular closure. Multiple scattered foci (recurrent tumour–node–metastasis stage T2) were identified around the arytenoid cartilage and beneath the musculocutaneous flap. Four years after supracricoid laryngectomy with cricohyoidoepiglottopexy, the patient's recovery was following a favourable course and he had satisfactory laryngeal function.
Appropriate case selection and proficient surgical skills were essential for a successful outcome. Head and neck surgeons should not be afraid to adopt functional preservation open surgical procedures in well-selected and well-motivated patients. A requirement for more challenging surgical procedures and meticulous rehabilitation processes should not exclude appropriate treatments from a surgeon's repertoire.
To assess the clinical utility of elective neck dissection in node-negative recurrent laryngeal carcinoma after curative radiotherapy for initial early glottic cancer.
A retrospective review was undertaken of 110 consecutive early glottic cancer patients who developed laryngeal recurrence after radiotherapy (34 recurrent T1, 36 recurrent T2, 29 recurrent T3 and 11 recurrent T4a) and received salvage laryngeal surgery between 1995 and 2005.
Six patients presented with laryngeal and neck recurrence and underwent salvage laryngectomy with therapeutic neck dissection, 97 patients with recurrent node-negative tumours underwent salvage laryngeal surgery without neck dissection and only 7 underwent elective neck dissection. No occult positive lymph nodes were documented in neck dissection specimens. During follow up, only three patients with neck failure were recorded, all in the group without neck dissection. There was no significant association between the irradiation field (larynx plus neck vs larynx) and the development of regional failure. A higher rate of post-operative pharyngocutaneous fistula development occurred in the neck dissection group than in the group without neck dissection (57.2 per cent vs 13.4 per cent, p = 0.01). Multivariate logistic regression analysis showed that early (recurrent tumour-positive, node-positive) or delayed (recurrent tumour-positive, node-negative) neck relapse was not significantly related to the stage of the initial tumour or the recurrent tumour. An age of less than 60 years was significantly associated with early neck failure (recurrent tumour-positive, node-positive).
Owing to the low occult neck disease rate and high post-operative fistula rate, elective neck dissection is not recommended for recurrent node-negative laryngeal tumours after radiation therapy if the initial tumour was an early glottic cancer.
Acute respiratory decompensation can occur on a background of slowly progressive airway compromise, for example in laryngeal squamous cell cancer. Surgeons in ENT, together with anaesthetists, are often asked to evaluate airway risk and as yet there is no widely adopted standardised approach.
This paper reports the case of an 82-year-old male, who presented with acute airway compromise due to both endolaryngeal obstruction from a squamous cell cancer and extralaryngeal compression from massive subcutaneous emphysema.
Primary total laryngectomy was performed, but the patient declined adjuvant radiotherapy. He died a year later from a heart attack without evidence of recurrence.
To the best of our knowledge, this is the first case report of acute airway compromise from extralaryngeal subcutaneous emphysema secondary to laryngeal cancer. Options for acute airway management are discussed.
The Cumberland Infirmary, Carlisle, serves a largely remote, rural population of 330 000. The aim of this study was to report the treatment and survival figures for patients treated for laryngeal cancer at this centre.
The study included 209 consecutive patients with squamous cell carcinoma of the larynx diagnosed between 1996 and 2010 at the Cumberland Infirmary.
Disease-specific survival was 100 per cent for stage one, 76 per cent for stage two, 87 per cent for stage three and 46 per cent for stage four. In total, 76 patients (36 per cent) had a laryngectomy, either as primary treatment or as a salvage procedure.
Our tumour-specific survival rate was very high, and this success may be due in part to high rates of surgical intervention. Survival data compared favourably with other centres, despite less radical radiotherapy regimes. Laryngeal cancer can be managed effectively in a small, relatively remote, multidisciplinary team setting.
This study investigated the expression and functional effects, and related molecular mechanisms, of microRNA-519a in laryngeal squamous cell carcinoma.
MicroRNA-519a and HuR messenger RNA in laryngeal squamous cell carcinoma were measured using reverse transcription polymerase chain reaction. MicroRNA-519a effects on the growth of human epithelial type 2 cells were tested using an MTT assay. The influence of microRNA-519a on the expression levels of HuR and other related genes in protein was tested by Western blotting. Cell cycle analyses were performed using flow cytometry. Associations between expression levels and patients' clinical parameters were analysed with Pearson correlation analysis.
Expression of microRNA-519a in laryngeal squamous cell carcinoma tissues was significantly lower than in adjacent non-cancerous tissues. The expression of microRNA-519a was negatively associated with histological differentiation, tumour–node–metastasis stage, lymphatic metastasis and disease-free survival time. After increasing the level of microRNA-519a in laryngeal squamous cell carcinoma human epithelial type 2 cells, cell growth was inhibited and cell cycle was arrested in the G2/M phase. MicroRNA-519a down-regulated HuR gene expression in protein levels without affecting messenger RNA levels.
MicroRNA-519a may function as a tumour suppressor by inhibiting HuR expression, and may serve as a therapeutic target for laryngeal squamous cell carcinoma.
To report and discuss the outcome of a treatment algorithm for patients with tumour stage 1 glottic squamous cell carcinoma.
A retrospective outcome analysis study was performed using data from a tertiary referral centre.
Sixty-nine patients were treated with radiotherapy and 26 with surgery, in accordance with the treatment algorithm. Five-year overall survival rates were the same for both treatment groups (92 per cent). Five-year disease-specific survival rates were 100 per cent for surgery, 98 per cent for radiotherapy and 99 per cent overall. The overall 5-year laryngeal preservation rate was 89.1 per cent, being 95.7 per cent for surgery patients and 86.7 per cent for radiotherapy patients (p = 0.502). There was no significant association between laryngeal preservation rates and age (p = 0.779), anterior commissure involvement (p = 0.081), tumour stage (1a or 1b) (p = 0.266) or treatment modality (surgery or radiotherapy; p = 0.220). There was no significant difference in local recurrence rates between the two treatment groups (19.3 per cent for radiotherapy vs 10.0 per cent for surgery; p = 0.220). The overall 5-year regional recurrence rate was 1.2 per cent.
Tumour stage 1 glottic carcinoma can be managed with different treatment modalities, following an individualised treatment algorithm, with results comparable to published outcomes.
To investigate the relationship between development of laryngeal cancer and the presence of polymorphisms of the MnSOD Val16Ala, CAT-262 C < T and GPx1 Pro198Leu genes in a smoking population.
Patients and methods:
Single nucleotide polymorphisms were determined in DNA from the peripheral blood erythrocytes of 48 heavy smokers (25 patients with laryngeal cancer and 23 cancer-free controls), using polymerase chain reaction.
There were no significant differences in age, smoking duration or smoking intensity, comparing the two groups. The homozygous AA genotype of MnSOD Val16Ala was significantly more prevalent in the cancer group than the control group (92 vs 13 per cent, respectively), while the heterozygous AV genotype of MnSOD Val16Ala was more prevalent in the control group than the cancer group (87 vs 8 per cent, respectively) (p < 0.001). There were no significant differences between the cancer and control groups regarding GPx1 Pro198Leu or CAT-262 C < T polymorphisms.
Polymorphism of the MnSOD Val16Ala gene may contribute to susceptibility to laryngeal cancer among smokers.
The terms neck dissection and laryngectomy describe a wide variety of surgical procedures that attempt to remove a cancer and its main route of spread. Neck dissection is commonly performed during laryngectomy for cancer to prevent and treat any local spread of the primary disease. A careful airway evaluation is an essential part of preparation for a patient undergoing laryngectomy with neck dissection. The treatment of laryngeal cancer has three primary goals: tumor removal, prevention of spread and recurrence, and preservation of organ function (phonation and swallowing) where possible. Neck radiation changes can make airway management difficult as its presence is an independent predictor of failure for both bag-mask ventilation and GlideScope intubation. Systolic blood pressure variation of the arterial line tracing can help guide fluid replacement. Alternatively a central line, at a different location from the neck dissection, can be used.
The differential diagnosis of endolaryngeal mesenchymal neoplasms includes a wide spectrum of benign and malignant pathologies, which have been rarely photo-documented and assessed as a group.
Non-epithelial neoplasms of the endolarynx seen at our centre from 2002 to 2011 (n = 38; 36 treated at our institution) were retrospectively reviewed, with attention to clinical presentation, radiographic imaging, operative management, histology, and pre- and post-operative endoscopy. Submucosal squamous cell carcinomas, mucosal cysts, amyloid and Teflon granulomas were excluded.
Twenty-three of a total of 36 patients underwent definitive endoscopic surgical treatment. Supraglottic pathologies included lymphoma, lipoma, neuroendocrine carcinoma, lymphangioma, oncocytoma, haemangioma, synovial cell sarcoma and benign spindle cell neoplasm. Transglottic pathologies included synovial cell sarcoma and granular cell tumour. Glottic pathologies included granular cell tumour, osteoma, rhabdomyoma, rhabdomycosarcoma and myofibroblastic sarcoma. Subglottic pathologies included chondrosarcoma, neurofibroma, adenoid cystic carcinoma and vascular malformation.
The site of origin, degree of malignant behaviour and sensitivity to adjuvant treatment determined the course of surgical management, i.e. endolaryngeal versus transcervical, and limited removal versus wider resection.
To investigate the characteristics of the laryngeal mucosal microvascular network in suspected laryngeal cancer patients, using narrow band imaging, and to evaluate the value of narrow band imaging endoscopy in the early diagnosis of laryngeal precancerous and cancerous lesions.
Patients and methods:
Eighty-five consecutive patients with suspected precancerous or cancerous laryngeal lesions were enrolled in the study. Endoscopic narrow band imaging findings were classified into five types (I to V) according to the features of the mucosal intraepithelial papillary capillary loops assessed.
A total of 104 lesions (45 malignancies and 59 nonmalignancies) was detected under white light and narrow band imaging modes. The sensitivity and specificity of narrow band imaging in detecting malignant lesions were 88.9 and 93.2 per cent, respectively. The intraepithelial papillary capillary loop classification, as determined by narrow band imaging, was closely associated with the laryngeal lesions' histological findings. Type I to IV lesions were considered nonmalignant and type V lesions malignant. For type Va lesions, the sensitivity and specificity of narrow band imaging in detecting severe dysplasia or carcinoma in situ were 100 and 79.5 per cent, respectively. In patients with type Vb and Vc lesions, the sensitivity and specificity of narrow band imaging in detecting invasive carcinoma were 83.8 and 100 per cent, respectively.
Narrow band imaging is a promising approach enabling in vivo differentiation of nonmalignant from malignant laryngeal lesions by evaluating the morphology of mucosal capillaries. These results suggest endoscopic narrow band imaging may be useful in the early detection of laryngeal cancer and precancerous lesions.
We had previously treated patients with advanced stage laryngeal cancer by laryngectomy with or without post-operative radiotherapy. In order to improve such patients' quality of life, we sought to preserve the larynx by selective (intra-arterial), rapid infusion chemotherapy combined with radiotherapy.
Chemotherapy was administered intra-arterially in the angiography suite via transfemoral catheterisation of the superior thyroid artery. Patients received up to four once-weekly infusions of cisplatin (75 mg/patient) with simultaneous intravenous administration of sodium thiosulphate, a neutralising agent. Patients also received external radiation simultaneously at a dose of 1.8 or 2.0 Gy per fraction, once daily for five days a week for 7 weeks.
Intra-arterial infusion chemo-radiotherapy was performed in eight patients with advanced laryngeal carcinoma (four glottic, three supraglottic and one subglottic type carcinoma). A complete response was achieved at the primary site and at lymph node metastases in all eight patients. Overall toxic side effects were modest. No catheter-related thrombo-embolic complications were observed during any of the chemotherapy sessions.
Selective (intra-arterial), rapid infusion chemo-radiotherapy may enable laryngeal preservation in patients with advanced laryngeal carcinoma.
During a 20-year period, we treated 26 patients with radiation after total laryngectomy because of laryngeal cancer with subglottic extension (LCSE). The paratracheal lymph nodes superior (and inferior in two cases) to the suprasternal notch were irradiated in addition to the primary tumour bed. With a follow-up period ranging from 5 to 185 months, the occurrence of neoplastic disease in the upper mediastinum was not observed in a single case. The rates of recurrent tumour in the neck and distant metastasis were both 8%. The 6-year survival rate was 67%. The observed results lead us to the conclusion that even with non-irradiation of the superior mediastinal paratracheal lymph nodes, postoperative radiotherapy can achieve reasonable long-term disease-free survival in patients with LCSE.
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