Carcinoid tumour

Laryngeal carcinoid is an extremely rare tumour. It is a well-differentiated malignant lesion that possesses a well-demonstrated capacity for both regional and distant metastases.Reference Ferlito, Devaney, Hunt and Rinaldo⁶

Carcinoid tumours have a distinct male predominance, most commonly occurring in middle-age.Reference Devaney, Ferlito and Rinaldo⁷ These tumours have been reported both in smoking and non-smoking patients.Reference Ferlito and Rinaldo⁸

The site of origin is most commonly the supraglottic larynx, especially the arytenoid or the aryepiglottic fold (Figure 1).Reference Ferlito and Rinaldo⁸ The presenting symptoms are similar to other laryngeal tumours, namely hoarseness, dysphagia, sore throat or a feeling of a lump. Symptoms may be present from 4 weeks to 10 years.Reference Ferlito and Rinaldo⁸ The tumour rarely presents with nodal metastases, but may metastasise over the course of extended follow up.Reference Soga⁹ One case of associated carcinoid syndrome has been reported, after the tumour metastasised to the liver.Reference Ferlito, Rinaldo, Bishop, Hunt, Vander Poorten and Williams¹⁰

Fig. 1.

Carcinoid tumour. (a) A submucosal mass is seen involving the right aryepiglottic fold on stroboscopy (arrows). (b) The tumour cells are uniform, growing in nests without mitoses, necrosis or atypia (H&E; ×200).

Macroscopically, the tumour presents as a submucosal or polypoid mass. Histologically, typical carcinoid tumours consist of small- to medium-sized nests and trabeculae of small- to medium-sized cells, with moderate cytoplasm, and round, regular nuclei with speckled chromatin with a salt and pepper appearance. These cells are fairly regular, without substantial pleomorphism and without significant cytological atypia. The rate of mitotic activity is very low (< 2 per 10 high power fields). There is no necrosis and sparse to absent perineural and vascular invasion.

Carcinoid tumours typically express neuroendocrine markers on immunohistochemistry, including chromogranin and synaptophysin.Reference Dieler and Dämmrich¹¹ The tumours are also positive for cytokeratin stains, and, similar to laryngeal atypical carcinoid tumours, carcinoid tumours are often immunoreactive for calcitonin.Reference Nozières, Chardon, Goichot, Borson-Chazot, Hervieu and Chikh¹²

As initial biopsies are often small and crushed, tumour grading of carcinoid versus atypical carcinoid tumours may require resection for definitive grading. Although atypical carcinoid tumours are more common, the quality of biopsy and histological features should be verified prior to assuming a well-differentiated carcinoid tumour.

Primary conservation surgery, particularly supraglottic laryngectomy, is the preferred treatment.Reference Ferlito, Silver, Bradford and Rinaldo^2, Reference Ferlito and Rinaldo⁸ Transoral carbon dioxide (CO₂) laser surgery can be a good alternative in selected cases because of the potential for improved functional results and lower morbidity.Reference Cevizci, Karakullukçu, van den Brekel and Balm¹³ Given the very low rate of regional metastasis, elective neck dissection is not indicated. Bilateral neck dissection (levels II and III) should be reserved for clinically or pathologically proven cervical metastases.Reference Ferlito, Lewis and Rinaldo^4, Reference Ferlito, Devaney and Rinaldo¹⁴ Chemotherapy and radiotherapy have not been found to be of any benefit in treatment.Reference Ferlito, Barnes, Rinaldo, Gnepp and Milroy¹⁵

Carcinoid tumours are associated with the best prognosis of the laryngeal neuroendocrine carcinomas. Although many patients do not die of disease, carcinoid tumours are not indolent.Reference Ferlito, Silver, Bradford and Rinaldo² Soga et al. observed that 33 per cent of patients with carcinoid of the larynx developed metastases.Reference Soga, Ferlito and Rinaldo¹⁶ The five-year survival rate reported in one large series was 49 per cent.Reference Soga, Ferlito and Rinaldo¹⁶ However, this low survival rate may be due to the erroneous inclusion of cases of atypical carcinoid tumour as typical carcinoid tumours.Reference Ferlito, Devaney and Rinaldo¹⁴

Atypical carcinoid tumour

Atypical carcinoid tumour is the most frequent laryngeal neuroendocrine carcinoma.Reference Ferlito, Barnes, Rinaldo, Gnepp and Milroy¹⁵ It is a moderately differentiated tumour, with aggressive biological behaviour, and frequent regional and distant metastases. In contrast to other disease sites, atypical carcinoid of the larynx is said to be associated with particularly high rates of metastatic disease.Reference Soga, Ferlito and Rinaldo¹⁶

It occurs most frequently in men. The mean age at diagnosis is 61 years (range, 33–83 years), with a peak incidence in the sixth and seventh decades of life. Most patients are heavy smokers.Reference Ferlito and Rinaldo⁸

The tumour usually involves the supraglottic larynx (over 90 per cent of reported tumours), with most tumours being situated in the aryepiglottic fold, arytenoid or laryngeal surface of the epiglottis. Occasionally, tumours occur in the glottis and subglottis.Reference Ferlito and Rinaldo⁸ Presenting symptoms include hoarseness, dysphagia, sore throat, haemoptysis and otalgia. On occasion, patients may be asymptomatic. Atypical carcinoid metastasises to lymph nodes in approximately 50 per cent of casesReference Woodruff and Senie¹⁷ and metastasises distantly in as many as 40–45 per cent.Reference Soga, Ferlito and Rinaldo¹⁶ One peculiar aspect of the natural history of these tumours is the predilection to give rise to disseminated skin or subcutaneous metastases.Reference Woodruff and Senie¹⁷ Carcinoid syndrome associated with this tumour has been reported,Reference Ferlito, Rinaldo, Bishop, Hunt, Vander Poorten and Williams^10, Reference Ferlito and Rinaldo¹⁸ and elevated serum levels of calcitonin may be detected.Reference Chung, Lee, Shim, Kim, Nam and Kim³

Tumours usually present as nodular, pedunculated or polypoid submucosal masses (Figure 2), with or without ulceration of the overlying mucosa.Reference Chung, Lee, Shim, Kim, Nam and Kim³ Histologically, atypical carcinoid tumours show a similar morphology and growth pattern to typical carcinoid tumours, but with a moderate degree of atypia, with nuclei exhibiting moderate pleomorphism and prominent nucleoli, and a slight increased mitotic activity (more than 2 but less than 10 mitoses per 10 high power fields). If there is abundant mitotic activity (more than 10 mitoses per 10 high power fields), a diagnosis of large cell neuroendocrine carcinoma must be considered. Mucin can be present,Reference McCluggage, Cameron, Arthur and Toner¹⁹ and there may be patchy necrosis. Atypical carcinoid tumours are positive for chromogranin and synaptophysin, and frequently calcitonin.Reference Chung, Lee, Shim, Kim, Nam and Kim^3, Reference Woodruff and Senie^17, Reference Abiko, Ogawa, Hattori, Kusano, Nishimura and Ohuchi²⁰ Occasionally, sustentacular cells can be positive for the S100 stain.Reference Alujević, Jurić, Separović and Kruslin²¹ Rarely, patients have also been described as showing elevated serum levels of calcitonin.Reference Chung, Lee, Shim, Kim, Nam and Kim³

Fig. 2.

Atypical carcinoid tumour. (a) A submucosal mass of spindled cells with mild nuclear variability (H&E; ×200). (b) Another example with more oncocytic cytoplasm, variable nuclear hyperchromasia and increased anaplasia with occasional mitoses (H&E; ×200).

The differential diagnoses must include typical carcinoid tumour (histological criteria), paraganglioma (negative for cytokeratin), medullary thyroid carcinoma (positive for thyroid transcription factor 1), and small and large cell neuroendocrine carcinomas (high-grade neoplastic lesions).

The mainstay of treatment for atypical carcinoid tumours is surgical resection. Supraglottic laryngectomy, by transoral CO₂ laser, is often the procedure of choice.Reference Chang, Lee, Yeh, Dai and Hao²² In patients considered clinically free of regional disease, elective neck dissection is indicated in view of the high incidence of both early cervical metastasis and subsequent involvement of cervical lymph nodes. However, surgery may be restricted to bilateral dissection of sublevel IIA and level III if the tumour does not extend beyond the supraglottis.Reference Ferlito, Lewis and Rinaldo⁴ For patients with regional disease, therapeutic neck dissection is indicated. Post-operative (chemo)radiotherapy is indicated in the presence of confirmed cervical lymph node metastases.Reference Ferlito, Silver, Bradford and Rinaldo² Radical chemoradiotherapy has not been considered as an effective primary treatment option.Reference Ferlito, Barnes, Rinaldo, Gnepp and Milroy¹⁵

Death usually results from metastatic disease rather than local recurrence. The size of the primary tumour is important prognostically; patients with tumours greater than 1 cm demonstrate twice the mortality rate to those with small volume disease (44 per cent vs 23 per cent).Reference Woodruff and Senie¹⁷ The 5-year survival rate is approximately 50 per cent,Reference Ferlito, Silver, Bradford and Rinaldo^2, Reference Soga^9, Reference Woodruff and Senie¹⁷ with a 10-year survival rate of 30 per cent.Reference Woodruff and Senie¹⁷ For patients with atypical carcinoid tumour, extended follow up is advised, as late recurrences are common.Reference van der Laan, van der Laan, Plaat, Wedman, Van Hemel and Halmos²³

Small cell neuroendocrine carcinoma

Small cell neuroendocrine carcinoma is quite rare, representing about 0.5 per cent of all laryngeal cancers.Reference Ferlito and Rinaldo²⁴ The larynx is one of the most common sites for extrapulmonary small cell neuroendocrine carcinoma.Reference Ferlito²⁵ It is a biologically aggressive malignancy,Reference Gnepp²⁶ with an increased tendency to present with nodal metastases and a very high rate of distant metastasis. Therefore, most patients die of their disease within two to three years.Reference Ferlito and Rinaldo^24, Reference Ferlito and Rinaldo²⁷ Small cell neuroendocrine carcinoma can be regarded as a systemic disease,Reference Gripp, Risse, Leverstein, Snow and Meijer²⁸ and the absence of regional or distant metastasis on staging scans does not preclude the existence of micrometastasis.Reference Ferlito and Rinaldo²⁴

The majority of patients are male and aged over 50 years. This subtype of neuroendocrine carcinoma develops in an older age group than seen in carcinoid or atypical carcinoid tumours. Most patients are heavy smokers.

The disease can involve any laryngeal subsite, but the supraglottis is again the most common.Reference Iqbal, Paleri, Moor, Dobrowsky, Kelly and Kovarik²⁹ Presenting symptoms and clinical signs vary according to the region involved and the extent of the disease, with hoarseness and a neck mass being the most common presenting complaints.Reference Iqbal, Paleri, Moor, Dobrowsky, Kelly and Kovarik²⁹ About half of patients present with cervical lymph node metastasis, and over 90 per cent eventually develop systemic metastatic disease. Different paraneoplastic syndromes, including Schwartz–Bartter, Cushing's and Eaton–Lambert syndromes, have been reported in association with small cell neuroendocrine carcinoma, and all such patients died.Reference Ferlito, Rinaldo, Bishop, Hunt, Vander Poorten and Williams¹⁰

A correct diagnosis and comprehensive staging are essential for choosing the most suitable therapeutic approach. Staging investigations should include computed tomography and/or positron emission tomography to assess the burden of disease.

The tumour presents as a submucosal lesion, often with surface ulceration. Histological analysis (Figure 3) reveals that small cell neuroendocrine carcinoma encompasses oat cell, intermediate cell and combined variants. The oat cell variant has small, irregular and very hyperchromatic cells, with sparse cytoplasm and frequently abundant crush artifact. Nuclei are small and darkly staining, with finely granular, salt-and-pepper chromatin and inconspicuous nucleoli.Reference Lewis, Ferlito, Gnepp, Rinaldo, Devaney and Silver⁵ The nuclei can display what is referred to as nuclear moulding, where one nucleus conforms to the shape of adjacent cells. The size of small cell neuroendocrine carcinoma cells is around the size of three lymphocytes, or less.Reference Lewis, Ferlito, Gnepp, Rinaldo, Devaney and Silver⁵

Fig. 3.

Small cell neuroendocrine carcinoma. (a) A low power micrograph shows an infiltrating tumour with extensive necrosis (lower right side of image, arrows) (H&E; ×40). (b) The tumour cells overlap without clear cytoplasmic borders. Nuclei are hyperchromic with numerous mitoses, and apoptotic bodies (H&E; ×200).

The tumours show immunoreactivity for typical neuroendocrine markers, such as chromogranin, synaptophysin, neuron-specific enolase, clusters of differentiation 56 and 57, and neuropeptides. The cells will also be positive for cytokeratins, epithelial membrane antigen, carcinoembryonic antigen, calcitonin, somatostatin, adrenocorticotropic hormone, bombesin and serotonin. In addition, small cell neuroendocrine carcinoma may be positive for thyroid transcription factor 1.Reference Ferlito, Silver, Bradford and Rinaldo²

The intermediate cell variant has slightly more abundant cytoplasm, and the combined (or composite) type is a tumour with an obvious component of small cell neuroendocrine carcinoma mixed with SCC or adenocarcinoma.Reference Ferlito, Silver, Bradford and Rinaldo² These composite tumours are rare in the larynx.Reference Jaiswal and Hoang³⁰

The differential diagnoses for small cell neuroendocrine carcinoma includes other small round blue cell tumours that can arise primarily in the larynx, such as melanoma (positive for melan-A, tyrosinase, HMB45, SOX10), rhabdomyosarcoma (positive for desmin), extraskeletal Ewing's sarcoma or peripheral neuroectodermal tumour (positive for cluster of differentiation 99, though this is not specific), Merkel cell carcinoma (positive for keratin 20), and metastatic lesions such as metastatic pulmonary small cell neuroendocrine carcinoma.

A therapeutic protocol using a combination of local irradiation and chemotherapy, similar to that used for pulmonary small cell carcinoma, is indicated. Radical surgical procedures (total laryngectomy and radical neck dissection) have failed in the majority of cases reported.Reference Ferlito, Silver, Bradford and Rinaldo^2, Reference Ferlito and Rinaldo^24, Reference Ferlito and Rinaldo^27, Reference Ferlito, Pesavento, Recher, Caruso, Dal Fior and Montaguti^31, Reference Ferlito, Shaha and Rinaldo³² The commonly used chemotherapeutic agents are cisplatin, carboplatin, cyclophosphamide, doxorubicin, vincristine, methotrexate and lomustine.Reference Jiang, Yang, Guan, Mi and Wang³³ Galanis et al. reported a higher response rate to platinum-based chemotherapy (72 per cent, with a median duration of 8.5 months) compared with a doxorubicin-based regimen (57 per cent, with a median duration of 4.5 months) for extensive or recurrent extrapulmonary small cell carcinomas.Reference Galanis, Frytak and Lloyd³⁴ However, in some highly selected cases, minimally invasive approaches, such as transoral CO₂ laser surgery, may be used to remove the primary tumour.Reference Iqbal, Paleri, Moor, Dobrowsky, Kelly and Kovarik²⁹ Prophylactic cranial irradiation is advocated by some authors because of the high incidence of intracranial metastasis; however, a recent review by Coca-Pelaz et al. concluded that it does not appear to have a role in the treatment of these patients.Reference Coca-Pelaz, Devaney, Rodrigo, Halmos, Strojan and Mendenhall³⁵

The prognosis of this tumour is dismal and the clinical course tends to be rapidly fatal.Reference Ferlito and Rinaldo^27, Reference Ferlito, Shaha and Rinaldo³² The two- and five-year survival rates have been reported as 16 per cent and 5 per cent, respectively, similar to those for small cell lung cancer, and these outcomes do not correlate with the tumour size.Reference Ferlito, Silver, Bradford and Rinaldo^2, Reference Ferlito and Rinaldo^24, Reference Ferlito and Rinaldo²⁷ Gnepp reported a mean survival time of less than 10 months (range, 1–26 months), with 73 per cent of patients dying of widespread metastasis.Reference Gnepp²⁶ Soga reported a five-year overall survival rate of 8 per cent.Reference Soga⁹

Large cell neuroendocrine carcinoma

Large cell neuroendocrine carcinoma is a high-grade malignant neuroendocrine tumour that was first defined in the lung by Travis et al. in 1991.Reference Travis, Linnoila, Tsokos, Hitchcock, Cutler and Nieman³⁶ It is rare in the larynx. This tumour has generated considerable discussion.Reference Thompson, Stelow, Mills, Westra and Bishop³⁷ In the most recent edition of the World Health Organization Classification of Tumours, large cell neuroendocrine carcinoma is described as a subtype of poorly differentiated neuroendocrine carcinoma.Reference El-Naggar, Chan, Grandis, Takata and Slootweg¹ The tumour has a unique morphology and behaviour, and should be classified as a specific tumour diagnosis.Reference Devaney, Ferlito and Rinaldo⁷ There are reports of these tumours arising in different head and neck subsites, with the most common site being the larynx.Reference Ferlito, Strojan, Lewis, Perez-Ordoñez and Rinaldo³⁸

Large cell neuroendocrine carcinoma is an extremely aggressive tumour. It is poorly differentiated, and can share biological and clinical characteristics with small cell neuroendocrine carcinoma and atypical carcinoid tumour.Reference Ferlito, Strojan, Lewis, Perez-Ordoñez and Rinaldo^38, Reference Alos, Hakim, Larque, de la Oliva, Rodriguez-Carunchio and Caballero³⁹ However, the prognosis is similar to that for small cell neuroendocrine carcinoma; it appears to be exceedingly poor, with most patients developing lymph node metastases and distant metastatic disease, with subsequent demise within two years.Reference Lewis, Ferlito, Gnepp, Rinaldo, Devaney and Silver^5, Reference Ferlito, Strojan, Lewis, Perez-Ordoñez and Rinaldo³⁸

Given the limitations of the current classifications, estimation of the true epidemiology of large cell neuroendocrine carcinoma is unreliable.Reference Ferlito, Strojan, Lewis, Perez-Ordoñez and Rinaldo³⁸ In a meta-analysis of neuroendocrine carcinoma, the median age of patients who presented with large cell neuroendocrine carcinoma was comparable to those with small cell neuroendocrine carcinoma. Although a male preponderance still exists, the proportion of female patients was somewhat larger in comparison with small cell neuroendocrine carcinoma (29.6 vs 18.6 per cent). Patients are usually heavy smokers. Some recent studies found a potential relationship between large cell neuroendocrine carcinoma and human papillomavirus (HPV), as up to 30 per cent of cases may be HPV-positive.Reference Thompson, Stelow, Mills, Westra and Bishop^37, Reference Alos, Hakim, Larque, de la Oliva, Rodriguez-Carunchio and Caballero³⁹ Unfortunately, the presence of HPV does not confer an altered prognosis in these tumours, which remains poor.

Patients with large cell neuroendocrine carcinoma usually present with a painless mass located in the supraglottic region (Figure 4). Cervical nodal metastases are very common and should raise strong suspicion clinically. Association with paraneoplastic syndromes has not been reported for large cell neuroendocrine carcinoma.Reference Ferlito, Rinaldo, Bishop, Hunt, Vander Poorten and Williams¹⁰

Fig. 4.

Large cell neuroendocrine carcinoma. (a) Sagittal computed tomography image shows a pedunculated mass of the epiglottis (within dotted circle). (b) Microscopic overview of the resection specimen, with the pedunculated tumour arising from the epiglottic surface with underlying cartilage (H&E; ×10). (c) Neoplastic cells are hyperchromatic, overlapping with enlarged nuclei, apoptotic bodies, mitoses and focal necrosis (H&E; ×200). (d) Tumour cells show expression for chromogranin (immunohistochemical evaluation; ×200).

The diagnosis of large cell neuroendocrine carcinoma is based on high-grade features, and on the presence of both neuroendocrine morphology and immunohistochemical evidence of neuroendocrine differentiation. The criteria for diagnosis of large cell neuroendocrine carcinoma for lung tumours, according to Travis et al., include: (1) the presence of neuroendocrine differentiation features, including organoid nesting, trabecular growth, rosettes and peripheral palisading; (2) the presence of enlarged tumour cells, with vesicular chromatin, small to prominent nucleoli, and moderate to abundant cytoplasm; (3) increased mitotic activity (greater than 10 mitoses per 10 high power fields (2 mm²)); and (4) confirmation of neuroendocrine differentiation using immunohistochemical staining for chromogranin and/or synaptophysin.Reference Travis, Linnoila, Tsokos, Hitchcock, Cutler and Nieman³⁶ Markers including neuron-specific enolase, and/or neural cell adhesion molecule, and clusters of differentiation 56 and 57 are not specific for neuroendocrine differentiation, and interpretation should be made in conjunction with morphology and other markers.

Macroscopically, the tumour presents as a submucosal unencapsulated mass. More specifically, from a histopathological point of view, large cell neuroendocrine carcinoma has large polygonal cells with generous eosinophilic cytoplasm. There is no absolute cell size cut-off between large cell neuroendocrine carcinoma and small cell neuroendocrine carcinoma, although cell size in the latter is usually smaller than the diameter of three resting lymphocytes. Nuclear characteristics, however, are key to this distinction. Large cell neuroendocrine carcinoma usually has vesicular or coarse salt-and-pepper chromatin and prominent nucleoli. This is in contrast to small cell neuroendocrine carcinoma, where nucleoli are inconspicuous or absent, and chromatin is finely granular. The growth pattern shows characteristic neuroendocrine features, with sheets and nests of tumour cells, and organoid and trabecular architecture. The tumours frequently display necrosis and lymphovascular invasion.

The distinguishing feature to separate large cell neuroendocrine carcinoma from atypical carcinoid tumour, which can have quite similar histological features, is mitotic activity. Mitotic activity is more than 10 per 10 high power fields in large cell neuroendocrine carcinoma (although most have higher rates, usually more than 50 per 10 high power fields), whereas it is less than or equal to 10 in atypical carcinoid tumour.Reference Lewis, Ferlito, Gnepp, Rinaldo, Devaney and Silver^5, Reference Travis, Linnoila, Tsokos, Hitchcock, Cutler and Nieman³⁶

Although not necessarily discriminating, large cell neuroendocrine carcinoma typically has much more cytological atypia and more necrosis than atypical carcinoid tumour. On immunohistochemistry, large cell neuroendocrine carcinoma is positive for chromogranin, synaptophysin, cluster of differentiation 56, neuron-specific enolase and calcitonin.Reference Ferlito, Strojan, Lewis, Perez-Ordoñez and Rinaldo^38, Reference Kusafuka, Ferlito, Lewis, Woolgar, Rinaldo and Slootweg⁴⁰

The treatment of large cell neuroendocrine carcinoma has not been standardised. Chemoradiotherapy is accepted as the primary treatment modality.Reference Ferlito, Strojan, Lewis, Perez-Ordoñez and Rinaldo³⁸ It appears that in all but the most early stage tumours, some forms of systemic therapy acting against possible micrometastases should be considered as part of the treatment regimen.Reference Ferlito, Strojan, Lewis, Perez-Ordoñez and Rinaldo³⁸ In tumours with a high propensity for distant dissemination, such as large cell neuroendocrine carcinoma, the administration of systemic therapy seems to be important. For patients with systemic disease, palliative chemotherapy or best supportive care remain appropriate options.Reference Ferlito, Strojan, Lewis, Perez-Ordoñez and Rinaldo³⁸ Combined cisplatin-based chemotherapy, similar to that used for small cell neuroendocrine carcinoma, seems to be most effective.

Despite aggressive therapy, survival remains poor. The five-year disease-specific survival rate is 15 per cent for large cell neuroendocrine carcinoma, the worst of all four histological neuroendocrine tumour subtypes.