Primary typical carcinoid tumour in the retromolar region with prominent squamous differentiation: a case report


Primary carcinoid tumours of the oral cavity are rare, with only one case of atypical carcinoid tumour reported in the literature. In this article, a case of primary typical carcinoid tumour in the retromolar region in a 46-year-old woman is described. Histologically, the tumour was characterized by submucosal proliferation of medium-sized monomorphous epithelioid cells with an organoid and nesting pattern of growth. Mitoses and necrosis were not found. Prominent squamous differentiation was present. Immunohistochemically, the tumour was diffuse positive for cytokeratin (CK) (AE1/AE3), CK7, p63, neurone-specific enolase, synaptophysin, and chromogranin. To the authors’ knowledge, this is the first report of primary typical carcinoid tumour in the oral cavity.

Neuroendocrine carcinomas are a heterogeneous family of neoplasms that can occur widely in various organs and tissues. The majority of neuroendocrine carcinomas in the head and neck region arise in the larynx and salivary glands . Their occurrence in intraoral mucosal sites is rare, and only 15 cases of oral neuroendocrine carcinomas have been reported as Merkel cell carcinoma (7 cases), small cell neuroendocrine carcinoma (5 cases), large cell neuroendocrine carcinoma (1 case), atypical carcinoid (1 case) and moderately differentiated neuroendocrine carcinoma (1 case) . According to the World Health Organization classification, laryngeal neuroendocrine carcinomas are subclassified into typical carcinoid, atypical carcinoid, and small cell carcinoma, corresponding to well, moderately, and poorly differentiated neuroendocrine carcinomas, respectively . Owing to their rarity, neuroendocrine carcinomas of the oral cavity were not incorporated into the classification of neuroendocrine neoplasms of the head and neck. In a recent review, M ahomed proposed classifying oral neuroendocrine carcinomas into typical carcinoid, atypical carcinoid, small cell neuroendocrine carcinoma (including the Merkel cell type and the pulmonary type), and large cell neuroendocrine carcinoma. To the authors’ knowledge, the existence of primary typical carcinoid tumour in the oral cavity has not been published before. The authors present the first case of oral typical carcinoid tumour in the retromolar region in a 46-year-old woman. Unusual prominent squamous differentiation was noted.

Case report

A 46-year-old woman presented with a 5-year history of a painless swelling in the retromolar region. Intraoral examination showed a relatively well-defined, elastic, and immobile mass that measured about 1.5 cm × 2 cm. It was covered with normal, healthy, non-ulcerated mucosa. A panoramic radiograph showed no bony involvement. There was no palpable cervical lymphadenopathy. A detailed general physical examination, chest X-ray, and abdominal ultrasound scan showed no evidence of distant metastasis. The patients’ laboratory findings were within normal limits, including complete blood count, blood biochemistry, and urine analysis. The clinical differential diagnosis included benign minor salivary gland neoplasm, benign mesenchymal neoplasm, and low-grade malignant tumour of minor salivary gland or mesenchymal origin. The lesion was excised completely with free margins under general anaesthesia. The patient is being followed up and showed no evidence of disease 11 months postoperatively.

Histopathological examination revealed that the resected tumour was 2 cm in diameter, whitish in colour and relatively hard in consistency. There was a circumscribed, but not encapsulated, submucosal tumour covered by normal surface epithelium. The tumour was composed of medium-sized monomorphous epithelioid cells, arranged in nests, trabeculae, and cords surrounded by thin to thick fibrovascular septa ( Fig. 1 a) . The cytoplasm of the tumour cells varied from eosinophilic to pale. The nuclei were central, round with finely granular chromatin and inconspicuous nucleoli. Mitoses and necrosis were not found ( Fig. 1 b). Extensive squamous differentiation was noted. Prominent thin, elongated blood vessels were seen.

Fig. 1
(a) Low power showing a circumscribed submucosal proliferation covered by normal surface epithelium. Tumour cells arranged in organoid and nesting pattern. Prominent squamous differentiation was noted. Haematoxylin–eosin stain (H–E stain): ×40. (b) High power showing the relatively uniform tumour cells with round or oval, centrally placed nuclei and granular eosinophilic cytoplasm. H–E stain: ×400.

Immunohistochemically, the tumour was diffuse positive for cytokeratin (CK) AE1/AE3 ( Fig. 2 a) , CK7, neurone-specific enolase ( Fig. 2 b), synaptophysin ( Fig. 2 c), chromogranin, and p63 ( Fig. 2 d); focal positive for S100, vimentin, and CD57; negative for CD56, thyroid transcription factor 1 (TTF-1), and CK20. The components of squamous differentiation were positive for CKAE1/AE3 and CK7. The association of the immunoprofile with the microscopic morphology confirmed the diagnosis of typical carcinoid tumour.

Fig. 2
(a) Tumour cells were strongly immunostained with CKAE1/AE3: ×200. (b) Tumour cells were strongly positive for neurone-specific enolase whilst the squamous components were negative: ×200. (c) Tumour cells were positive for synaptophysin: ×200. (d) Tumour cells were positive for p63: ×200.


Carcinoid tumour is the most common of the neuroendocrine tumours. It is usually found in the gastrointestinal tract (55%) and in the bronchopulmonary tract (30%) . Occurrence of carcinoid tumour in the head and neck area mainly involves the larynx, followed by the middle ear . Primary carcinoid tumours of the oral cavity are rare, with only one case of atypical carcinoid tumour reported in the literature . The present case is the first report of typical carcinoid tumour in the oral cavity.

The clinical presentation of carcinoid tumours varies depending on the site of origin. In general, they are slow-growing tumours that pose a diagnostic challenge because they are often innocuous at the time of presentation . In accordance with the observation that the present case was a small, slow-growing lesion without osseous erosion, it was thought most likely to represent a benign or low-grade malignant process. Neuroendocrine tumours were not included in the clinical differential diagnosis. Not surprisingly the patient did not complain of carcinoid syndrome; less than 10% of patients with carcinoid tumour have the classical carcinoid syndrome .

The diagnosis of carcinoid tumour is initially based on histology with confirmation by immunohistochemistry and/or electron microscopy . The histological features of carcinoid tumours consist of an organoid and nesting growth pattern with uniform cytological features consisting of a moderate amount of eosinophilic cytoplasm. The nuclear chromatin is finely granular. The cells are separated by a fibrovascular or hyalinized stroma. Oncocytic, oncocytoid, mucinous and amyloid changes, focal ‘zellballen’, squamous differentiation and rosettes may be seen. Typical carcinoid tumours show no necrosis and are characterized by a mitotic rate of less than 2/10 high-power fields (HPFs). Atypical carcinoid tumours exhibit punctuate areas of necrosis and a mitotic rate higher than 2/10 HPFs but less than 11/10 HPFs. Immunohistochemically, carcinoid tumours are positive for the most sensitive and specific neuroendocrine markers, in particular for synaptophysin, chromogranin, and CD56, and almost always for low-molecular-weight cytokeratins as well as other epithelial markers (carcinoembryonic antigen and epithelial membrane antigen). The neoplastic cells are also variably positive for S-100 protein and for a variety of neuropeptides, including adrenocorticotropic hormone, calcitonin, bombesin, serotonin, somatostatin . On electron microscopy, tumour cells contain abundant membrane-bound, electron-dense neurosecretory granules. Complex intercellular digitation, tight intercellular junctions and mitochondria are variably present . The histopathological and immunohistochemical features seen in the present case are consistent with typical carcinoid tumour. In particular, unusual prominent squamous differentiation was present.

The differential diagnosis for the present case includes any primary or secondary tumour with neuroendocrine differentiation . Atypical carcinoid tumours are distinguished from typical carcinoid tumours by increased nuclear atypia, a higher mitotic activity that ranges from 2 to 10 mitoses/10 HPFs and punctate foci of necrosis that may be seen. The high-grade neuroendocrine carcinoma, including small cell neuroendocrine carcinoma, Merkel cell carcinoma and large cell neuroendocrine carcinoma, can be distinguished from carcinoid tumours easily by their high mitotic rate and frequent necrosis in addition to characteristic morphology. Rare cases of paragangliomas arising in the oral cavity have been reported . These are composed of chief cells and sustentacular cells in a nesting or zellballen pattern. The chief cells are immunoreactive for neuroendocrine markers and the sustentacular cells are S100 positive. Positivity for cytokeratin, carcinoembryonic antigen and epithelial membrane antigen are all findings that are incompatible with a diagnosis of paraganglioma. The possibility of a metastatic typical carcinoid tumour should be excluded by extensive clinical investigation. In the present case, a detailed metastatic workup, including computed tomography of the patient’s head and neck, chest and abdomen, and PET scan was not performed because of the patient’s poor economic condition, but the chest X-ray and abdominal ultrasonograph revealed no abnormalities. Together with the medical history, physical examination and TTF-1 negativity, the authors think the present case represents a primary tumour rather than a metastatic tumour.

The treatment for typical carcinoid tumour of the oral cavity has not been established, therefore a treatment similar to that of a typical carcinoid tumour of the larynx was used. Complete local excision is the treatment of choice. Neck dissection is not indicated in view of the usual absence of lymph node metastases. Chemotherapy and radiotherapy appear to be ineffectual . The clinical nature and prognosis of carcinoid tumours vary widely depending on the location of the primary tumour . For laryngeal typical carcinoid tumours, the clinical course is not indolent as was thought. About one-third of cases developed metastases and the 5-year survival rate was reported to be 49% . It is possible that the low survival rate may be due to the erroneous inclusion of several cases of atypical carcinoids as typical carcinoids. The prognosis of typical carcinoid tumour of the oral cavity remains unknown. 11 months after surgery, the present patient is tumour free.

The histogenesis of oral neuroendocrine carcinomas remains unclear. In the oral mucosa, the Merkel cells are the most authenticated neuroendocrine cell with diverse subpopulations and elusive biologic roles. The Merkel cells show a preferential distribution along the basal layer of the keratinized epithelium of the hard palate and gingiva where they are present as widely scattered clear cells occurring singly or in clusters . The presence of a novel cluster of neuroendocrine cells with a non-Merkel cell phenotype has been recently described in the squamous epithelium of the human tongue base . These neuroendocrine cells normally found in the oral cavity are thought by some authors to be the cells of origin of neuroendocrine carcinomas . Another hypothesis is that neuroendocrine carcinomas derive from pluripotential indifferent cells of either the squamous epithelium or the minor salivary gland . The present case showed an abrupt transition from neuroendocrine differentiation to well differentiated squamous areas, favouring this hypothesis.

In conclusion, a rare case of typical carcinoid tumour of the retromolar region is presented. Although intraoral occurrences are rare, the surgeon and pathologist should be aware of this possibility. The correct diagnosis is ascertained by combining morphologic and immunohistochemical evaluations. A thorough clinical evaluation of the patient is necessary to exclude a metastatic tumour. Conservative surgical resection without elective neck dissection is the recommended treatment for typical carcinoid tumour of the oral cavity.

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Feb 5, 2018 | Posted by in Oral and Maxillofacial Surgery | Comments Off on Primary typical carcinoid tumour in the retromolar region with prominent squamous differentiation: a case report

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