SURGICAL ONCOLOGY AND RECONSTRUCTION
Primary Neuroendocrine Carcinoma in Oral Cavity: Two Case Reports and Review of the Literature Bin-Zhang Wu, DDS,* Yan Gao, DDS, PhD,y and Biao Yi, DDS, PhDz Neuroendocrine carcinoma (NEC) is a tumor that occurs in different locations, particularly the lungs and larynx. The oral cavity is a rare site for a primary NEC. This report describes 2 cases of primary NEC in the oral cavity. Case 1 occurred in the anterior mandibular gingiva in a 25-year-old woman and presented with a special histologic appearance. This patient showed no evidence of recurrence 13 months after marginal resection of the anterior mandible. Case 2 was a primary NEC with some foci of squamous cell differentiation arising in the right buccal region in a 38-year-old woman. This patient showed no evidence of disease 8 months after tumor resection and postoperative iodine-125 brachytherapy. To the best of the authors’ knowledge, case 1 is the youngest patient with NEC reported in the oral cavity to date in the Englishlanguage literature, and case 2 is the first report of a primary NEC in the buccal region. Ó 2014 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 72:633-644, 2014 Neuroectodermal neoplasms are divided into 2 groups. Group I consists of neoplasms with primarily epithelial differentiation, such as neuroendocrine carcinomas (NECs), and Group II consists of nonepithelial neoplasms, such as malignant melanoma, neurofibroma, paraganglioma, olfactory neuroblastoma, and Ewing sarcoma or peripheral neuroectodermal tumor.1 NECs constitute a heterogeneous family that has different locations, clinical manifestations, histologic appearances, origins, degrees of differentiation, biologic behaviors, and prognoses. They may have certain histochemical, immunohistochemical, and ultrastructural characteristics. Yao et al2 reported on 35,618 patients with neuroendocrine tumors (NETs). They found that the data on the reported annual ageadjusted incidence of NETs markedly increased from 1973 (1.09 in 100,000) to 2004 (5.25 in 100,000) according to the Surveillance, Epidemiology, and End Results program. Most NECs in the head and neck region originate in the larynx. The second most common location is the salivary glands. The oral cavity is a rare site for a primary NEC.1
This report describes 2 rare cases of primary NEC in the oral cavity. These cases occurred in the gingiva and buccal region, respectively. To the best of the authors’ knowledge, only 2 previous articles have described NEC in the gingiva. The occurrence of NEC in the buccal region has not been reported previously, making this case the first in the English-language literature. Further, the published literature on NEC in the oral cavity is reviewed. The classification, clinical manifestation, diagnosis, differential diagnosis, treatment, prognosis, and histogenesis are discussed.
Report of Cases CASE 1
A 25-year-old Chinese woman was admitted to the department of oral and maxillofacial surgery in April 2012 with a slow-growing painless mass in the labioalveolar mucosa and gingiva of the anterior mandible. She had noticed the mass in December 2010. Intraoral examination showed a relatively well-defined, elliptic, elastic, and fixed mass of approximately 1.5 2 cm that engaged the mucosa from the left mandibular lateral
Received from the Peking University School and Hospital of
District, Beijing 100081, People’s Republic of China; e-mail:
Stomatology, Beijing, China.
[email protected]
*Resident, Department of Oral and Maxillofacial Surgery.
Received July 8 2013
yProfessor, Department of Oral Pathology. zProfessor, Department of Oral and Maxillofacial Surgery.
Ó 2014 American Association of Oral and Maxillofacial Surgeons
Address correspondence and reprint requests to Dr Yi: Depart-
0278-2391/13/01108-7$36.00/0
Accepted August 16 2013
ment of Oral and Maxillofacial Surgery, School and Hospital of Stoma-
http://dx.doi.org/10.1016/j.joms.2013.08.020
tology, Peking University, 22 Zhongguancun Nandajie, Haidian
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634 incisor to the right mandibular lateral incisor. The surface characteristic was normal, smooth, and nonulcerated. Cone-beam computed tomographic (CT) images showed the resorption of mandibular alveolar bone from the left mandibular central incisor to the right mandibular lateral incisor (Fig 1). An incisional biopsy from the mass was performed. The gross specimen was a solid mass with a rugged surface. Microscopically, the tumor infiltrated under the oral epithelium and consisted of round cells that grew in small nests and trabeculae (Fig 2A, B). Immunohistochemical staining showed that the tumor cells were positive for S100, neuron-specific enolase, and synaptophysin (Fig 2C-E) but negative for chromogranin A, neurofilament, thyroid transcription factor-1, vimentin, leucocyte common antigen, CD68, cytokeratin (CK; AE1/AE3), CK-7, CK-20, and HMB-45. Positron emission tomography showed an area of high uptake only in the central mandible and nearby soft tissues. From these findings, a diagnosis of primary NEC of the gingiva was made. Interestingly, the histologic appearance differed from that of a carcinoid, yet there were no mitoses, necrosis, and pleomorphism, leading to a difficult classification. The patient underwent marginal resection of the anterior mandible under general anesthesia. Postoperative radiotherapy or chemotherapy was not administered. The patient is being followed and has shown no evidence of disease 13 months postoperatively. CASE 2
A 38-year-old Chinese woman presented with a 1month history of a painful swelling in the right cheek. She was originally treated for an infection and received
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an anti-inflammatory drug. Later, the swelling increased rapidly and she was admitted to the department of oral and maxillofacial surgery in September 2012. The initial clinical examination showed a reddish and nonulcerated right buccal mucosa with a well-defined, elastic, and mobile submucosal mass of approximately 2.0 3.0 cm. CT images depicted a solid mass anterior to the right masseter muscle (Fig 3). CT image of the patient’s chest and abdomen and a bone scan showed no abnormalities. Resection of the right buccal tumor was performed under general anesthesia. The gross specimen was a round mass without a true capsule and contained a small amount of turbid fluid. Histopathologic examination showed that the tumor was composed mainly of round cells that grew in sheets, with extensive necrosis (Fig 4A-D). The tumor cells immunohistochemically expressed CK (AE1/AE3), epithelial membrane antigen, and synaptophysin (Fig 4E-G). They were negative for CK-20, chromogranin A, vimentin, S100, calponin, neuron-specific enolase, HMB-45, leucocyte common antigen, neurofilament, and smooth muscle actin. Based on the morphologic and immunohistochemical features, the final diagnosis was primary NEC with squamous cell differentiation. She underwent postoperative treatment with iodine-125 brachytherapy, which was delivered up to 110 Gy. The patient has shown no evidence of disease up to 8 months postoperatively.
Discussion NECs constitute a heterogenous group of neoplasms that have a wide range of histomorphology, tissue
FIGURE 1. Cone-beam computed tomogram shows resorption of mandibular alveolar bone from the left mandibular central incisor to the right mandibular lateral incisor. Wu, Gao, and Yi. Primary Oral Neuroendocrine Carcinoma. J Oral Maxillofac Surg 2014.
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FIGURE 2. A, Histologic examination shows that the infiltrated tumor under the oral epithelium grew in small nests and trabeculae (hematoxylin and eosin stain; magnification, 40). B, Microscopic examination shows long cellular cords of a single row of tumor cells that had vesicular chromatin and conspicuous centrally located nucleoli, without mitoses, necrosis, and pleomorphism (hematoxylin and eosin stain; magnification, 200). Immunohistochemical studies show positivity for C, S100, D, neuron-specific enolase, and E, synaptophysin (magnification, 200). Wu, Gao, and Yi. Primary Oral Neuroendocrine Carcinoma. J Oral Maxillofac Surg 2014.
origin, and clinical behavior.3 There are several classifications of NEC. As presented in Table 1,1,4-7 the World Health Organization has classified lung NECs as carcinoid, atypical carcinoid, large cell carcinoma, and small cell carcinoma. According to the World
Health Organization classification of head and neck tumors in 2005, NECs can be categorized as typical carcinoid, atypical carcinoid, and small cell carcinoma. However, Kao et al8 studied 23 cases of primary head and neck NETs and concluded that large
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FIGURE 3. Computed tomogram depicts a solid mass in front of the right masseter muscle (arrow). Wu, Gao, and Yi. Primary Oral Neuroendocrine Carcinoma. J Oral Maxillofac Surg 2014.
cell NEC (LCNEC) in the head and neck should be separated from atypical carcinoid according to clinical features, overall survival, and pathogenesis. A more recent classification has categorized NECs into 3 groups: well-differentiated NEC (WDNEC; typical carcinoid), moderately differentiated NEC (MDNEC; atypical carcinoid), and poorly differentiated NEC (PDNEC; small cell and large cell subtypes).6 Lewis et al6 recently proposed that the classification of NEC should contain combined small cell NEC (SCNEC), which is SCNEC associated with a squamous or adenocarcinomatous component. Abiko et al9 found that the reported cases occurring in the oral cavity had been named Merkel cell carcinoma and the others had been named neuroendocrine carcinoma. CK-20 positivity is a specific marker for a diagnosis of Merkel cell carcinoma.10 Merkel cells can exist in the oral cavity and are positive for CK-20 and S100 protein.11 Lewis et al12 found that oral cavity NECs can have a Merkel cell phenotype with positivity for CK-20 and a small cell or highgrade NEC phenotype with negativity for CK-20. Owing to their rarity, NECs of the oral cavity were not incorporated in the independent classification. WDNEC is rare and the least common of the NECs of the larynx and generally has no connection to smoking. A paraneoplastic syndrome rarely occurs.13,14 The clinical features of WDNEC vary by origin and
site. In general, WDNEC is a slow-growing and usually innocuous tumor that leads to a diagnostic challenge.15 Primary WDNECs of the oral cavity are extremely rare, with only 2 cases reported in the English-language literature.16,17 These cases were found in the retromolar region and mandible. MDNEC is the most frequent nonsquamous carcinoma of the larynx and the most frequent NEC of the larynx, being 5 to 15 times more common than the WDNEC.13,18 Most patients have a history of heavy tobacco smoking and a paraneoplastic syndrome is rare.1,14,19 Three cases of primary MDNEC in the oral cavity have been reported in the literature.9,20,21 These cases occurred in the gingiva, uvula, and floor of the mouth. There is a predilection for men in their sixth and seventh decades. An aggressive clinical course is observed. Of 127 cases, metastasis to the neck nodes, skin or subcutaneous sites, and distant sites occurred in 43%, 22%, and 44%, respectively.18 PDNEC is composed of large cell and small cell types. The lung is the most frequent location for LCNEC, although cases have been reported in many other sites.22 However, LCNEC of the oral cavity remains a rare entity. Two cases of primary LCNEC in the oral cavity have been reported in the Englishlanguage literature.23,24 These cases appeared in the tongue and retromolar trigone. LCNEC of the parotid is often a rapidly growing, indolent mass with
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FIGURE 4. A, Histopathologic examination shows that the tumor grew in sheets, with extensive necrosis (hematoxylin and eosin stain; magnification, 40). B, Tumor cells are rather uniform, with a high nucleus-to-cytoplasm ratio and unclear cell borders (hematoxylin and eosin stain; magnification, 200). (Fig 4 continued on next page.) Wu, Gao, and Yi. Primary Oral Neuroendocrine Carcinoma. J Oral Maxillofac Surg 2014.
occasional evidence of facial nerve paralysis. Salivary gland LCNEC occurs only in the parotid gland according to all reported cases in the Englishlanguage literature.22 The typical patient with mucosal LCNEC is usually a heavy smoker with a painless mass. Cervical nodal metastases are very frequent and paraneoplastic syndromes are not observed.22 Two cases of primary SCNEC in the oral cavity have been reported in the literature.25,26 These cases were seen in the tongue and retromolar trigone. SCNEC has been reported in all salivary glands. Salivary SCNEC
has a strong predilection for men older than 50 years, but patients younger than 30 years have been reported to be affected.1 Primary laryngeal SCNEC is a rare malignancy and constitutes fewer less than 0.5% of laryngeal carcinomas. This tumor usually occurs in men with a heavy smoking background in their sixth and seventh decades. Associated paraneoplastic syndromes may be observed, such as ectopic adrenocorticotropic hormone syndrome, Schwartz-Bartter syndrome or syndrome of inappropriate secretion of antidiuretic hormone, and Eaton-Lambert myasthenic
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FIGURE 4 (cont’d). C, Nucleoli are inconspicuous and mitoses are easily seen (hematoxylin and eosin stain; magnification, 400). D, In the sheets of tumor cells, there are some foci of squamous cell differentiation (arrows) (hematoxylin and eosin stain; magnification, 200). (Fig 4 continued on next page.) Wu, Gao, and Yi. Primary Oral Neuroendocrine Carcinoma. J Oral Maxillofac Surg 2014.
syndrome. Ectopic hormone production also has been seen in some patients.27 As presented in Table 2,9,16,17,20,21,23-26,28 the 10 cases reported in the oral cavity occurred in 4 women and 6 men, with a mean age of 58 years (range, 34 to 79 yr). These cases occurred in Asian and black patients. The growth period varied from 1 month to 5 years. The size of tumors varied. Four patients had a painful mass, and nodal metastasis was observed preoperatively in half the cases. The
patients in cases 1 and 2 were 25 and 38 years old, younger than in previously reported cases. In particular, case 1 is the youngest patient with NEC in the oral cavity reported to date. This patient had uteri defectus; whether this had some association with the occurrence of the tumor is unknown. Case 2 is the first reported case of a primary NEC in the buccal region. In addition, these 12 cases had no paraneoplastic syndrome. However, the patient with SCNEC in the tongue showed a decrease in blood
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FIGURE 4 (cont’d). Immunohistochemical studies show positivity for E, cytokeratin (AE1/AE3), F, epithelial membrane antigen. (Fig 4 continued on next page.) Wu, Gao, and Yi. Primary Oral Neuroendocrine Carcinoma. J Oral Maxillofac Surg 2014.
sugar level with reversion of the tumor, so the researchers believed that the tumor might have secreted a hormone or hormone-like substance.25 The diagnosis of NEC depends on histologic, immunohistochemical, and ultrastructural features. Microscopically14, WDNEC is a tumor with an organoid or a trabecular growth pattern and fibrovascular stroma. Pleomorphism, mitoses, and necrosis are absent. MDNEC is characterized by organoid, trabecular, cribriform, or solid growth and fibrovascular stroma. Mild to marked cellular pleomorphism is present; mitotic activity and necrosis are uncommon. PDNEC presents with solid nests, sheets, or ribbons and there is an ab-
sence of fibrovascular stroma. ‘‘Crush’’ artifact is frequently present, and confluent foci of necrosis and abundant mitoses are seen. The pathologic classification of NEC in the oral cavity is usually based on criteria established for NEC in the lungs or larynx. For example, Kusafuka et al23 reported a case of tongue base NEC as LCNEC, according to the NEC classification of the lungs. Similarly, the diagnosis of SCNEC in the tongue and atypical carcinoid (MDNEC) in the gingiva were based on characteristics of NEC in the larynx.9,25 However, case 1 cannot be classified into any subtype of NEC based on the classification of NEC in the lungs or larynx because the histologic
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FIGURE 4 (cont’d). G, synaptophysin (magnification,200). Wu, Gao, and Yi. Primary Oral Neuroendocrine Carcinoma. J Oral Maxillofac Surg 2014.
appearance was unusual. The histologic appearance of case 1 may be a new finding in NEC or a specific characteristic confined to the oral cavity. Some foci of squamous cell differentiation in the sheets of tumor cells in case 2 also need to be studied further. NEC is so rare in the oral cavity that routine light microscopic examination is insufficient to determine the final diagnosis. Immunohistochemistry is re-
quired to determine the origin of the tumor. A series of special markers is required, such as epithelial markers, neuroendocrine markers, and neuroendocrine polypeptides. Neuron-specific enolase, chromogranin, synaptophysin, S100, and CD56 are usually used as neuroendocrine markers.29 NECs often express at least 1 neuroendocrine marker. It is insufficient to confirm neuroendocrine differentiation
Table 1. CLASSIFICATION OF NEUROENDOCRINE CARCINOMA
WHO Larynx4
Mills1
Carcinoid Atypical carcinoid
Typical carcinoid Atypical carcinoid
Low grade Typical carcinoid Intermediate grade Atypical carcinoid
Typical carcinoid Atypical carcinoid
Small cell carcinoma
Small cell carcinoma
Well differentiated Moderately differentiated Poorly differentiated
High grade
Small cell neuroendocrine carcinoma
Poorly differentiated
High grade
Poorly differentiated
High grade
Large cell neuroendocrine carcinoma Combined small cell neuroendocrine carcinoma
Small cell neuroendocrine carcinoma (including Merkel cell type or pulmonary type) Large cell neuroendocrine carcinoma
WHO Lung
Large cell carcinoma
Moran and Suster5
Abbreviation: WHO, World Health Organization. Wu, Gao, and Yi. Primary Oral Neuroendocrine Carcinoma. J Oral Maxillofac Surg 2014.
Lewis et al6
Mahomed7
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Table 2. REPORTED CASES OF PRIMARY NEUROENDOCRINE CARCINOMA ARISING IN ORAL CAVITY
Report
Age (yr)/ Gender Race
Mochizuki et al28
62/F
NR
Gingiva
8 mo
Abiko et al9 Kusafuka et al23 Yoshida et al25 Krishnamurthy et al24 Yang et al16 Goldman and Barnes20
68/M 79/M 76/M 34/F 46/F 57/M
A A NR NR NR NR
Gingiva Tongue Tongue Retromolar trigone Retromolar region Uvula
NR NR 7 mo NR 5 yr 1 mo
Baker and Alguacil-Garcia21 49/M
NR
Floor of the mouth 3 mo
3.7 2.4 1.4 NR
NM
Coleman et al17 Benning et al26
46/F 63/M
B B
Mandible NR Retromolar trigone NR
4.0 3.8 5.0 Y NR Y
NOM NOM
Wu et al*
25/F 38/F
A A
Gingiva Buccal region
Site
GP
Metastasis (preoperative)
Primary/PT
2.0 0.8 0.6 Y
NOM
Y/NR
2.0 2.0 1.0 1.0 1.5 1.4 0.6 2.0 1.5 1.5 2.0 2.0
NM NOM NM NM NOM NM
Size (cm)
16 mo 1.5 2.0 1 mo 2.0 3.0
Pain
Y NR NR NR N N
N Y
NOM NOM
Treatment
Exc, partial maxillectomy Y/AC Exc Y/LCNEC Partial Exc Y/SCNEC RT (72 Gy) Y/LCNEC Exc, RND, RT, C Y/TC Exc Y (NR)/AC Exc, RND, MND, (MDNEC) RT, C Y/MDNEC Exc, RND, marginal mandibulectomy Y/TC Wide Exc Y/SCNEC C, RT (60 Gy) Y/unknown Wide Exc Y/PDNEC Exc, RT (iodine-125 seed 110 Gy)
Prognosis (mo) NED (23) NR NED (18) DUC (2) DM (1), LWD (9) NED (11) LR (4), DM (6), DOD (9) DM (NR), DOD (0.3) NED (24) LR (8), DM (20), DOD (24) NED (13) NED (8)
Abbreviations: A, Asian; AC, atypical carcinoid; B, Black; C, chemotherapy; DM, distant metastasis; DOD, died of disease; DUC, died of unrelated cause; Exc, excision; F, female; GP, growth period; LCNEC, large cell neuroendocrine carcinoma; LR, local recurrence; LWD, live with disease; M, male; MDNEC, moderately differentiated neuroendocrine carcinoma; MND, modified neck dissection; N, no; NED, no evidence of disease; NM, nodal metastasis; NOM, no metastasis; NR, not reported; PDNEC, poorly differentiated neuroendocrine carcinoma; PT, pathologic type; RND, radical neck dissection; RT, radiation therapy; SCNEC, small cell neuroendocrine carcinoma; TC, typical carcinoid; Y, yes. * Present report. Wu, Gao, and Yi. Primary Oral Neuroendocrine Carcinoma. J Oral Maxillofac Surg 2014.
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642 of the tumor when only neuron-specific enolase exhibits positivity.4 At electron microscopy, tumor cells show numerous membrane-bound and electron-dense neurosecretory granules in different sizes and numbers. Complex intercellular digitation, a rough marked endoplasmic reticulum, and abundant mitochondria are variably seen. Once NEC is suspected or diagnosed, a systemic whole-body examination is needed to exclude a primary tumor or a metastatic tumor. Positron emission tomography, CT imaging, and magnetic resonance imaging are recommended to pinpoint the location of the primary tumor, identify tumor extent, and further confirm the diagnosis.30 The differential diagnosis includes poorly differentiated squamous cell carcinoma (PDSCC), basaloid squamous cell carcinoma (BSCC), solid-type adenoid cystic carcinoma (ACC), lymphoma, melanoma, paraganglioma, and Ewing sarcoma. The appearance of PDNEC or MDNEC is similar to that of BSCC and PDSCC, which are negative for neuroendocrine markers. Highmolecular-weight cytokeratins, such as CK-5/6 and 34bE12, can be used to distinguish NEC from BSCC and solid-type ACC. They are usually strongly positive in BSCC and solid-type ACC but negative in NEC.31,32 HMB-45 is useful to exclude a diagnosis of melanoma. Negative staining with leukocyte common antigen can rule out malignant lymphoma. Calcitonin positivity can usually clearly distinguish NEC from paraganglioma. Interestingly, primary NEC in the oral cavity was reviewed and found to have an overlap or a correlation with SCC.16,21,26,28 Mochizuki et al28 reported a case of primary NEC combined with SCC in the upper gingiva. Yang et al16 reported that a patient with primary typical carcinoid in the retromolar region had prominent squamous differentiation. Baker and AlguacilGarcia21 observed the presence of SCC in situ in a patient with MDNEC in the floor of the mouth. In addition, Benning et al26 reported the recurrence of primary SCNEC in the oral cavity with focal squamous differentiation. In the present case 2, there were some foci of squamous cell differentiation in the sheets of tumor cells, favoring this hypothesis. Although the features of NEC have been documented, it is still difficult to diagnose NEC from preoperative biopsy specimens alone. Most cases of NEC have been confirmed from surgical specimens postoperatively. Hence, most reported cases of NEC were diagnosed retrospectively.33 Krishnamurthy et al24 reported that fine-needle aspiration cytology and incisional biopsy could determine a poorly differentiated carcinoma preoperatively, failing to recognize the neuroendocrine feature of malignancy. For WDNEC, surgery is the treatment of choice because radiotherapy and chemotherapy are ineffective. Surgical excision should be complete, but conserva-
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tive. Neck dissection is not warranted.14 As presented in Table 2, 2 cases of WDNEC were treated with only tumor excision. In general, the biological behavior is favorable, but different locations, origins, extents of tumor, and times of diagnosis can contribute to a variable prognosis.15 The prognosis of WDNEC of the oral cavity remains unknown. These 2 patients had a good prognosis without evidence of disease after excision up to 11 and 24 months, respectively. Similarly, for MDNEC, complete surgical excision is the mainstay of treatment. Owing to the high incidence of cervical lymph node metastasis, elective lymph node dissection is recommended in even clinically N0 necks, and radical lymph node dissection is required when the lymph nodes are clinically positive. Radiotherapy and chemotherapy are not considered reliable because MDNEC is resistant to these therapies.14,18,34 As presented in Table 2, a case of MDNEC in the gingiva was treated with excision alone. A case of MDNEC in the uvula was treated with excision, radical neck dissection on the right, modified neck dissection on the left, and radiochemotherapy. A case of MDNEC in the floor of the mouth was managed with excision, radical neck dissection, and marginal mandibulectomy. The overall 5-year survival rate was 48%, and the 10-year survival rate was only 30%. Radiotherapy did not have a significant effect on improving survival rate, so the differential diagnosis from more radiation-sensitive tumors is very important.18 The prognosis of MDNEC of the oral cavity remains obscure. As presented in Table 2, the patient with MDNEC in the uvula died of disease 9 months after surgery. The patient with MDNEC in the floor of the mouth died 10 days after surgery. Multiorgan failure and wide hepatic necrosis were considered the cause of death. The prognosis of the patient with MDNEC of the gingiva was not reported. Radical surgery, postoperative radiotherapy, and chemotherapy are required for PDNEC. However, many patients have disseminated disease at the time of diagnosis, thus excluding the feasibility of radical surgery. Therefore, therapeutic radiotherapy and chemotherapy are advocated.14,34 The treatment for combined carcinoma is similar to that for SCNEC without combined SCC or adenocarcinoma.14 Concurrent chemoradiotherapy may improve long-term survival.27 Kusafuka et al22 advocated primary chemotherapy and radiotherapy, instead of primary surgery with postoperative radiotherapy or systemic therapy, in the head and neck, because the clinical features of PDNEC are similar to those of small cell carcinoma. In particular, Barker et al35 reported that chemotherapy is crucial for PDNEC in the head and neck. Likewise, Benning et al26 found that a patient with SCNEC in the retromolar trigone attained an 8month clinical remission using a standard
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chemotherapeutic regimen for pulmonary small cell carcinoma. As presented in Table 2, LCNEC of the tongue was treated with partial excision alone. LCNEC of the retromolar trigone was treated with excision, radical neck dissection, and radiochemotherapy. Owing to the localized tumor and the patient’s poor general condition, SCNEC of the tongue was managed with radiation therapy alone. SCNEC of the retromolar trigone was treated with radiation therapy and chemotherapy. The prognosis of primary LCNEC in the oral cavity is not entirely known. In general, LCNECs arising in other sites have significantly unfavorable outcomes.22 The prognosis of SCNEC of the oral cavity also remains unclear. Laryngeal SCNEC has a poor prognosis. The most important influential factor of survival rate is tumor extent. About 50% of patients with SCNEC have cervical lymph nodes involved, whereas approximately 60% to 90% have possible distant metastasis to the lungs, liver, and bones.27,34 The prognosis of laryngeal SCNEC is dismal: The reported 2-year survival rate was 16% and the 5-year survival rate was 5%.14 As presented in Table 2, a patient with LCNEC of the tongue had a good prognosis, with 18 months without any evidence of disease. A case of LCNEC of the retromolar trigone showed distant metastasis after surgery, but the patient lived with disease at 9 months of follow-up. A patient with SCNEC of the tongue died from debility 2 months after completing treatment. A patient with SCNEC of the retromolar trigone died of disease 2 years after treatment. The adrenal medulla, pituitary gland, pancreatic islets, etc, are endocrine glands that consist of many agminated neuroendocrine cells. However, in other sites, neuroendocrine cells are distributed throughout the mucosa, constituting a disseminated or diffuse neuroendocrine system.7,17 The histogenesis of oral NECs remains obscure. In the oral cavity, Merkel cells are considered the origin, because they preferentially scatter in the basal layer of the keratinized epithelium in the hard palate and gingiva.7,11 Some researchers have proposed that LCNEC of the tongue base arises from some special cells that have neuroendocrine characteristics and are located in the basal cell layer of the squamous epithelium.23 Thus, LCNEC has been suggested to originate from neuroendocrine cells. However, a coexistence of divergent differentiation has been observed, such as NEC associated with a squamous or adenocarcinomatous component, suggesting that NEC is derived from primitive and pluripotential stem cells rather than neuroendocrine cells.27 This report has described 2 new cases of NEC in the oral cavity. The particular histologic appearance of case 1 provides new information on NEC in the oral cavity. The NEC in case 2 arose in the buccal region, adding to the known sites of NEC in the oral cavity.
Nevertheless, to propose a specific classification, understand the clinical behavior, and establish an optimal treatment of NEC in the oral cavity, more cases need to be reported. Acknowledgments The authors offer many thanks to Dr Xin-Li Zhai, Dr Hai-Yan Luo, Dr Chi Mao, and Dr Jian-Guo Zhang for their contributions to this report.
References 1. Mills SE: Neuroectodermal neoplasms of the head and neck with emphasis on neuroendocrine carcinomas. Mod Pathol 15:264, 2002 2. Yao JC, Hassan M, Phan A, et al: One hundred years after ‘ carcinoid’’: Epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 26:3063, 2008 3. Barakat MT, Meeran K, Bloom SR: Neuroendocrine tumours. Endocr Relat Cancer 11:1, 2004 4. Barnes L, Eveson JW, Reichart P, et al: Pathology and Genetics. Head and Neck Tumours. World Health Organisation Classification of Tumours. Lyon, France, IARC Press, 2005, pp 135–139 5. Moran CA, Suster S: Neuroendocrine carcinomas (carcinoid, atypical carcinoid, small cell carcinoma, and large cell neuroendocrine carcinoma): Current concepts. Hematol Oncol Clin North Am 21:395, 2007 6. Lewis JJ, Ferlito A, Gnepp DR, et al: Terminology and classification of neuroendocrine neoplasms of the larynx. Laryngoscope 121:1187, 2011 7. Mahomed F: Neuroendocrine cells and associated malignancies of the oral mucosa: A review. J Oral Pathol Med 39: 121, 2010 8. Kao HL, Chang WC, Li WY, et al: Head and neck large cell neuroendocrine carcinoma should be separated from atypical carcinoid on the basis of different clinical features, overall survival, and pathogenesis. Am J Surg Pathol 36:185, 2012 9. Abiko Y, Ogawa I, Hattori Y, et al: Atypical carcinoid (neuroendocrine carcinoma) of the gingiva: Counterpart of a laryngeal tumor. Pathol Int 54:97, 2004 10. Scott MP, Helm KF: Cytokeratin 20: A marker for diagnosing Merkel cell carcinoma. Am J Dermatopathol 21:16, 1999 11. Barrett AW, Cort EM, Patel P, et al: An immunohistological study of cytokeratin 20 in human and mammalian oral epithelium. Arch Oral Biol 45:879, 2000 12. Lewis JJ, Duncavage E, Klonowski PW: Oral cavity neuroendocrine carcinoma: A comparison study with cutaneous Merkel cell carcinoma and other mucosal head and neck neuroendocrine carcinomas. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 110:209, 2010 13. Soga J, Ferlito A, Rinaldo A: Endocrinocarcinomas (carcinoids and their variants) of the larynx: A comparative consideration with those of other sites. Oral Oncol 40:668, 2004 14. Wenig BM: Atlas of Head and Neck Pathology (ed 2). Edinburgh, UK, Saunders Elsevier, 2008, pp 503–505 15. Pinchot SN, Holen K, Sippel RS, et al: Carcinoid tumors. Oncologist 13:1255, 2008 16. Yang S, Chen S, Chen X, et al: Primary typical carcinoid tumour in the retromolar region with prominent squamous differentiation: A case report. Int J Oral Maxillofac Surg 40:991, 2011 17. Coleman H, Kennedy M, Altini M, et al: Neuroendocrine (carcinoid) tumor of the mandible: A case report and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 81:74, 1996 18. Woodruff JM, Senie RT: Atypical carcinoid tumor of the larynx. A critical review of the literature. ORL J Otorhinolaryngol Relat Spec 53:194, 1991
644 19. Ferlito A, Barnes L, Rinaldo A, et al: A review of neuroendocrine neoplasms of the larynx: Update on diagnosis and treatment. J Laryngol Otol 112:827, 1998 20. Goldman NC, Barnes RJ: Atypical carcinoid (moderately differentiated neuroendocrine carcinoma) of the uvula. Ear Nose Throat J 91:75, 2012 21. Baker P, Alguacil-Garcia A: Moderately differentiated neuroendocrine carcinoma in the floor of the mouth: A case report. J Oral Maxillofac Surg 57:1143, 1999 22. Kusafuka K, Ferlito A, Lewis JJ, et al: Large cell neuroendocrine carcinoma of the head and neck. Oral Oncol 48:211, 2012 23. Kusafuka K, Asano R, Kamijo T, et al: Large cell neuroendocrine carcinoma of the tongue base: Case report of an unusual location with immunohistochemical analysis. Int J Oral Maxillofac Surg 38:296, 2009 24. Krishnamurthy A, Vaidhyanathan A, Majhi U: Large cell neuroendocrine carcinoma of the retromolar trigone. J Cancer Res Ther 7:343, 2011 25. Yoshida H, Onizawa K, Hirohata H: Neuroendocrine carcinoma of the tongue: Report of a case. J Oral Maxillofac Surg 53:823, 1995 26. Benning TL, Vollmer RT, Crain BJ, et al: Neuroendocrine carcinoma of the oral cavity. Mod Pathol 3:631, 1990 27. Ferlito A, Rinaldo A: Primary and secondary small cell neuroendocrine carcinoma of the larynx: A review. Head Neck 30:518, 2008
PRIMARY ORAL NEUROENDOCRINE CARCINOMA 28. Mochizuki Y, Omura K, Sakamoto K, et al: A case of primary combined neuroendocrine carcinoma with squamous cell carcinoma in the upper gingiva. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 109:e34, 2010 29. Salama AR, Jham BC, Papadimitriou JC, et al: Metastatic neuroendocrine carcinomas to the head and neck: Report of 4 cases and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 108:242, 2009 € 30. Oberg KE: The management of neuroendocrine tumours: Current and future medical therapy options. Clin Oncol 24:282, 2012 31. Morice WG, Ferreiro JA: Distinction of basaloid squamous cell carcinoma from adenoid cystic and small cell undifferentiated carcinoma by immunohistochemistry. Hum Pathol 29:609, 1998 32. Serrano MF, El-Mofty SK, Gnepp DR, et al: Utility of high molecular weight cytokeratins, but not p63, in the differential diagnosis of neuroendocrine and basaloid carcinomas of the head and neck. Hum Pathol 39:591, 2008 33. Iyoda A, Hiroshima K, Nakatani Y, et al: Pulmonary large cell neuroendocrine carcinoma: Its place in the spectrum of pulmonary carcinoma. Ann Thorac Surg 84:702, 2007 34. Barnes L: Surgical Pathology of the Head and Neck (ed 3). Vol I. New York, Informa Healthcare, 2009, pp 162–167 35. Barker JJ, Glisson BS, Garden AS, et al: Management of nonsinonasal neuroendocrine carcinomas of the head and neck. Cancer 98:2322, 2003
Primary Neuroendocrine Carcinoma in Oral Cavity: Two Case Reports and Review of the Literature Bin-Zhang Wu, DDS,* Yan Gao, DDS, PhD,y and Biao Yi, DDS, PhDz Neuroendocrine carcinoma (NEC) is a tumor that occurs in different locations, particularly the lungs and larynx. The oral cavity is a rare site for a primary NEC. This report describes 2 cases of primary NEC in the oral cavity. Case 1 occurred in the anterior mandibular gingiva in a 25-year-old woman and presented with a special histologic appearance. This patient showed no evidence of recurrence 13 months after marginal resection of the anterior mandible. Case 2 was a primary NEC with some foci of squamous cell differentiation arising in the right buccal region in a 38-year-old woman. This patient showed no evidence of disease 8 months after tumor resection and postoperative iodine-125 brachytherapy. To the best of the authors’ knowledge, case 1 is the youngest patient with NEC reported in the oral cavity to date in the Englishlanguage literature, and case 2 is the first report of a primary NEC in the buccal region. Ó 2014 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 72:633-644, 2014 Neuroectodermal neoplasms are divided into 2 groups. Group I consists of neoplasms with primarily epithelial differentiation, such as neuroendocrine carcinomas (NECs), and Group II consists of nonepithelial neoplasms, such as malignant melanoma, neurofibroma, paraganglioma, olfactory neuroblastoma, and Ewing sarcoma or peripheral neuroectodermal tumor.1 NECs constitute a heterogeneous family that has different locations, clinical manifestations, histologic appearances, origins, degrees of differentiation, biologic behaviors, and prognoses. They may have certain histochemical, immunohistochemical, and ultrastructural characteristics. Yao et al2 reported on 35,618 patients with neuroendocrine tumors (NETs). They found that the data on the reported annual ageadjusted incidence of NETs markedly increased from 1973 (1.09 in 100,000) to 2004 (5.25 in 100,000) according to the Surveillance, Epidemiology, and End Results program. Most NECs in the head and neck region originate in the larynx. The second most common location is the salivary glands. The oral cavity is a rare site for a primary NEC.1
This report describes 2 rare cases of primary NEC in the oral cavity. These cases occurred in the gingiva and buccal region, respectively. To the best of the authors’ knowledge, only 2 previous articles have described NEC in the gingiva. The occurrence of NEC in the buccal region has not been reported previously, making this case the first in the English-language literature. Further, the published literature on NEC in the oral cavity is reviewed. The classification, clinical manifestation, diagnosis, differential diagnosis, treatment, prognosis, and histogenesis are discussed.
Report of Cases CASE 1
A 25-year-old Chinese woman was admitted to the department of oral and maxillofacial surgery in April 2012 with a slow-growing painless mass in the labioalveolar mucosa and gingiva of the anterior mandible. She had noticed the mass in December 2010. Intraoral examination showed a relatively well-defined, elliptic, elastic, and fixed mass of approximately 1.5 2 cm that engaged the mucosa from the left mandibular lateral
Received from the Peking University School and Hospital of
District, Beijing 100081, People’s Republic of China; e-mail:
Stomatology, Beijing, China.
[email protected]
*Resident, Department of Oral and Maxillofacial Surgery.
Received July 8 2013
yProfessor, Department of Oral Pathology. zProfessor, Department of Oral and Maxillofacial Surgery.
Ó 2014 American Association of Oral and Maxillofacial Surgeons
Address correspondence and reprint requests to Dr Yi: Depart-
0278-2391/13/01108-7$36.00/0
Accepted August 16 2013
ment of Oral and Maxillofacial Surgery, School and Hospital of Stoma-
http://dx.doi.org/10.1016/j.joms.2013.08.020
tology, Peking University, 22 Zhongguancun Nandajie, Haidian
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634 incisor to the right mandibular lateral incisor. The surface characteristic was normal, smooth, and nonulcerated. Cone-beam computed tomographic (CT) images showed the resorption of mandibular alveolar bone from the left mandibular central incisor to the right mandibular lateral incisor (Fig 1). An incisional biopsy from the mass was performed. The gross specimen was a solid mass with a rugged surface. Microscopically, the tumor infiltrated under the oral epithelium and consisted of round cells that grew in small nests and trabeculae (Fig 2A, B). Immunohistochemical staining showed that the tumor cells were positive for S100, neuron-specific enolase, and synaptophysin (Fig 2C-E) but negative for chromogranin A, neurofilament, thyroid transcription factor-1, vimentin, leucocyte common antigen, CD68, cytokeratin (CK; AE1/AE3), CK-7, CK-20, and HMB-45. Positron emission tomography showed an area of high uptake only in the central mandible and nearby soft tissues. From these findings, a diagnosis of primary NEC of the gingiva was made. Interestingly, the histologic appearance differed from that of a carcinoid, yet there were no mitoses, necrosis, and pleomorphism, leading to a difficult classification. The patient underwent marginal resection of the anterior mandible under general anesthesia. Postoperative radiotherapy or chemotherapy was not administered. The patient is being followed and has shown no evidence of disease 13 months postoperatively. CASE 2
A 38-year-old Chinese woman presented with a 1month history of a painful swelling in the right cheek. She was originally treated for an infection and received
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an anti-inflammatory drug. Later, the swelling increased rapidly and she was admitted to the department of oral and maxillofacial surgery in September 2012. The initial clinical examination showed a reddish and nonulcerated right buccal mucosa with a well-defined, elastic, and mobile submucosal mass of approximately 2.0 3.0 cm. CT images depicted a solid mass anterior to the right masseter muscle (Fig 3). CT image of the patient’s chest and abdomen and a bone scan showed no abnormalities. Resection of the right buccal tumor was performed under general anesthesia. The gross specimen was a round mass without a true capsule and contained a small amount of turbid fluid. Histopathologic examination showed that the tumor was composed mainly of round cells that grew in sheets, with extensive necrosis (Fig 4A-D). The tumor cells immunohistochemically expressed CK (AE1/AE3), epithelial membrane antigen, and synaptophysin (Fig 4E-G). They were negative for CK-20, chromogranin A, vimentin, S100, calponin, neuron-specific enolase, HMB-45, leucocyte common antigen, neurofilament, and smooth muscle actin. Based on the morphologic and immunohistochemical features, the final diagnosis was primary NEC with squamous cell differentiation. She underwent postoperative treatment with iodine-125 brachytherapy, which was delivered up to 110 Gy. The patient has shown no evidence of disease up to 8 months postoperatively.
Discussion NECs constitute a heterogenous group of neoplasms that have a wide range of histomorphology, tissue
FIGURE 1. Cone-beam computed tomogram shows resorption of mandibular alveolar bone from the left mandibular central incisor to the right mandibular lateral incisor. Wu, Gao, and Yi. Primary Oral Neuroendocrine Carcinoma. J Oral Maxillofac Surg 2014.
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FIGURE 2. A, Histologic examination shows that the infiltrated tumor under the oral epithelium grew in small nests and trabeculae (hematoxylin and eosin stain; magnification, 40). B, Microscopic examination shows long cellular cords of a single row of tumor cells that had vesicular chromatin and conspicuous centrally located nucleoli, without mitoses, necrosis, and pleomorphism (hematoxylin and eosin stain; magnification, 200). Immunohistochemical studies show positivity for C, S100, D, neuron-specific enolase, and E, synaptophysin (magnification, 200). Wu, Gao, and Yi. Primary Oral Neuroendocrine Carcinoma. J Oral Maxillofac Surg 2014.
origin, and clinical behavior.3 There are several classifications of NEC. As presented in Table 1,1,4-7 the World Health Organization has classified lung NECs as carcinoid, atypical carcinoid, large cell carcinoma, and small cell carcinoma. According to the World
Health Organization classification of head and neck tumors in 2005, NECs can be categorized as typical carcinoid, atypical carcinoid, and small cell carcinoma. However, Kao et al8 studied 23 cases of primary head and neck NETs and concluded that large
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FIGURE 3. Computed tomogram depicts a solid mass in front of the right masseter muscle (arrow). Wu, Gao, and Yi. Primary Oral Neuroendocrine Carcinoma. J Oral Maxillofac Surg 2014.
cell NEC (LCNEC) in the head and neck should be separated from atypical carcinoid according to clinical features, overall survival, and pathogenesis. A more recent classification has categorized NECs into 3 groups: well-differentiated NEC (WDNEC; typical carcinoid), moderately differentiated NEC (MDNEC; atypical carcinoid), and poorly differentiated NEC (PDNEC; small cell and large cell subtypes).6 Lewis et al6 recently proposed that the classification of NEC should contain combined small cell NEC (SCNEC), which is SCNEC associated with a squamous or adenocarcinomatous component. Abiko et al9 found that the reported cases occurring in the oral cavity had been named Merkel cell carcinoma and the others had been named neuroendocrine carcinoma. CK-20 positivity is a specific marker for a diagnosis of Merkel cell carcinoma.10 Merkel cells can exist in the oral cavity and are positive for CK-20 and S100 protein.11 Lewis et al12 found that oral cavity NECs can have a Merkel cell phenotype with positivity for CK-20 and a small cell or highgrade NEC phenotype with negativity for CK-20. Owing to their rarity, NECs of the oral cavity were not incorporated in the independent classification. WDNEC is rare and the least common of the NECs of the larynx and generally has no connection to smoking. A paraneoplastic syndrome rarely occurs.13,14 The clinical features of WDNEC vary by origin and
site. In general, WDNEC is a slow-growing and usually innocuous tumor that leads to a diagnostic challenge.15 Primary WDNECs of the oral cavity are extremely rare, with only 2 cases reported in the English-language literature.16,17 These cases were found in the retromolar region and mandible. MDNEC is the most frequent nonsquamous carcinoma of the larynx and the most frequent NEC of the larynx, being 5 to 15 times more common than the WDNEC.13,18 Most patients have a history of heavy tobacco smoking and a paraneoplastic syndrome is rare.1,14,19 Three cases of primary MDNEC in the oral cavity have been reported in the literature.9,20,21 These cases occurred in the gingiva, uvula, and floor of the mouth. There is a predilection for men in their sixth and seventh decades. An aggressive clinical course is observed. Of 127 cases, metastasis to the neck nodes, skin or subcutaneous sites, and distant sites occurred in 43%, 22%, and 44%, respectively.18 PDNEC is composed of large cell and small cell types. The lung is the most frequent location for LCNEC, although cases have been reported in many other sites.22 However, LCNEC of the oral cavity remains a rare entity. Two cases of primary LCNEC in the oral cavity have been reported in the Englishlanguage literature.23,24 These cases appeared in the tongue and retromolar trigone. LCNEC of the parotid is often a rapidly growing, indolent mass with
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FIGURE 4. A, Histopathologic examination shows that the tumor grew in sheets, with extensive necrosis (hematoxylin and eosin stain; magnification, 40). B, Tumor cells are rather uniform, with a high nucleus-to-cytoplasm ratio and unclear cell borders (hematoxylin and eosin stain; magnification, 200). (Fig 4 continued on next page.) Wu, Gao, and Yi. Primary Oral Neuroendocrine Carcinoma. J Oral Maxillofac Surg 2014.
occasional evidence of facial nerve paralysis. Salivary gland LCNEC occurs only in the parotid gland according to all reported cases in the Englishlanguage literature.22 The typical patient with mucosal LCNEC is usually a heavy smoker with a painless mass. Cervical nodal metastases are very frequent and paraneoplastic syndromes are not observed.22 Two cases of primary SCNEC in the oral cavity have been reported in the literature.25,26 These cases were seen in the tongue and retromolar trigone. SCNEC has been reported in all salivary glands. Salivary SCNEC
has a strong predilection for men older than 50 years, but patients younger than 30 years have been reported to be affected.1 Primary laryngeal SCNEC is a rare malignancy and constitutes fewer less than 0.5% of laryngeal carcinomas. This tumor usually occurs in men with a heavy smoking background in their sixth and seventh decades. Associated paraneoplastic syndromes may be observed, such as ectopic adrenocorticotropic hormone syndrome, Schwartz-Bartter syndrome or syndrome of inappropriate secretion of antidiuretic hormone, and Eaton-Lambert myasthenic
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FIGURE 4 (cont’d). C, Nucleoli are inconspicuous and mitoses are easily seen (hematoxylin and eosin stain; magnification, 400). D, In the sheets of tumor cells, there are some foci of squamous cell differentiation (arrows) (hematoxylin and eosin stain; magnification, 200). (Fig 4 continued on next page.) Wu, Gao, and Yi. Primary Oral Neuroendocrine Carcinoma. J Oral Maxillofac Surg 2014.
syndrome. Ectopic hormone production also has been seen in some patients.27 As presented in Table 2,9,16,17,20,21,23-26,28 the 10 cases reported in the oral cavity occurred in 4 women and 6 men, with a mean age of 58 years (range, 34 to 79 yr). These cases occurred in Asian and black patients. The growth period varied from 1 month to 5 years. The size of tumors varied. Four patients had a painful mass, and nodal metastasis was observed preoperatively in half the cases. The
patients in cases 1 and 2 were 25 and 38 years old, younger than in previously reported cases. In particular, case 1 is the youngest patient with NEC in the oral cavity reported to date. This patient had uteri defectus; whether this had some association with the occurrence of the tumor is unknown. Case 2 is the first reported case of a primary NEC in the buccal region. In addition, these 12 cases had no paraneoplastic syndrome. However, the patient with SCNEC in the tongue showed a decrease in blood
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FIGURE 4 (cont’d). Immunohistochemical studies show positivity for E, cytokeratin (AE1/AE3), F, epithelial membrane antigen. (Fig 4 continued on next page.) Wu, Gao, and Yi. Primary Oral Neuroendocrine Carcinoma. J Oral Maxillofac Surg 2014.
sugar level with reversion of the tumor, so the researchers believed that the tumor might have secreted a hormone or hormone-like substance.25 The diagnosis of NEC depends on histologic, immunohistochemical, and ultrastructural features. Microscopically14, WDNEC is a tumor with an organoid or a trabecular growth pattern and fibrovascular stroma. Pleomorphism, mitoses, and necrosis are absent. MDNEC is characterized by organoid, trabecular, cribriform, or solid growth and fibrovascular stroma. Mild to marked cellular pleomorphism is present; mitotic activity and necrosis are uncommon. PDNEC presents with solid nests, sheets, or ribbons and there is an ab-
sence of fibrovascular stroma. ‘‘Crush’’ artifact is frequently present, and confluent foci of necrosis and abundant mitoses are seen. The pathologic classification of NEC in the oral cavity is usually based on criteria established for NEC in the lungs or larynx. For example, Kusafuka et al23 reported a case of tongue base NEC as LCNEC, according to the NEC classification of the lungs. Similarly, the diagnosis of SCNEC in the tongue and atypical carcinoid (MDNEC) in the gingiva were based on characteristics of NEC in the larynx.9,25 However, case 1 cannot be classified into any subtype of NEC based on the classification of NEC in the lungs or larynx because the histologic
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FIGURE 4 (cont’d). G, synaptophysin (magnification,200). Wu, Gao, and Yi. Primary Oral Neuroendocrine Carcinoma. J Oral Maxillofac Surg 2014.
appearance was unusual. The histologic appearance of case 1 may be a new finding in NEC or a specific characteristic confined to the oral cavity. Some foci of squamous cell differentiation in the sheets of tumor cells in case 2 also need to be studied further. NEC is so rare in the oral cavity that routine light microscopic examination is insufficient to determine the final diagnosis. Immunohistochemistry is re-
quired to determine the origin of the tumor. A series of special markers is required, such as epithelial markers, neuroendocrine markers, and neuroendocrine polypeptides. Neuron-specific enolase, chromogranin, synaptophysin, S100, and CD56 are usually used as neuroendocrine markers.29 NECs often express at least 1 neuroendocrine marker. It is insufficient to confirm neuroendocrine differentiation
Table 1. CLASSIFICATION OF NEUROENDOCRINE CARCINOMA
WHO Larynx4
Mills1
Carcinoid Atypical carcinoid
Typical carcinoid Atypical carcinoid
Low grade Typical carcinoid Intermediate grade Atypical carcinoid
Typical carcinoid Atypical carcinoid
Small cell carcinoma
Small cell carcinoma
Well differentiated Moderately differentiated Poorly differentiated
High grade
Small cell neuroendocrine carcinoma
Poorly differentiated
High grade
Poorly differentiated
High grade
Large cell neuroendocrine carcinoma Combined small cell neuroendocrine carcinoma
Small cell neuroendocrine carcinoma (including Merkel cell type or pulmonary type) Large cell neuroendocrine carcinoma
WHO Lung
Large cell carcinoma
Moran and Suster5
Abbreviation: WHO, World Health Organization. Wu, Gao, and Yi. Primary Oral Neuroendocrine Carcinoma. J Oral Maxillofac Surg 2014.
Lewis et al6
Mahomed7
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Table 2. REPORTED CASES OF PRIMARY NEUROENDOCRINE CARCINOMA ARISING IN ORAL CAVITY
Report
Age (yr)/ Gender Race
Mochizuki et al28
62/F
NR
Gingiva
8 mo
Abiko et al9 Kusafuka et al23 Yoshida et al25 Krishnamurthy et al24 Yang et al16 Goldman and Barnes20
68/M 79/M 76/M 34/F 46/F 57/M
A A NR NR NR NR
Gingiva Tongue Tongue Retromolar trigone Retromolar region Uvula
NR NR 7 mo NR 5 yr 1 mo
Baker and Alguacil-Garcia21 49/M
NR
Floor of the mouth 3 mo
3.7 2.4 1.4 NR
NM
Coleman et al17 Benning et al26
46/F 63/M
B B
Mandible NR Retromolar trigone NR
4.0 3.8 5.0 Y NR Y
NOM NOM
Wu et al*
25/F 38/F
A A
Gingiva Buccal region
Site
GP
Metastasis (preoperative)
Primary/PT
2.0 0.8 0.6 Y
NOM
Y/NR
2.0 2.0 1.0 1.0 1.5 1.4 0.6 2.0 1.5 1.5 2.0 2.0
NM NOM NM NM NOM NM
Size (cm)
16 mo 1.5 2.0 1 mo 2.0 3.0
Pain
Y NR NR NR N N
N Y
NOM NOM
Treatment
Exc, partial maxillectomy Y/AC Exc Y/LCNEC Partial Exc Y/SCNEC RT (72 Gy) Y/LCNEC Exc, RND, RT, C Y/TC Exc Y (NR)/AC Exc, RND, MND, (MDNEC) RT, C Y/MDNEC Exc, RND, marginal mandibulectomy Y/TC Wide Exc Y/SCNEC C, RT (60 Gy) Y/unknown Wide Exc Y/PDNEC Exc, RT (iodine-125 seed 110 Gy)
Prognosis (mo) NED (23) NR NED (18) DUC (2) DM (1), LWD (9) NED (11) LR (4), DM (6), DOD (9) DM (NR), DOD (0.3) NED (24) LR (8), DM (20), DOD (24) NED (13) NED (8)
Abbreviations: A, Asian; AC, atypical carcinoid; B, Black; C, chemotherapy; DM, distant metastasis; DOD, died of disease; DUC, died of unrelated cause; Exc, excision; F, female; GP, growth period; LCNEC, large cell neuroendocrine carcinoma; LR, local recurrence; LWD, live with disease; M, male; MDNEC, moderately differentiated neuroendocrine carcinoma; MND, modified neck dissection; N, no; NED, no evidence of disease; NM, nodal metastasis; NOM, no metastasis; NR, not reported; PDNEC, poorly differentiated neuroendocrine carcinoma; PT, pathologic type; RND, radical neck dissection; RT, radiation therapy; SCNEC, small cell neuroendocrine carcinoma; TC, typical carcinoid; Y, yes. * Present report. Wu, Gao, and Yi. Primary Oral Neuroendocrine Carcinoma. J Oral Maxillofac Surg 2014.
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642 of the tumor when only neuron-specific enolase exhibits positivity.4 At electron microscopy, tumor cells show numerous membrane-bound and electron-dense neurosecretory granules in different sizes and numbers. Complex intercellular digitation, a rough marked endoplasmic reticulum, and abundant mitochondria are variably seen. Once NEC is suspected or diagnosed, a systemic whole-body examination is needed to exclude a primary tumor or a metastatic tumor. Positron emission tomography, CT imaging, and magnetic resonance imaging are recommended to pinpoint the location of the primary tumor, identify tumor extent, and further confirm the diagnosis.30 The differential diagnosis includes poorly differentiated squamous cell carcinoma (PDSCC), basaloid squamous cell carcinoma (BSCC), solid-type adenoid cystic carcinoma (ACC), lymphoma, melanoma, paraganglioma, and Ewing sarcoma. The appearance of PDNEC or MDNEC is similar to that of BSCC and PDSCC, which are negative for neuroendocrine markers. Highmolecular-weight cytokeratins, such as CK-5/6 and 34bE12, can be used to distinguish NEC from BSCC and solid-type ACC. They are usually strongly positive in BSCC and solid-type ACC but negative in NEC.31,32 HMB-45 is useful to exclude a diagnosis of melanoma. Negative staining with leukocyte common antigen can rule out malignant lymphoma. Calcitonin positivity can usually clearly distinguish NEC from paraganglioma. Interestingly, primary NEC in the oral cavity was reviewed and found to have an overlap or a correlation with SCC.16,21,26,28 Mochizuki et al28 reported a case of primary NEC combined with SCC in the upper gingiva. Yang et al16 reported that a patient with primary typical carcinoid in the retromolar region had prominent squamous differentiation. Baker and AlguacilGarcia21 observed the presence of SCC in situ in a patient with MDNEC in the floor of the mouth. In addition, Benning et al26 reported the recurrence of primary SCNEC in the oral cavity with focal squamous differentiation. In the present case 2, there were some foci of squamous cell differentiation in the sheets of tumor cells, favoring this hypothesis. Although the features of NEC have been documented, it is still difficult to diagnose NEC from preoperative biopsy specimens alone. Most cases of NEC have been confirmed from surgical specimens postoperatively. Hence, most reported cases of NEC were diagnosed retrospectively.33 Krishnamurthy et al24 reported that fine-needle aspiration cytology and incisional biopsy could determine a poorly differentiated carcinoma preoperatively, failing to recognize the neuroendocrine feature of malignancy. For WDNEC, surgery is the treatment of choice because radiotherapy and chemotherapy are ineffective. Surgical excision should be complete, but conserva-
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tive. Neck dissection is not warranted.14 As presented in Table 2, 2 cases of WDNEC were treated with only tumor excision. In general, the biological behavior is favorable, but different locations, origins, extents of tumor, and times of diagnosis can contribute to a variable prognosis.15 The prognosis of WDNEC of the oral cavity remains unknown. These 2 patients had a good prognosis without evidence of disease after excision up to 11 and 24 months, respectively. Similarly, for MDNEC, complete surgical excision is the mainstay of treatment. Owing to the high incidence of cervical lymph node metastasis, elective lymph node dissection is recommended in even clinically N0 necks, and radical lymph node dissection is required when the lymph nodes are clinically positive. Radiotherapy and chemotherapy are not considered reliable because MDNEC is resistant to these therapies.14,18,34 As presented in Table 2, a case of MDNEC in the gingiva was treated with excision alone. A case of MDNEC in the uvula was treated with excision, radical neck dissection on the right, modified neck dissection on the left, and radiochemotherapy. A case of MDNEC in the floor of the mouth was managed with excision, radical neck dissection, and marginal mandibulectomy. The overall 5-year survival rate was 48%, and the 10-year survival rate was only 30%. Radiotherapy did not have a significant effect on improving survival rate, so the differential diagnosis from more radiation-sensitive tumors is very important.18 The prognosis of MDNEC of the oral cavity remains obscure. As presented in Table 2, the patient with MDNEC in the uvula died of disease 9 months after surgery. The patient with MDNEC in the floor of the mouth died 10 days after surgery. Multiorgan failure and wide hepatic necrosis were considered the cause of death. The prognosis of the patient with MDNEC of the gingiva was not reported. Radical surgery, postoperative radiotherapy, and chemotherapy are required for PDNEC. However, many patients have disseminated disease at the time of diagnosis, thus excluding the feasibility of radical surgery. Therefore, therapeutic radiotherapy and chemotherapy are advocated.14,34 The treatment for combined carcinoma is similar to that for SCNEC without combined SCC or adenocarcinoma.14 Concurrent chemoradiotherapy may improve long-term survival.27 Kusafuka et al22 advocated primary chemotherapy and radiotherapy, instead of primary surgery with postoperative radiotherapy or systemic therapy, in the head and neck, because the clinical features of PDNEC are similar to those of small cell carcinoma. In particular, Barker et al35 reported that chemotherapy is crucial for PDNEC in the head and neck. Likewise, Benning et al26 found that a patient with SCNEC in the retromolar trigone attained an 8month clinical remission using a standard
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chemotherapeutic regimen for pulmonary small cell carcinoma. As presented in Table 2, LCNEC of the tongue was treated with partial excision alone. LCNEC of the retromolar trigone was treated with excision, radical neck dissection, and radiochemotherapy. Owing to the localized tumor and the patient’s poor general condition, SCNEC of the tongue was managed with radiation therapy alone. SCNEC of the retromolar trigone was treated with radiation therapy and chemotherapy. The prognosis of primary LCNEC in the oral cavity is not entirely known. In general, LCNECs arising in other sites have significantly unfavorable outcomes.22 The prognosis of SCNEC of the oral cavity also remains unclear. Laryngeal SCNEC has a poor prognosis. The most important influential factor of survival rate is tumor extent. About 50% of patients with SCNEC have cervical lymph nodes involved, whereas approximately 60% to 90% have possible distant metastasis to the lungs, liver, and bones.27,34 The prognosis of laryngeal SCNEC is dismal: The reported 2-year survival rate was 16% and the 5-year survival rate was 5%.14 As presented in Table 2, a patient with LCNEC of the tongue had a good prognosis, with 18 months without any evidence of disease. A case of LCNEC of the retromolar trigone showed distant metastasis after surgery, but the patient lived with disease at 9 months of follow-up. A patient with SCNEC of the tongue died from debility 2 months after completing treatment. A patient with SCNEC of the retromolar trigone died of disease 2 years after treatment. The adrenal medulla, pituitary gland, pancreatic islets, etc, are endocrine glands that consist of many agminated neuroendocrine cells. However, in other sites, neuroendocrine cells are distributed throughout the mucosa, constituting a disseminated or diffuse neuroendocrine system.7,17 The histogenesis of oral NECs remains obscure. In the oral cavity, Merkel cells are considered the origin, because they preferentially scatter in the basal layer of the keratinized epithelium in the hard palate and gingiva.7,11 Some researchers have proposed that LCNEC of the tongue base arises from some special cells that have neuroendocrine characteristics and are located in the basal cell layer of the squamous epithelium.23 Thus, LCNEC has been suggested to originate from neuroendocrine cells. However, a coexistence of divergent differentiation has been observed, such as NEC associated with a squamous or adenocarcinomatous component, suggesting that NEC is derived from primitive and pluripotential stem cells rather than neuroendocrine cells.27 This report has described 2 new cases of NEC in the oral cavity. The particular histologic appearance of case 1 provides new information on NEC in the oral cavity. The NEC in case 2 arose in the buccal region, adding to the known sites of NEC in the oral cavity.
Nevertheless, to propose a specific classification, understand the clinical behavior, and establish an optimal treatment of NEC in the oral cavity, more cases need to be reported. Acknowledgments The authors offer many thanks to Dr Xin-Li Zhai, Dr Hai-Yan Luo, Dr Chi Mao, and Dr Jian-Guo Zhang for their contributions to this report.
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