A ocri upp S, PhD DDS, t occu bio poorl ca us cell 62 ed. Hi ex The tu squ ests sta N- ity wa an nents dif . The mo s of ne pe ndod Ne oc do gro co vid aty Th roe mo ica cri of tia (hi Most neuroendocrine carcinomas in the head and neck arise in the larynx.3 The second-most common site is the salivary glands.3 A review of the literature by Abiko et al.6 found that several cases originating in the aPart-time Lecturer, Oral and Maxillofacial Surgery, Department of Oral Restitution, Division of Oral Health Sciences, Graduate School, To bPr titu Me cAs Div and dPa Div and eGr Ora To fAs Ora To gPr of O Un Re acc 107 © 2 doi e3 oral region have been reported as Merkel cell carci- noma, including cases reported as neuroendocrine car- cinoma. Neuroendocrine carcinomas are considered ag- gressive, but the biological behaviors of these tumors are poorly understood. Combined-type neuroendocrine carcinoma is very rare. We report an extremely rare case of neuroendocrine carcinoma combined with squamous cell carcinoma in the upper gingiva and discuss the clinicopathological characteristics of this disease on the basis of the exist- ing literature. CASE A 62-year-old woman was admitted to our clinic in January 2008 with a painful mass in the buccal alveolus mucosa of the left maxillary second molar region. She had noticed the mass in May 2007. Oral examination showed an elastic soft pol- ypoid mass, measuring 2.0 � 0.8 � 0.6 cm, with a smooth kyo Medical and Dental University, Tokyo, Japan. ofessor, Oral and Maxillofacial Surgery, Department of Oral Res- tion, Division of Oral Health Sciences, Graduate School, Tokyo dical and Dental University, Tokyo, Japan. sistant Professor, Oral Pathology, Department of Oral Restitution, ision of Oral Health Sciences, Graduate School, Tokyo Medical Dental University, Tokyo, Japan. rt-time Lecturer, Oral Pathology, Department of Oral Restitution, ision of Oral Health Sciences, Graduate School, Tokyo Medical Dental University, Tokyo, Japan. aduate Student, Oral and Maxillofacial Surgery, Department of l Restitution, Division of Oral Health Sciences, Graduate School, kyo Medical and Dental University, Tokyo, Japan. sistant Professor, Oral and Maxillofacial Surgery, Department of l Restitution, Division of Oral Health Sciences, Graduate School, kyo Medical and Dental University, Tokyo, Japan. ofessor, Oral Pathology, Department of Oral Restitution, Division ral Health Sciences, Graduate School, Tokyo Medical and Dental iversity, Tokyo, Japan. ceived for publication Jun 6, 2009; returned for Dec 2, 2009; epted for publication Dec 9, 2009. 9-2104/$ - see front matter case of primary combined neuroend squamous cell carcinoma in the Yumi Mochizuki, DDS, PhD,a Ken Omura, DD Shoichi Nakanishi, DDS, PhD,d Kiyoshi Satoh, Akira Yamaguchi, DDS, PhD,g Tokyo, Japan TOKYO MEDICAL AND DENTAL UNIVERSITY Neuroendocrine carcinoma is a rare neoplasm tha logical behavior of this tumor in the oral region remains se of combined neuroendocrine carcinoma with squamo -year-old woman. Left partial maxillectomy was perform tensive necrosis and nuclear palisading at the periphery. amous differentiation. Immunohistochemically, tumor n CAM (CD56), and neuron-specific enolase. Strong positiv d for K7 in the neuroendocrine component. Both compo ferentiation and K14 staining occasionally expressed p63 nths postoperatively. Given the aggressive characteristic rformed. (Oral Surg Oral Med Oral Pathol Oral Radiol E uroendocrine carcinoma is a rare neoplasm that can cur widely in various organs and tissues.1-3 Neuroen- crine carcinomas are a component of the epithelial up in the neuroectodermal neoplasms, which is mposed of nonepithelial and epithelial groups.3 In 2004, the World Health Organization (WHO) di- ed lung neuroendocrine carcinomas into carcinoid, pical carcinoid, and large- and small-cell carcinoma. and ph 010 Mosby, Inc. All rights reserved. :10.1016/j.tripleo.2009.12.018 4 ne carcinoma with er gingiva ,b Kei Sakamoto, DDS, PhD,c e Eriko Marukawa, DDS, PhD,f and rs widely in various organs and tissues. The y understood. We encountered an extremely rare carcinoma, occurring at the buccal gingiva in a stological examinations revealed solid nests with mor also showed areas of stratified neoplastic ined positive for synaptophysin, chromogranin, s seen for K14 and K17 in the squamous component showed K19 staining. Cells with squamous patient showed no evidence of disease as of 23 uroendocrine carcinoma, strict follow-up has been 2010;109:e34-e39) e current classifications and nomenclature of neu- ndocrine carcinomas in other organs have been deled after those of the lung. Based on morpholog- l and biological behaviors, the entity of neuroendo- ne carcinoma has been replaced by subclassifications well-differentiated (low-grade), moderately differen- ted (intermediate-grade), and poorly differentiated gh-grade) neuroendocrine carcinoma3,4 (Table I). partially bright red surface (Fig. 1). Computed tomogra- y (CT) of the head and neck demonstrated a relatively we cor (PE me dia tom no PA gin tiv sal rev cro we ce cle ery niz lar Ki tot po are (F co ine sta 6, (F en ne sq en pe are nu K1 ab of ser co Ta s3-5 W Cel Ca Mild Aty Moder Lar Severe Sm Severe WH Fig tum Fig alv arr OOOOE Volume 109, Number 4 Mochizuki et al. e35 ll-demarcated mass and resorption of the posterior buccal tex of the maxilla (Fig. 2). Positron emission tomography T) showed an area of high uptake in the same region. No tastatic lesions were detected. Biopsy of the tumor led to a gnosis of neuroendocrine carcinoma. Left partial maxillec- y was performed in February 2008. The patient showed evidence of disease as of 23 months postoperatively. THOLOGICAL FINDINGS The tumor was a polypoid mass in the left upper giva that had infiltrated to the subepithelial connec- e tissue, but was located separate from the minor ivary gland (Fig. 3, A, B). Histological examination ealed closely packed, solid nests with extensive ne- sis (Fig. 3, C). Basaloid cells with scant cytoplasm re dominant, but oval, polyhedral, or spindle-shaped lls with abundant cytoplasm were also present. Nu- ar palisading was frequently observed at the periph- of the nest, and rosette-like structures were recog- ed (Fig. 3, D, E). Cellular atypia was apparent and ge pleomorphic cells were frequently seen. The -67 labeling index was over than 80% (Fig. 4). Mi- ic counts were in excess of 86 cells per 10 high- wer fields (HPF) (Fig. 3, F). The tumor also showed as of stratified neoplastic squamous differentiation ig. 3, G, H). Tumor stroma were positive for type IV llagen (Fig. 5, A, B, C). No lymphovascular or per- ble I. Classification of primary neuroendocrine tumor HO classification of lung Classification by Mills Classification by Moran et al. rcinoid Well-differentiated Low-grade pical carcinoid Moderately differentiated Intermediate-grade ge-cell carcinoma Poorly differentiated High-grade all-cell carcinoma Poorly differentiated High-grade O, World Health Organization; HPF, high-power fields. . 1. Intraoral photographs taken at first visit showing the or in the left maxillary second molar region. ural invasion was evident. Immunohistochemical ining showed positive results for synaptophysin (Fig. A), chromogranin A (CgA), and N-CAM (CD56) ig. 6, B), with focal positivity for neuron-specific olase (NSE). These observations suggested that the tumor showed uroendocrine differentiation with a tendency toward uamous differentiation. To further assess the differ- tiation state of tumor cells, keratin profiling was rformed. The primary antibodies used in this study listed in Table II. K5 was positive only in a small mber of basaloid cells in the squamous component. 4, K15, and K17 expressions were also observed in undance in the squamous component. Small numbers K14-, K15-, and K17-positive cells were also ob- ved in a scattered fashion even in the neuroendocrine mponent. Cells showing squamous differentiation d staining for K14 occasionally expressed p63. Ex- ssions of K1, K4, K10, and K13 were detected in uamous components. K7 was positive in most tumor lls in the neuroendocrine components. Both compo- nts were positive for K19. The immunoprofile for s study is shown in Table III, and staining profiles of , K4, K7, K10, K14, K17, K19, and p63 are dis- yed in Fig. 6. lular atypia Mitotic figures (�10 HPF) Necrosis �3 Small focus of comedonecrosis ate 4-9 More extensive foci or prominent �10 Extensive area or prominent �10 Extensive area . 2. Preoperative axial CT showing a lesion in the buccal eolus of the left maxillary second molar region (yellow ows). an pre sq ce ne thi K1 pla Fig Fig the (� par com (� sho OOOOE e36 Mochizuki et al. April 2010 Taking the morphological and immunohistochemical tures into account, the final diagnosis was neuroen- crine carcinoma combined with squamous cell car- oma. SCUSSION Although the tumors are clinically quite distinct, saloid-appearing carcinomas of the head and neck ch as basaloid squamous cell carcinoma and high- de neuroendocrine carcinoma show morphological ilarities.7 In this case, histologically, hematoxylin d eosin (HE)-stained sections revealed solid nests th extensive necrosis and nuclear palisading at the riphery. Tumor nests were positive for synaptophy- , CgA, and N-CAM (CD56), exhibiting distinctive otomicrograph showing continuity between the tumor and was ulcerated and composed of fibrin and necrotic debris 3, A (�10). C, Photomicrograph of surgical specimen that showing closely packed, solid-pattern tumor nests and alisading is frequently apparent at the periphery of nests lear size, shape, and chromaticity (�200). G, H, Tumor orphic, hyperchromatic keratinized cells (�200). fea do cin DI ba su gra sim an wi pe sin. 4. Image of Ki67 positive cells (�200). . 3. Images of hematoxylin-eosin (HE) staining. A, Low-power ph oral surface epithelium with epithelial dysplasia. The tumor surface 5). B, The partial area displayed through the high-power field in Fig. tially peeled off from the upper gingiva during surgery. Tumor edonecrosis (�10). D, E, Basaloid cells are dominant. Nuclear p 200). F, Tumor cells show irregular shapes with variations in nuc wing stratified neoplastic squamous epithelium consisting of pleom dif de pla Im of sq po im vio co Fig ith co dis ype IV ins display Fig and Sq p6 sho 200). OOOOE Volume 109, Number 4 Mochizuki et al. e37 ferentiation toward neuroendocrine cells with a ten- ncy toward squamous differentiation. In our study, the keratin profile of the tumor dis- yed different staining patterns in each component. munoreactivity for K1,8 K5, and K149 and absence immunoreactivity for K8 have been reported in oral uamous cell carcinoma. In the neuroendocrine com- nent, focal immunoreactivity to K710 and absence of munoreactivity to K1411 have been described in pre- us reports. In our study, the tumor cells of both mponents were positive for K19. In normal oral . 5. Image of type IV collagen staining. A, Tumor nests w played in Fig. 5, A. Tumor stroma show positive staining for t ide the nests (type IV collagen, �100). C, The partial area . 6. Images of profiling neuroendocrine markers, keratin, and K7 is observed (A, synaptophysin; B, CD56; C, K7) (�2 uamous components show positive results for K14 (K14, �1 3 (p63, �100). G-J, Immunoreactivity for K1, K4, K10, and K w differing distributions (G, K1; H, K4; I, K10; J, K17) (� cosa tissue, K19 protein expression is positive only the basal layer of the mucosa. Although the clinical nificance of K19 detection has not been confirmed oral squamous cell carcinoma, increased K19 ex- ssion and gene transcription in oral squamous cell rcinoma tissue reportedly shows a significant corre- ion with grade of pathological differentiation.12 In s case, K14-positive cells in squamous components casionally expressed p63. The keratin immunopro- s in our study could reflect the differentiation abil- s of the tumor in terms of both squamous cell and medonecrosis (asterisks) (HE, �100). B, The same area collagen (double asterisks) . No immunoreactivity is seen ed through the high-power field in Fig. 5, B (�200). -C, Immunoreactivity for synaptophysin, N-CAM (CD56) , All tumor cells are positive for K19 (K19, �100). E, , Squamous differentiated cells show partial positivity for e apparent in squamous components. Immunoreactive cells mu in sig for pre ca lat thi oc file itie p63. A 00). D 00). F 17 ar ne for ep ha ch co tha an or sh ati eso am rar dir ste co alo co the no sca pe ple rad as me fec pre en 19 rep on a 2 pa du ne ity ag su su am ma inv co the de act Ta be ca Syp Cg N-C NS K1 K2 K4 K5 K6 K7 K8 K9 K1 K1 K1 K1 K1 K1 K1 K1 K2 NE of s A; 0% Ta K1 K2 K4 K5 K6 K7 K8 K9 K1 K1 K1 K1 K1 K1 K1 K1 K2 Ch Syn N-C NS p63 Co Ab Ep den UK nol OOOOE e38 Mochizuki et al. April 2010 uroendocrine components. Keratins could be helpful determining whether there was differentiation for ithelial-derived tumors or not.13 On the other hand, it s since become apparent that a minority of mesen- ymal-derived sarcomas may express keratin.13 P63 uld be helpful as one of the subtle screening markers t classify what appears to be undifferentiated head d neck tumor as epithelial, mesenchymal, lymphoid, melanocytic type.13,14 Neuroendocrine carcinomas owing adenocarcinomatous and squamous differenti- on have been reported to arise in the hypopharynx,15 phagus,16 gastrointestinal tract,17 lungs,5 and uterus,18 ong others. To our knowledge, this type of tumor is e, particularly in the oral region. A capacity for multi- ectional differentiation could arise from pluripotent m cells. Neuroendocrine and squamous cell carcinomas uld have arisen from pluripotent cells that differentiated ng 2 distinct paths, or the neuroendocrine carcinoma uld have differentiated secondarily from cells arising in squamous cell carcinoma.5,18,19 When neuroendocrine carcinoma is suspected or diag- sed, the patient should undergo a systemic whole-body n to exclude another lesion in the chest, abdomen, or lvis.20 Generally, primary management includes com- te resection of the tumor followed by postoperative ble II. Primary antibodies used in this study Antigen Supplier Clone name Dilution Santa Cruz N-20 1:500 e Progen Ks2.342.7.1 1:500 Epitomics EP1599Y 1:500 Epitomics EP1601Y 1:500 Neomarkers LHK6B 1:500 Dako RN7 1:500 Novocastra TS1 1:500 Eurodiagnostica Ks9.70/Ks9.216 1:500 0 Neomarkers DE-K10 1:500 3 Novocastra KS-1A3 1:500 4 Abcam LL002 1:500 5 Epitomics EPR1614Y 1:500 6 Neomarkers LL025 1:500 7 Dako E3 1:500 8 Dako DC10 1:500 9 Epitomics EP1580Y 1:500 0 Dako PW1 1:500 romogranin A Dako DAK-A3 1:500 aptophysin Dako SY38 1:500 AM (CD56) Novocastra NCL-CD56-1B6 1:500 E Dako BBS/NC/VI-H14 1:500 Dako 4A4 1:500 llagen IV Dako CIV22 1:500 cam, Cambridge, UK; Dako Cytomation, Glostrup, Denmark; itomics, South San Francisco, CA; Eurodiagnostica, Malmo, Swe- ; NeoMarkers, Fremont, CA; Novocastra, Newcastle-upon-Tyne, ; Progen Biotechnik, Heidelberg, Germany; Santa Cruz Biotech- ogy, Santa Cruz, CA. iotherapy.20 Neoadjuvant chemotherapy is considered well, particularly if the tumor is suspected to represent tastasis.20 Prognosis for neuroendocrine tumors is af- ted by the location and size of the primary tumor, the sence of metastatic lesions,21 and the degree of differ- tiation of the tumors.22 Neuroendocrine tumors are considered aggressive. A 91 study of neuroendocrine carcinoma of the larynx orted a local recurrence rate of 23% to 60%23 and ly 5% of patients with poorly differentiated type had -year survival rate.24 In our case, the tumor showed an exophytic growth ttern and partial peeling off from the upper gingiva ring surgery. Microscopically, an extensive area of crosis, severe cellular atypia, and high mitotic activ- indicated high-grade malignancy. From the CT im- ing of aspect, tumor invasion was suspected. The rface buccal cortex of the maxilla revealed rough by bperiosteal dissection. However, on histological ex- ination, invasion into the adjacent tissue including xillary bone or focal lymphovascular and perineural asions were not present. Some nontumorous factors uld promote bone-remodeling process. At present, patient has shown no radiographic or clinical evi- nce of recurrence. In our case, the morphological char- eristic of neuroendocrine differentiation with a ten- ble III. The comparative table of immunoprofile tween neuroendocrine carcinoma and squamous cell rcinoma in this study NEC SCC �� � A �� � AM (CD56) � � E � � � � � � � � � � � � �� � � � � � 0 � � 3 � � 4 � �� 5 � � 6 � � 7 � �� 8 � � 9 �� � 0 � � C, components of neuroendocrine carcinoma; SCC, components quamous cell carcinoma; Syn, synaptophysin; CgA, chromogranin NSE, neuron-specific enolase; ��, 75%-100%; �, 25%-75%; �, -25%; �, 0. dency toward squamous differentiation could have some eff tio pa tre rel po rep ca su the no CO do cin for reg to de Th Pa stu RE 1. 2. 3. 4. 5. 6. 7. 8. 9. a spliced transcript of type II keratin K5. Oral Oncol 1998; 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. Rep Yu De Div Gra 1-5 To mo OOOOE Volume 109, Number 4 Mochizuki et al. e39 ect on the prognosis. Furthermore, the anatomic loca- ns of most malignant tumors in the oral area are com- ratively noticeable macroscopically, enabling radical atment by surgical resection under direct vision at a atively early stage. This characteristic may also have sitively affected prognosis in the present case. To the best of our knowledge, only one previous ort has described combined-type neuroendocrine rcinoma in the oral region.25 Further evidence to pport our treatment and prognosis is needed. Given aggressive characteristics of neuroendocrine carci- ma, we have been performing intensive follow-up. NCLUSION We have reported an extremely rare case of neuroen- crine carcinoma combined with squamous cell car- oma in the upper gingiva. This report provides in- mation on neuroendocrine carcinoma in the oral ion. More cases of this tumor in the oral region need be accumulated to clarify biological behaviors and termine optimal treatment. e authors are grateful to Miwako Hamagaki (Oral thology) for skillful technical assistance throughout the dy. FERENCES Brandwein MS, Kapadia SB, Gnepp DR. Nonsquamous pathol- ogy of the larynx, hypopharynx and trachea. In: Gnepp DR, editor. Diagnostic surgical pathology of the head and neck. New York: WB Saunders; 2001. p. 281-3. Hurt MA, Santa Cruz DJ. Tumor of the skin. In: Fletcher CDM, editor. Diagnostic histopathology of tumors. New York: Chur- chill Livingstone; 2000. p. 1404-5. Mills SE. Neuroectodermal neoplasms of the head and neck with emphasis on neuroendocrine carcinoma. Modern Pathol 2002;15: 264-78. Moran CA, Suster S. Neuroendocrine carcinomas (carcinoid, atypical carcinoid, small cell carcinoma, and large cell neuroen- docrine carcinoma): current concepts. Hematol Oncol Clin North Am 2007;21:395-407. McDowell EM, Trump BJ. 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Japanese. rint requests: mi Mochizuki, DDS, PhD partment of Oral Restitution ision of Oral Health Sciences duate School, Tokyo Medical and Dental University -45 Yushima, Bunkyo-ku kyo 113-8549, Japan
[email protected] A case of primary combined neuroendocrine carcinoma with squamous cell carcinoma in the upper gingiva CASE PATHOLOGICAL FINDINGS DISCUSSION CONCLUSION ACKNOWLEDGMENT REFERENCES