1130-0108/2017/109/2/160-162Revista española de enfeRmedades digestivas© Copyright 2017. sepd y © ARÁN EDICIONES, S.L.

Rev esp enfeRm dig2017, Vol. 109, N.º 2, pp. 160-162

Juanmartiñena JF, Fernández-Urien I, Córdoba A, Miranda C, Borda A. Mixed adenoneuroendocrine carcinoma (MANEC) of the gastroesophageal junction: a case report and review of the literature. Rev Esp Enferm Dig 2017;109(2):160-162.

DOI: 10.17235/reed.2016.4315/2016

Received: 12-03-2016Accepted: 14-03-2016

Correspondence: Jose Francisco Juanmartiñena. Department of Endoscopy. Complejo Hospitalario de Navarra. Irunlarrea, 4. 31008 Pamplona, Navarra. Spaine-mail: jf.juanmartinena@gmail.com

Mixed adenoneuroendocrine carcinoma (MANEC) of the gastroesophageal junction: a case report and review of the literatureJosé Francisco Juanmartiñena1,2, Iñaki Fernández-Urien1,2, Alicia Córdoba3, Coro Miranda4 and Ana Borda2

Departments of 1Endoscopy, 2Digestive Diseases, 3Pathology and 4Surgery. Complejo Hospitalario de Navarra. Pamplona, Spain

ABSTRACT

Esophageal cancer is the fourth most common neoplasm of the gastrointestinal tract. It is responsible for 1.7% of all deaths related with cancer. The two main types of esophageal cancer are squamous cell carcinoma and adenocarcinoma. Other types of esophageal cancer are uncommon. We present a 57-year-old man admitted to the hospital with nausea and vomiting due to a high-grade malignant mixed adenoneuroendocrine carcinoma of the gastroesophageal junction. The patient underwent Ivor-Lewis esophagectomy and adyuvant chemoradiotherapy. At 8-month follow-up he was alive without evidence of recurrence.

Key words: Mixed adenoneuroendocrine carcinoma. Mixed exocrine-endocrine carcinoma. Gastroesophageal junction. Carcinoid tumor. Gut.

INTRODUCTION

Mixed exocrine-neuroendocrine carcinomas, now renamed by the 2010 World Health Organization (WHO) classification as mixed adenoneuroendocrine carcinomas (MANECs) are uncommon tumors (1). They are by defini-tion neoplasms in which each component represents at least 30% of the lesion. MANECs have different morphological features ranging and degrees of differentiation (well to poorly differentiated neoplasm). These tumors have non-specific symptoms and are mainly diagnosed histopathologically and immunohistochemically after surgery. To date, the optimal management strategy is unknown and no therapeutic stra-tegies are recommended, although taking into account the more aggressive component of MANECs seems reasonable.

CASE REPORT

A 57-year-old male was admitted to our department with nausea, vomiting, dysphagia and weight loss. Physical

examination and laboratory markers were unremarkable. Upper endoscopy revealed an ulcerative and stenotic mass arising from the mucosa of the gastroesophageal junction. It was initially biopsied and diagnosed as large cell neu-roendocrine carcinoma with a Ki-67 proliferation rate of > 95%. Subsequently, regional disease was confirmed by computed tomography and Ivor-Lewis esophagectomy was performed. On histopathological examination the neoplasm showed two distinct components with an abrupt transition. On the one hand, a poorly differentiated adeno-carcinoma with some isolated ring cells. On the other hand, a neuroendocrine carcinoma with small cell component arranged in cords was observed (Fig. 1). The neoplasm involved all layers of the gastrointestinal wall, invaded perineural and lymphovascular tissue and infiltrated up to 14 regional lymph nodes (pT3N3M0 stage III-B according to the 7th edition of the American Joint Committee on Can-cer TNM classification). On immunohistochemical study, it presented a strong immunoexpression of synaptophysin and isolated positivity for chromogranin in the neuroen-docrine component (Fig. 2), while a strong immunoex-presion of periodic acid-Schiff (PAS) was observed in the adenocarcinoma component. In both cases, a high Ki-67 proliferation rate (> 60%) and a strikingly positivity for citokeratin-7 and E-cadherin was detected. Therefore, according to the current WHO criteria the final patholo-gical diagnosis was high-grade malignant MANEC of the gastroesophageal junction.

DISCUSSION

Esophageal cancer is the fourth most common tumor of the gastrointestinal tract, and it is responsible for 1.7% of all cancer-related deaths. It is usually three to four times more common among men than among women. The two

2017, Vol. 109, N.º 2 MIXED ADENONEUROENDOCRINE CARCINOMA (MANEC) OF THE GASTROESOPHAGEAL JUNCTION: 161 A CASE REPORT AND REVIEW OF THE LITERATURE

Rev esp enfeRm Dig 2017;109(2):160-162

in the literature as a case report. They are, by definition, neoplasms in which each component (exocrine and neu-roendocrine differentiation) represents at least 30% of the lesion, and have usually different morphological features ranging and degrees of differentiation (well to poorly diffe-rentiated). The first description was published by Cordier in 1924 (3). Since then, several cases have been reported using different names. In 2000 the WHO classification defi-ned them as mixed exocrine-endocrine carcinomas, and renamed them as mixed adenoneuroendocrine carcinomas (MANECs) ten years later (4). However, this classification did not contemplate subcategories assessing the grade of malignancy of each component, which helps to improve and standardize therapeutic protocols. Thus, in 2012, Rose et al. (5) stratified gastrointestinal MANECs in different prognostic categories: a) High-grade malignant MANECs (adenomatous or carcinomatous component and a poorly differentiated neuroendocrine carcinoma); b) Intermediate grade malignant MANECs (adenomatous or carcinomatous component with different degrees of differentiation, and differentiated neuroendocrine tumor or amphicrine carcino-ma); and c) Mixed adenoneuroendocrine tumor (adenoma and well differentiated neuroendocrine tumor). Because MANECs neoplasms are rare entities, to date few aspects are known about their clinical presentation, histogenesis or treatment. No specific symptoms or carcinoid syndro-me have been reported in the literature and little is known about their origin, although most authors admit this could be in a multi-potent stem cell with bidirectional differen-tiation (6-8). Diagnosis is mainly based on the neoplasm architecture, completed by the immunostains with specific neuroendocrine markers (chromogranin, synaptophysin, CD56 or nueuron-specific enolase) combined with the markers on non-endocrine differentiation (9). To date, the optimal management strategy is unknown and no therapeu-tic strategies are recommended, although it seems reasona-ble to take into account the more aggressive component of MANECs (10). According to the 2010 WHO classification, surgery seems to be the treatment of choice, and adjuvant chemotherapy can be administered after surgery, although there is insufficient evidence about its effectiveness.

In conclusion, we report an uncommon case of high-grade mixed adenoneuroendocrine carcinoma of the gastrointestinal junction, categorized by the 2010 WHO classification as MANEC. Because of its uncommon pre-sentation, to date little is known about the optimal manage-ment strategy and more studies are needed to recommend new therapeutic strategies.

REFERENCES

1. Rindi G, Arnold R, Bosman FT, et al. Nomenclature and classifica-tion of neuroendocrine neoplasms of the digestive system. In: WHO Classification of Tumors of the Digestive System, 4th ed. Bosman TF, Carneiro F, Hruban RH, Theise N.D (Eds); International Agency for Research on cancer (IARC). Lyon: 2010. p. 13.

Fig. 1. A. Subcardial area with erosion and loss of mucosal architecture (x 22; H-E). B. Diffuse tumor growth infiltrating the mucosa; a well-preserved crypt can be seen at the left bottom (x 100; H-E). C. Mixed adenoneuroendocrine carcinoma firstly represented by diffuse signet ring cells (x 200; H-E). D. Second component of MANECs is a poorly differentiated neuroendocrine carcinoma(x 200; H-E).

Fig. 2. A-B. Cytoplasmatic vacuoles are positive with PAS in adenoneu-roendocrine component, whereas they are negative in neuroendocrine component (x 40-PAS, x 100-PAS). C-D. Areas with neuroendocrine dif-ferentiation are positive for synaptophysin, while this marker is negative in the adenocarcinoma component (x 100-synaptophysin, x 200-syn-aptophysin).

main types of esophageal cancer are squamous cell carci-noma and adenocarcinoma. Incidence rates vary interna-tionally, the highest rates being in Eastern Asia and Eas-tern and Southern Africa (2). Nowadays, the incidence of squamous cell carcinoma is decreasing while the incidence of adenocarcinoma is rising (most of them involving gas-troesophageal junction and gastric cardia). Other types of cancers are uncommon. We present an exceedingly rare case of MANEC of the gastroesophageal junction. Due to their infrequent presentation, they are often presented

162 J. F. JUANMARTIÑENA ET AL. Rev esp enfeRm Dig

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2. Hasegawa S, Yoshikawa T. Adenocarcinoma of the esophagogastric junction: Incidence, characteristics, and treatment strategies. Gastric Cancer 2010;13:63-73. DOI: 10.1007/s10120-010-0555-2

3. Cordier R. Les cellules argentaffines dans les tumeurs intestinales. Arch Int Med Exp 1924;1:9-74.

4. Solcia E, Kloppel G, Sobin LH. Histological typing of endocrine tumors. In: WHO International Histological Classification of Tumors, 2nd Springer: Berlin, Germany; 2000.

5. La Rosa S, Marando A, Sessa F, et al. MANECs of the gastrointestinal tract: An update. Cancers 2012;4:11-30. DOI: 10.3390/cancers4010011

6. Kitajima T, Kaida S, Lee S, et al. Mixed adeno(neuro)endocrine car-cinoma arising from the ectopic gastric mucosa of the upper thoracic esophagus. World J Surg Oncol 2013;11:218. DOI: 10.1186/1477-7819-11-218

7. Jain A, Singla S, Jagdeesh KS, et al. Mixed adenoneuroendocrine car-cinoma of cecum: A rare entity. J Clin Imaging Sci 2013;3:10. DOI: 10.4103/2156-7514.107995

8. Kim JJ, Kim JY, Hur H, et al. Clinicopathologic significance of gas-tric adenocarcinoma with neuroendocrine features. J Gastric Cancer 2011;11:195-9. DOI: 10.5230/jgc.2011.11.4.195

9. Gurzu S, Kadar Z, Bara T, et al. Mixed adenoneuroendocrine carcino-ma of gastrointestinal tract: Report of two cases. World J Gastroenterol 2015;21:1329-33. DOI: 10.3748/wjg.v21.i4.1329

10. Veits L, Lang-Schwarz C, Volkholz H, et al. Mixed adenoneu-roendocrine carcinoma (MANEC) of the esophagogastric junction predominantly consisting of poorly differentiated neuroendocrine carcinoma. Endoscopy 2013;45(Suppl. 2):16-7. DOI: 10.1055/s-0032-1326113