Mixed Adeno-Neuroendocrine Carcinoma; Case Series of Ten Patients with Review of the Literature.
MATERIALS AND METHODS
Following the approval of the local ethics committee, the pathology database was explored to identify patients with a pathological diagnosis of "MANEC" at a single tertiary referral center. The diagnosis had been made based on the current WHO classification, defining that each tumor component had at least 30% ofthe specimen. The patients were identified retrospectively and evaluated for their demographic details, histopathological examination results, and tumor properties, including immunohistochemical markers, stage at diagnosis, treatment modalities, clinical outcome, and survival follow-up. The mean follow-up duration was 18.1 months (minimum: 3, maximum: 51 months) starting from the date of operation.
A total of 10 patients had been diagnosed with MANECs in our center. The demographic details of the patients and other evaluation criteria are shown in Table 1. Nine patients were males and one patient was a female. The mean age at diagnosis was 64.7 years (range: 48-73 years). All the patients had undergone surgery. The histopathological examination confirmed that all the patients had been treated with curative surgery (R0 resections, tumor-free resection margins). Distant liver metastasis was observed in only one patient. The dominant component was an adenocarcinoma in four patients and a neuroendocrine tumor in six patients. The most common tumor localization was the stomach (five patients). Other tumor sites included the rectum, the pancreas, the ampulla of Vater, the sigmoid colon, and the ductus choledochus. The adenocarcinoma component was well-differentiated in six patients, medium-differentiated in three patients, and low-differentiated in one patient. The grades of the neuroendocrine component were as follows: grade 1 in three patients, grade 2 in one patient, grades 2-3 in one patient, and grade 3 in five patients. The histopathological images and the immunohistochemistry results of a gastric MANEC are shown in Figure 1b, 1c. Surgery alone had been performed in five patients, while adjuvant chemotherapy was administered to the remaining five patients. None of the patients had been operated for a recurrent disease. Following surgery, the median follow-up duration was 15 months (range: 3-51 months). At the time of the study, six patients were alive with a mean survival time of 23.5 months (range: 10-51 months). Four patients had died with a median survival time of 20.6 months (range: 3-22 months). Patient no. 3 had died due to acute exacerbation of chronic obstructive pulmonary disease in the postoperative third month. Patient no. 4 had died in the 22nd month due to irresectable local recurrence of gastric cancer. Patient no. 6 had died due to acute myocardial infarction during adjuvant chemotherapy in the third month. Patient no. 8 had died following the occurrence of multiple liver metastasis during the early postoperative term in the fifth month during neoadjuvant therapy.
MANEC is a rare entity that has been defined differently since its first definition by Cordier in 1924 and several years later by Lewin in 1987 until the final description given in 2010 by the WHO as neoplasms involving both the epithelial and the neuroendocrine components. Because of the rarity of the tumor, the diagnostic criteria and the treatment options have differed according to different researchers. Latest developments in immunohistochemical staining techniques have led to an increased frequency of identifying few neuroendocrine cells in adenocarcinomas in the tumor tissues. Similarly, exocrine components can be commonly found in especially high-grade gastrointestinal neuroendocrine carcinomas (NECs) (4). However, the latest MANEC definition of the WHO necessitates the presence of each component comprising at least 30% of the tumor and both components being malignant (1). Due to the lack of any specific radiologic or symptomatic predictors of the tumor, the diagnosis is made based on the histopathological findings. Although the etiopathogenesis of the tumor is completely unclear, immunohistochemical studies have confirmed that the NEC component may give rise to the adenocarcinoma component, with both of them deriving from a single stem cell (16). Till date, in the published literature, MANECs have been identified in various localizations, with the colon (7) and the stomach (6) being the most common. Biliary and pancreatic MANECs are highly exceptional entities, and prior to our study, 22 cases of ampullary MANECs have been reported in the literature (10). In our study, we diagnosed one tumor in the pancreas, one in the ampulla, and one in the choledochus. We had performed cholecystectomy and hepaticojejunostomy following the excision of the extrahepatic biliary tree with tumor-free margins. Other localizations were gastric tumor in five patients, one in the rectum, and one in the sigmoid colon. The tumor was also diagnosed in the uterine cervix (9). The presence of MANECs has been reported predominantly in females due to a limited number of case series published in the literature (5,14). Conversely, a higher ratio of male patients was observed in our case series (9/10 patients, 90%). La Rosa et al. (17) have shown that the majority of MANEC tumors (>50%) stain positively for both chromogranin and synaptophysin. Similarly, in our study, positivity for these two protein markers was observed in 60% of the cases (six patients). In our case series, the rate of lymphatic invasion was found to be similar to that reported in previous series (50%), whereas the perineural invasion rate was lower (20%) (4,14). Harada et al. (5) defined six biliary MANEC cases with both perineural and vascular invasions (5). Similarly, in our case series, we identified both invasions in our patient with the choledochal MANEC, while the patient with the ampullary MANEC showed positivity only for lymphovascular invasion. The rarity of the tumor has resulted in an uncertainty in determining the optimal treatment strategy till date (18). The majority of researchers recommend considering the more aggressive component of MANEC (19), although few studies indicate that MANEC with a well-differentiated neuroendocrine component (grade 1 or 2) should be treated as an adenocarcinoma, whereas MANECs with grade 3 NEC should be treated as an NEC (4,20). Treating according to the more aggressive component of the tumor appears to be reasonable considering the fact that the aggressiveness of the neuroendocrine component of MANEC is based on the mitotic index and the Ki-67 proliferation index (3). As a result, although the latest WHO report suggests that these tumors be treated as adenocarcinomas, the latest evidence indicates that the treatment should be based on the most aggressive histologic component (4,5,11). In our case series, the NEC was the dominant component in 60% of patients. The NEC was grade 1 in three patients, grade 2 in one patient, grades 2-3 in one patient, and grade 3 in five patients. Among the 10 patients, the adenocarcinoma component was low-differentiated in only one patient. None of our patients had received neoadjuvant therapy, and curative surgery had been performed in all patients, with tumorfree margins in 100%. MANECs are rare tumors, and the majority of cases have been diagnosed with distant metastases in the literature (12). Conversely, only one of our patients with a sigmoid colon tumor had liver metastasis. In the literature, periampullary MANECs have been suggested to be treated surgically like other periampullary tumors, with pancreaticoduodenectomy being performed whenever possible (10). In our patient with the MANEC in the ampulla of Vater, a successful pancreaticoduodenectomy had been performed, and distal pancreatectomy had been performed in another patient with pancreatic MANEC.
MANECs have been reported to be diagnosed at advanced stages according to the published studies; similarly, eight of our patients were diagnosed with T3 and T4 tumors. The lowest survival rate was determined in a 73-year-old patient with an ampullary MANEC, whereas the longest overall survival was 51 months in the patient with the gastric tumor. A limitation of our study may be the potential bias due to the fact that the study was conducted in a tertiary center designed for advanced gastrointestinal cancer surgery.
Despite the limited number of patients, this study is the most extended case series involving the Turkish population. MANECs are rare tumors diagnosed postoperatively using immunohistochemical evaluation. Although the presentation and surgical management are similar to that of pure adenocarcinomas or NECs, patients must undergo postoperative multidisciplinary oncologic and surgical management as soon as the tumor is diagnosed. Additional studies with more extended number of cases are required for determining the optimal treatment management and classification of these tumors.
Conflict of Interest: No conflict of interest was declared by the authors.
Financial Disclosure: No financial disclosure was declared by the authors.
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Yigit Duzkoylu (1), Orhan Aras (1), Erdal Birol Bostanci (1), Tulay Keklik Temucin (2), Murat Ulas (1)
(1) Clinic of Gastroenterological Surgery, Turkiye Yuksek Ihtisas Training and Research Hospital, Ankara, Turkey
(2) Clinic of Pathology, Turkiye Yuksek Ihtisas Training and Research Hospital, Ankara, Turkey
Address for Correspondence: Dr. Yigit Duzkoylu, Clinic of Gastroenterological Surgery, Turkiye Yuksek Ihtisas Training and Research Hospital, Ankara, Turkey
Phone: +90 533 261 25 33
ORCID ID: orcid.org/0000-0001-6894-6896
Received: 31 October 2017
Accepted: 15December 2017
TABLE 1. Demographics and tumor characteristics of participants Case 1 Case 2 Case 3 Age 67 72 68 Gender Male Male Male Tumor location Rectum Distal pancreas Gastric cardia Tumor size 8 cm 6*4 cm 3.5*2 cm Resection margins Clear Clear Clear Distant liver metastasis No No No Lymph nodes (resected to 37 to 0 1 to 0 11 to 0 positive) Curative resection Yes Yes Yes Tumor stage T4N0M0 T3N0M0 T3N1M0 Dominant component Adenocarcinoma Adenocarcinoma Adenocarcinoma Adenocarcinoma tumor Medium Medium Well differentiation Neuroendocrine tumor grade G3 Gl G2 Immunochemistry CgA+, Syn+ CgA-, Syn+ CgA+, Syn+ Mitotic count 35 2 18 Ki-67 index 50% 2% 4.6% Perineural invasion No No No Lymphovascular invasion No No No Treatment (Surgery alone/ S S+ChT S S+ChT) Outcome (months): Alive (A), dead (D) A (20 month) A (31 month) D (10 month) Case 4 Case 5 Case 6 Age 59 72 73 Gender Male Male Male Tumor location Gastric antrum Gastric antrum Ampulla vater Tumor size 3.5 cm 5 cm 1*1 cm Resection margins Clear Clear Clear Distant liver metastasis No No No Lymph nodes (resected to 0/9 61 to 47 6 to 1 positive) Curative resection Yes Yes Yes Tumor stage T3N0M0 T3N3M0 T3N1M0 Dominant Neuroendocrine Neuroendocrine Neuroendocrine component tumor tumor tumor Adenocarcinoma tumor Medium Well Well differentiation Neuroendocrine tumor grade G3 G3 G3 Immunochemistry CgA+, Syn+ CgA+, Syn+ CgA-, Syn+ Mitotic count 30 23 10_75 Ki-67 index 40% 55% 0.5-1% Perineural invasion No No No Lymphovascular invasion Yes Yes Yes Treatment (Surgery alone/ S S+ChT S+ChT S+ChT) Outcome (months): Alive (A), dead (D) D (22 month) A (10 month) D (3 month) Case 7 Case 8 Case 9 Age 65 52 71 Gender Male Male Male Tumor location Gastric cardia Sigmoid colon Ductus choledochus Tumor size 2*1.5 cm 3.5 cm 0.5 cm Resection margins Clear Clear Clear Distant liver metastasis No Yes No Lymph nodes (resected to 20 to 0 6 to 4 1 to 0 positive) Curative resection Yes Yes Yes Tumor stage T1bNOMO T3N2aMl T2N0M0 Dominant Neuroendocrine Neuroendocrine component Adenocarcinoma tumor tumor Adenocarcinoma tumor Well Low Well differentiation Neuroendocrine tumor grade Gl G3 Gl Immunochemistry CgA+, Syn- CgA-, Syn+ CgA+, Syn+ Mitotic count 2 60 1 Ki-67 index 1% 70% 1-2% Perineural invasion No Yes Yes Lymphovascular invasion No Yes Yes Treatment (Surgery alone/ S S+ChT S S+ChT) Outcome (months): Alive (A), dead (D) A (51 month) D (5 month) A (26 month) Case 10 Age 48 Gender Female Tumor location Gastric corpus Tumor size 7*5 cm Resection margins Clear Distant liver metastasis No Lymph nodes (resected to 20 to 7 positive) Curative resection Yes Tumor stage T3N2M0 Dominant Neuroendocrine component tumor Adenocarcinoma tumor Well differentiation Neuroendocrine tumor grade G2-3 Immunochemistry CgA+, Syn+ Mitotic count 5 Ki-67 index 8% Perineural invasion No Lymphovascular invasion No Treatment (Surgery alone/ S+ChT S+ChT) Outcome (months): Alive (A), dead (D) A (3 month) CgA: chromogranin A; S+ChT: surgery chemotherapy; Syn: synaptophysin; TNM: tumor/node/metastasis
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|Title Annotation:||Brief Report|
|Author:||Duzkoylu, Yigit; Aras, Orhan; Bostanci, Erdal Birol; Temucin, Tulay Keklik; Ulas, Murat|
|Publication:||Balkan Medical Journal|
|Date:||Jun 1, 2018|
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