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ABSTRACT Mixed adenoneuro endocrine carcinoma (MANEC) is a rare and relatively newer entity and classified into a separate category by the WHO 2010 Classification of Tumors. Accordingly, due to its rarity of diagnosis, further oncologic management is a challenge. They contain an adenocarcinoma part and a neuroendocrine part and are further classified based on grades. We present case series with a histological diagnosis of MANEC, its management, and clinical behavior in the follow-up period. Optimum mode of the management of these tumors is yet to be proposed, as these groups of tumors are highly aggressive and associated with poor prognosis. he  World  Health  Organization  (WHO)  in  the  year  2010  defined mixed adenoneuroendocrine carcinoma (MANEC) as  neoplasms  involving  both  the  neuroendocrine  and  the  epithelial  components.  The  diagnostic  criteria  of  MANEC  are  as  follows:  Both  the  components  must  be  malignant  and  each  component  has  to  comprise  at  least  30%  of  the  tumor  [1].  Cordier  in  the  year  1924  published  the  first  report  on  a  mixed  exocrine  and  a  neuroendocrine  tumor  (NET)  [2].  Since  then,  few  developments  have  been  made  in  this  field.  Composite  carcinoid,   argentaffin   cell   adenocarcinoma,   mucin-producing   carcinoid,  goblet  cell  carcinoid,  adenocarcinoid,  and  small  cell  undifferentiated carcinoma were some of the terminologies used earlier to describe this entity. The classification of these tumors was suggested in 1987 by Lewin as collision, combined, and amphicrine tumors [3]. In the year 2000, the WHO classified these endocrine tumors as mixed exocrine-endocrine  tumors  when  each  component  represents  at  least  30%  of  the  lesion  [4].  Finally,  in  2010,  the  WHO  classification named these tumors as MANECs [5].It is important to note that, according to this nomenclature, if a particular component does not form 30% of the lesions, it cannot be categorized as a mixed tumor but rather an adenoma or NETs separately. This entity has been subdivided into different categories based on the degree of differentiation of each component: High-grade  malignant  type  and  intermediate-grade  malignant  type,  (intermediate  type  also  includes  amphicrine  carcinoma)  [6].  We  present case series with a histological diagnosis of MANEC and its management. CASE REPORTSCase 1A  58-year-old  gentleman  presented  a  history  of  pain  abdomen  (dull aching) and intermittent bleeding per rectum for 4 months. On  clinical  examination,  vital  signs  were  stable  with  a  pulse  rate of 76/min and blood pressure of 126/84 mmHg. Pallor was present  with  no  significant  findings  on  per  abdomen  and  rectal  examination.  Except  for  anemia  with  hemoglobin  of  8  g/dL,  all  other  blood  investigations  were  normal.  Colonoscopy  revealed  a  nodular  thick  friable  growth  causing  narrowing  of  the  colonic  lumen (ascending colon). The biopsy showed features of a poorly differentiated  carcinoma,  while  neuroendocrine  differentiation  could  not  be  excluded.  Serum  carcinoembryonic  antigen  levels  were  7.19  ng/dL  (normal  value  <5  ng/dL).  Contrast-enhanced  computed   tomography   (CECT)   of   the   abdomen   and   pelvis   revealed  circumferential  enhancing  thickening  of  the  proximal  ascending  colon  for  a  length  of  5  cm  with  significant  luminal  obstruction, with no evidence of distant metastases.The patient was transfused with two units of packed red blood cells. He then underwent a right radical hemicolectomy (Fig. 1). The  final  histopathology  report  showed  MANEC  extending  microscopically  into  the  serosa  with  a  pathological  staging  of  pT3 N1a Mx. The neoplastic cells were positive to cytokeratin 20 (CK20), caudal type homeobox 2 (CDX2), and synaptophysin and were  negative  for  chromogranin.  Occasional  cells  were  positive  for  CD56  with  Ki  proliferative  index  of  60–70%.  The  patient   was on adjuvant treatment with irinotecan and capecitabine. Response assessment was done after 4 cycles with positron emission tomography-CT (PET-CT) scan which showed multiple periportal, retroperitoneal, and mesenteric and mediastinal lymph nodes. In view of progressive disease, the regimen was changed to capecitabine and oxaliplatin. Disease remained stable after 3 cycles. Hence, three more cycles of capecitabine and oxaliplatin were planned. At present, the patient is on the same regimen. Case 2A 60-year-old female presented with a history of gradually increasing jaundice for 3 months associated with nausea and vomiting. On clinical examination, icterus was present with palpable gallbladder on abdomen examination. No clinical signs of cholangitis were present. No other significant findings were noted. Biochemical tests revealed a conjugated hyperbilirubinemia with serum bilirubin levels of 11 mg/dL and direct bilirubin of 8.6 mg/dL. Serum gamma-glutamyl transpeptidase and serum alkaline phosphatase levels were 72 IU/L (normal value 0–35 IU/L) and 67 IU/L (normal value 0–35 IU/L), respectively, and a serum albumin of 3.6 g/dL with other liver function test parameters within normal limits. Subsequent CECT scan revealed a dilated common bile duct (C with abrupt narrowing of distal bile duct with an ill-defined enhancing mass lesion proximal to the pancreaticobiliary junction causing dilatation of the intrahepatic biliary radicles and pancreatic duct likely a neoplastic stricture). Endoscopic retrograde cholangio pancreatography (ERCP) was done and brush cytology revealed atypical cells suspicious of malignancy.She underwent a Whipple’s pancreaticoduodenectomy and the histopathology was reported as MANEC of intermediate grade with tumor extension into the pancreas and pathologic stage of pT3b N0 Mx. A ×10 view of hematoxylin and eosin stained tissue demonstrating the neuroendocrine and adenocarcinoma component of tumor is shown in Fig. 2. Immunohistochemistry report shows positivity for CK7, synaptophysin, chromogranin, and CD56. The Ki proliferative index was 8–10% (Fig. 3). The patient is presently on adjuvant chemotherapy (cisplatin and etoposide) without any evidence of recurrence after 4 cycles of chemotherapy. Case 3A 56-year-old gentleman presented with a complaint of jaundice of 1 month duration with loss of appetite for 15 days. On clinical examination, icterus was present with palpable gallbladder on abdomen examination. No other significant findings were noted. Biochemical tests revealed a conjugated hyperbilirubinemia with serum bilirubin levels of 8 mg/dL and direct bilirubin of 6.7 mg/dL. Other blood tests and liver function test values were within normal limits. A CECT scan revealed a dilated common bile duct with abrupt narrowing of distal bile duct with an ill-defined enhancing mass in the distal bile duct causing dilatation of the intrahepatic biliary radicles, likely a neoplastic etiology ERCP was done and biopsy revealed atypical cells suspicious of malignancy.He underwent Whipple’s pancreaticoduodenectomy, and the final histopathology report was suggestive of MANEC with predominant adenocarcinoma component and pathologic stage of pT3b N0 Mx. The patient received 3 cycles of adjuvant gemcitabine-based chemotherapy. As he could not tolerate the treatment, further chemotherapy was not given and lost to follow up. DISCUSSIONIn the era of personalized medicine, diagnostic modality we choose and treatment decisions we make have a huge impact on prognosis. When such is the scenario, making the best use of available modern diagnostic tools and tailored therapy does influence the survival. In gastrointestinal malignancies, particularly MANEC, the neuroendocrine component does influence the biology of a tumor based on available case studies. Diagnosis of this entity is made by the use of immunohistochemistry. No particular locus is identified yet, to make use of targeted therapy, unlike in adenocarcinoma. No large studies available yet to understand the exact nature of this entity. MANEC has been described in various sites such as stomach, colon [7], pancreas [8], esophagus [9], appendix [10], rectum [11], and cervix [12]. Irrespective of a site of the tumor, prognosis and treatment have remained the same.MANEC tumors are fluorodeoxyglucose avid, and gallium DOTANOC PET/CT has a role in staging and assessing the recurrence or progression [9]. While planning the management, the aggressiveness of this disease needs to be taken into account. For instance, MANEC of appendix needs to be treated with aggressive multimodality treatment with right hemicolectomy and adjuvant treatment rather than appendectomy alone [13]. Adjuvant chemotherapy regimen depends on higher grade and component of tumor (adeno or neuroendocrine). MANECs with a well-differentiated NET component and adenocarcinoma component can be treated as adenocarcinoma and a poorly differentiated NEC component can be treated as NECs [6].Patta reported a high response rate to cisplatin and etoposide in patients with high-grade neuroendocrine colorectal tumors [14]. The National Comprehensive Cancer Network recommends cisplatin or carboplatin and etoposide (based on protocols for small cell lung carcinoma) [15]. In our series, treatment was based on higher component and more aggressive component. Other protocols are based on cetuximab, FOLFOX, and octreotide or bevacizumab and FOLFOX6. In the case of hepatic metastases, transarterial chemoembolization with doxorubicin has been reported [16]. Other agents such as mitomycin C or streptozocin have been used with different success rates. The role of new drugs such as everolimus or sunitinib needs to be defined. Radiotherapy could be considered in patients at high risk of local recurrence.Research studies are required to understand the biology of the tumour, to predict the natural history of this entity. Cases reported in our series belong to elderly age group. The interval between detection of a primary tumor and metastases has been 2.5 months