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REVIEW
Year : 2019  |  Volume : 5  |  Issue : 2  |  Page : 33-36

Progress in diagnosis and treatment of mixed adenoneuroendocrine carcinoma of biliary-pancreatic system


1 Department of Clinical Medicine, Second Clinical Medical College, Southern Medical University, Guangzhou 510282, China
2 Department of Medical Imaging, Third Clinical Medical College, Guangdong Medical University, Zhanjiang 524023, China
3 Department of Medical Imaging, First Clinical Medical College, Southern Medical University, Guangzhou 510510, China
4 Department of Nursing, School of Nursing, Hubei Polytechnic Institute, Xiaogan 432100, China
5 Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China

Date of Submission22-Feb-2019
Date of Acceptance24-Apr-2019
Date of Web Publication28-Jun-2019

Correspondence Address:
Prof. Li Zhou
Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ctm.ctm_5_19

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  Abstract 


With the application of many kinds of advanced examination techniques, the detectable rate of mixed adenoneuroendocrine carcinoma (MANEC) of the biliary-pancreatic system has increased substantially. This kind of tumor with high degree of malignancy is rarely seen. Thus, the clinical studies are difficult to carry out, most of which are just case reports. Besides, its treatments do not work effectively, albeit the diagnosis and management have changed tremendously. To deepen the understanding of MANEC of biliary-pancreatic system, this article is an overview making a generalization and summarization of the related literature as well as reviewing the main diagnosis and therapies of these rare tumors. In addition, it lays the foundation for clinical diagnosis and treatment in the future.

Keywords: Biliary-pancreatic system, mixed adenoneuroendocrine carcinoma, mixed adenoneuroendocrine carcinoma diagnosis treatment


How to cite this article:
Zengzheng G, Ling HS, Li MF, Xiaoyan X, Kai Y, Tongzhen X, Zengyu G, Zhou L. Progress in diagnosis and treatment of mixed adenoneuroendocrine carcinoma of biliary-pancreatic system. Cancer Transl Med 2019;5:33-6

How to cite this URL:
Zengzheng G, Ling HS, Li MF, Xiaoyan X, Kai Y, Tongzhen X, Zengyu G, Zhou L. Progress in diagnosis and treatment of mixed adenoneuroendocrine carcinoma of biliary-pancreatic system. Cancer Transl Med [serial online] 2019 [cited 2019 Sep 20];5:33-6. Available from: http://www.cancertm.com/text.asp?2019/5/2/33/261828




  Introduction Top


According to the consensus published by the WHO in 2010, neuroendocrine neoplasm (NEN) of the digestive system is divided into five types: G1 NEN, G2 NEN, small cell NEN, large cell NEN, and mixed adenoneuroendocrine carcinoma (MANEC).[1] This is the first time that the concept of MANEC has emerged. It is a special type of tumor with a mixture of adenocarcinoma and neuroendocrine carcinoma, and both cancer cells account for >30%.[1] Other studies have found that these two components are monoclonal origin.[2] The pathogenesis of MANEC remains unclear. It may be due to the influence of some hormone microenvironment and gene stability on the differentiation of endodermal pluripotent stem cells that the tumor cells show double differentiation.[3] This is a rare type of tumor, which can occur in the stomach, gallbladder, bile duct, pancreas, colon, etc., The diagnosis and treatment methods of them are different, and there is no unified diagnosis and treatment standard.


  Diagnosis And Examination Top


MANEC of the biliopancreatic system grows slowly with atypical symptoms, and most patients seek treatment for abdominal pain or jaundice first. In the early stage of tumor physical examination, there was no obvious abnormality. Abdominal masses could often be touched in the middle and late stages. At this time, the tumor has a metastasis of lymph nodes and organs, causing symptoms of compression, and inducing complications such as gallbladder perforation and acute pancreatitis. Second, certain symptoms causing by the neuroendocrine components of the tumor should be highly vigilant. For example, the high level of glucagon in the plasma of patients with glucagon tumor can cause wandering necrotizing erythema, impaired glucose tolerance, and weight loss.[4] Early detection and treatment can significantly improve the prognosis, prolong life, and improve the quality of life. Therefore, it is essential to make timely diagnosis by the comprehensive use of laboratory examination, endoscopy, imaging examination, and other methods.

Blood tests

In addition to tumor markers that must be detected, some MANEC may show changes in other specific hematological indicators. Studies have shown that some neuroendocrine components secrete and release a variety of substances into the blood, such as glucagon tumor can secrete glucagon. Some hormone peptides, such as somatostatin and vasoactive intestinal peptide, can also be expressed in MANEC.[5] In addition, if tumor presses or blocks the biliary tract to cause obstruction of the biliary tract, total bilirubin and transaminase levels can rise. Blood test has low specificity and is generally used for auxiliary diagnosis or efficacy evaluation.

Endoscopic examination

Endoscopic retrograde cholangiopancreatography (ERCP) can be used for the examination of MANEC and other tumors in the biliary tract when they invade the hepatic hilum or extrahepatic bile duct and can also be used for the placement of endoscopic stent drainage before biliary tract surgery.[6]

Imaging examination

Ultrasonography is one of the preferred methods for the detection of tumors of the biliopancreatic system, which can clearly show the growth and occupation of tumors, also guide the biopsy of puncture tumors,[7] and extract bile for cytological examination.[6] In contrast, computed tomography (CT) and magnetic resonance imaging are more widely used in the diagnosis of MANEC, especially pancreatic MANEC.[8] A Beijing hospital has analyzed the imaging data of 99 patients with insulinoma and found that pancreatic perfusion CT has higher sensitivity and specificity for the diagnosis of insulinoma compared with conventional imaging detection.[9]

In addition, magnetic resonance cholangiopancreatography can be used to evaluate biliary obstruction and provide countermeasures for alleviating symptoms.[10] Somatostatin receptor imaging can localize and diagnose MANEC. Positron emission tomography (PET) can help detect tumor metastasis. A recent study has found that the images of PET obtained by (68)Ga-DOTATATE and (68) Ga-DOTANOC have comparable diagnostic accuracy, and (68) Ga-DOTATATE seems to have a higher lesion uptake.[11]

Pathological examination and immunohistochemistry

The gold standard for the diagnosis of biliopancreatic MANEC is pathological examination. Microscopically, the tumor tissue was composed of two cellular components, adenocarcinoma and neuroendocrine carcinoma, with obvious cell atypia. The growth of the two interspersed, each of which accounts for >30%.[12] Pathological examination can determine whether the tumor has invasion and metastasis and can guide the tumor-node-metastasis staging, providing a direction for the treatment of MANEC.

Immunohistochemical analysis can assist in the diagnosis. A recent has found that synaptophysin and chromogranin A were essential immunohistochemical markers for NEN detection, accompanied by CD56 detection if necessary.[13] Other commonly used indicators include neuron-specific enolase, ck8/18, and neuron-specific protein PGP9.5. Some immune markers which are related to pancreatic trypsin, such as protease and antichymotrypsin, can also assist in diagnosis, but their specificities are not high.


  Treatment Top


The treatment of biliopancreatic MANEC includes surgical treatment, chemotherapy, radiotherapy, and other adjuvant therapies. Surgical resection is still the main treatment method for MANEC of the biliopancreatic system. The principle is to achieve radical resection and completely remove the primary lesion as well as the blood vessels and organs invaded by the tumor. Other treatments include chemotherapy and radiotherapy, hormone therapy, peptide receptor radionuclide therapy, targeted therapy, and immunotherapy. In general, MANEC therapy is not unsupported by unilateral efforts but is based on the multidisciplinary team. At present, there are not many reports on MANEC of the biliopancreatic system at home and abroad, and there is no treatment standard for MANEC of biliopancreatic system. To provide reference for clinicians treating method, the author after reading vast amount of literature, the authors refers to the American Joint Committee on Cancer staging system and the National Comprehensive Cancer Network tumor guide (2017 edition), then sums up the common treatment of the gallbladder, biliary and pancreatic MANEC method, and progress. These are described below.

The mixed adenoneuroendocrine carcinoma of gallbladder

The gallbladder tumor usually refers to the gallbladder itself (and does not include the common bile duct and other bile duct system) by the tumor. MANEC rarely occurs in the gallbladder, and most gallbladder MANEC cases have been reported from Asia, North America, and Europe.

For patients with Stage 0 and I, surgery is the most active and effective method for the treatment of gallbladder tumors at present, and it is emphasized that complete tumors with negative margins should be removed as far as possible;[6] postoperative chemotherapy of gemcitabine + platinum-based drugs was suggested, and interventional therapy was feasible for some cases of biliary tract obstruction. Radiotherapy is generally not recommended.[14]

Stage II patients underwent multiple radical cholecystectomy, including liver tissue adjacent to the gallbladder bed (liver resection margin 2–3 cm above the gallbladder) and regional lymph nodes; For those tumors growing on the bedside of the gallbladder bed, hepatic segment IVb, V and/or partial hepatoduodenectomy may be performed if necessary. Chemotherapy is the same as stage 0 and stage I patients. Radiotherapy may be used if local metastasis occurs after operation.

The combination of cisplatin, etoposide, and octreotide is recommended for chemotherapy for patients at Stage IIIA;[16] platinum-based irradiation is feasible for patients receiving radiotherapy.[17]

Stage IIIB and IV patients have the worst prognosis. Surgical treatment is complicated; lymph nodes and organs (including blood vessels) that have metastasis should be removed as completely as possible to ensure negative resection margin, and the surrounding lymph nodes should be cleared. If necessary, the scope of resection may be expanded according to the actual situation; targeted drug therapy is preferred for chemotherapy, such as cetuximab, erlotinib, and combined with gemcitabine and oxaliplatin; if postoperative tumor recurrence is accompanied by local liver metastasis and regional lymph node metastasis, radiotherapy is feasible.[6]

The mixed adenoneuroendocrine carcinoma of bile duct

MANEC occurred in distal bile duct, especially in the ampullary region, predominated in the bile duct system. Therefore, the following treatment is mainly for the ampullary MANEC.

For patients with Stage 0 and I, it is effective to do the resection of the involved bile duct or extrahepatic cholangiostomy, while the chemoradiotherapy is not recommended;[18] if chemotherapy is required, oxaliplatin or folic acid calcium may be selected for the patients.

Stage II patients need to resect extrahepatic bile duct,[19] and the pancreaticoduodenectomy and regional lymph node dissection, followed by hepaticojejunostomy, will be performed in severe cases;[20] adjuvant concurrent radiotherapy based on 5-fluorouracil (5-FU) is recommended. For patients with regional lymph node positive, adjuvant concurrent radiotherapy based on FU chemotherapy will be performed, followed by additional FU or gemcitabine chemotherapy, or chemotherapy combined with oxaliplatin and gemcitabine.[21]

For Stage III and IV patients, pancreaticoduodenectomy is required;[19],[22] in case of metastasis of other organs, combined visceral resection should be performed. In patients with unresectable metastatic lesions, consideration should be given to gastric jejunostomy or yellow-reduction bypass-surgery or ERCP or percutaneous transhepatic cholangial drainage (PTCD). Postoperative chemotherapy consists of gemcitabine and platinum-based drugs;[22] gemcitabine monotherapy was effective in patients with unresectable tumors. When 5-FU is used for radiotherapy, chemotherapy can be performed at the same time, which has a certain curative effect. Concurrent chemoradiotherapy with capecitabine is also available.

The mixed adenoneuroendocrine carcinoma of pancreas

Pancreatic MANEC is a tumor with extremely high malignancy, poor efficacy of surgical treatment, radiotherapy, and chemotherapy, and difficult to diagnose. It progresses rapidly and has a poor prognosis. It occurs mostly in the head of the pancreas, and the most important clinical manifestation is space occupying. The most ideal treatment is performing radical surgery, such as pancreaticoduodenectomy for the head of the pancreas and distal pancreatectomy for tumors of the neck and tail of the pancreas. The treatment principle is to completely remove the primary lesion, including the infiltrating organs and metastases. For Stage I patients, total pancreatectomy and regional lymph node dissection should be recommended;[23] for Stage II patients, pancreaticoduodenectomy and peripheral lymph node dissection should be performed;[24] for Stage III and IV patients, extended radical resection, namely pancreaticoduodenectomy plus extensive regional lymph node dissection, is generally accepted,[25] which can be combined with vascular clearance to improve the R0 resection rate.

For Stage I patients, the effect of oral tegafur adjuvant chemotherapy was significant, while the effect of radiotherapy is of uncertainty, so it was not recommended. For Stage II patients, gemcitabine combined with capecitabine showed a significant effect, and capecitabine synchronous radiotherapy also had a positive effect. For Stage III and IV patients, studies have shown that the use of erlotinib combined with gemcitabine chemotherapy can delay local progression and improve the prognosis of patients with metastasis to a certain extent.[26] Meanwhile, 5-FU combined with gemcitabine during concurrent radiotherapy has a significant effect.

Except for the application of conventional antitumor drugs, targeted drugs targeting tumor cell surface receptors are also gradually being used in clinical practice. Some studies have found the presence of somatostatin receptors (SSTRs) in most gastrointestinal and pancreatic neuroendocrine tumors, especially somatostatin type 2 receptors (SSTR2), and positive SSTR2 expression helps determine whether patients can receive treatment with somatostatin analogs such as octreotide.[27] Immunotherapy has also made progress in the treatment of pancreatic cancer, and some immunosuppressants such as CTLA4 and CD40 antibodies have been gradually applied in clinical trials. Whether it can also be used for the treatment of pancreatic MANEC in the future remains to be further studied.


  Prognosis Top


At present, the prognosis of MANEC in the biliary-pancreatic system is still uncertain, and it is generally considered that the prognosis of MANEC is poor. Some scholars believe that the prognosis of MANEC depends on the composition of adenocarcinoma, but its accuracy needs to be studied.[28] Some scholars believe that the prognosis should be combined with many factors, such as Ki-67 index, coagulation status, and basic physical condition of patients.[29] A recent study indicates that the therapeutic effect of MANEC is closely related to the main invasive components in tumors.[30] However, early detection and treatment is the fundamental way to improve the prognosis and quality of life of patients. In addition, preoperative assessment of the patient's condition, such as distant metastasis of the tumor, plays a very important role in the prognosis. Postoperative psychological counseling should be actively carried out to maintain a good state of mind, which is conducive to recovery.


  Expectation Top


MANEC of the biliary-pancreatic system is a rare malignant tumor, lacking specific clinical manifestations. How to diagnose MANEC of the biliary-pancreatic system according to clinical manifestations and feasible detection methods is a major problem we need to solve. It is imperative to standardize the treatment methods because of the diversity of treatment methods and uneven treatment levels. Future research should explore the innovation of diagnosis and detection technology on the one hand and find more efficient and less invasive individual precise treatment methods, such as immunotherapy and targeted therapy, to improve the prognosis of patients and even achieve cure.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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