Key words neuroendocrine carcinoma; liver tumors
Liver primary neuroendocrine carcinoma is extremely rare in clinical practice, we met one cases, this report is as follows and review of the literature, combined with the clinical characteristics of the disease, differential diagnosis, treatment, and prognosis of a discussion.
1 Clinical data
Patients, female, 39 years old, because of the left hepatic primary neuroendocrine carcinoma resection 1 June, liver, abdominal lymph nodes, the descending duodenum transfer April 1, the left kidney area transferred to me more than a half hospital. The patient inadvertently discovered in August 2005 left upper abdomen about 5cm × 4cm mass, were not seriously. Progressive increases after mass, to a local hospital in February 2006 investigation abdominal CT showed: the uneven left hepatic lobe bulky mass, size 15.5cm x 10.0cm central liquefaction necrosis surrounding tissue compression, displacement, see Figure 1, March 2006, patients at a local hospital hepatic left lateral lobectomy “Pathological diagnosis was:" bulky outer leaves of the left hepatic adenocarcinoma. Biopsy consultation by the General Hospital of the Nanjing Military Region shows: left hepatic differentiated neuroendocrine carcinoma; immunohistochemistry: Syn (+ + +), of CgA part of the (+), CKpan (+ + +). The diagnosis of primary hepatic neuroendocrine carcinoma. After surgery in the hospital line fluorouracil + cisplatin + mitomycin chemotherapy cycle. May 2006 review of abdominal CT showed: the right lobe of the liver have a size of about 2.1cm × 2.0cm low density nodules, abdominal lymph nodes, the descending duodenum infringement may. Consider the the the postoperative liver, abdominal lymph nodes, and descending duodenum transfer. At a local hospital interferon 3000000 u 2 times / week, subcutaneous injection, once every 2 months the parallel right lobe of the liver lesions focused ultrasound treatment. Intermittent application the Thymopentin javanica oil emulsion treatment in October 2006. March 2007 to April line Xeloda + docetaxel + oxaliplatin combined with systemic thermo-chemotherapy treatment cycle, Evaluation stable. Local review of CT in August 2007 shows: see more than one class round low density in the right lobe of the liver, the maximum diameter of about 5.4cm; duodenal wall thickening, seemed on the occupying signs of soft tissue; left kidney region see group shaped soft tissue density, peripheral unclear, as shown in Figure 2. Due to the progress of the disease, in September 2007 to my office for treatment. Treatment when patients generally fair, non-clinical special symptoms, diet, sleep, and urine were normal. Examination: general superficial lymph nodes were not palpable enlargement. Upper abdomen shows a length of about 20cm vertical surgical scar, liver and spleen ribs, whole abdominal tenderness and rebound tenderness. Auxiliary examination: hepatitis B surface antigen negative, hepatitis C virus markers negative, AFP, CEA, CA19-9 and other tumor markers were within normal range. Our application of traditional Chinese medicine the treatment (Bazhen Tonga taste blood circulation, Endometriosis TCD) in patients with 2 more than a month, in November 2007 review of CT showed: liver multiple placeholder with former Similar left kidney area and duodenum area accounted for bit over the previous narrow, as shown in Figure 3. Review so far has been in the Chinese medicine decoction Treating stable condition, good general condition of patients, without any symptoms and signs, and a good quality of life. The repeat CT liver multiple placeholder in March 2008, left kidney area and over the front panel (in November 2007) is basically similar footprint duodenum. Liver and kidney function and tumor markers AFP, CEA, CA19-9 were normal, as shown in Figure 4.
Widely scattered outside classical endocrine glands of the body, the lungs, gastrointestinal tract, such as the distribution of many endocrine role of cells, these cells have the ability to intake amine precursor and decarboxylation, and with many common forms of nerve cells science, biology, and features, it is called neuroendocrine cells . Cell origin of these neuroendocrine tumor neuroendocrine tumor (Neuroendocrine tumor). Neuroendocrine tumors are generally divided into two categories: carcinoid and neuroendocrine cancer. Carcinoid prognosis is relatively good, the size of the tumor cells are more consistent, no atypia; neuroendocrine carcinoma was highly malignant, increased mitotic activity, nuclear pleomorphism . Neuroendocrine tumors occur in the gastrointestinal tract, pancreas, bronchial and other parts, and occasionally in the prostate, ovarian, breast, gallbladder, urinary tract, etc., the primary neuroendocrine tumors of the liver is extremely rare. Most of the liver neuroendocrine tumors reported in the literature for hepatic carcinoid, hepatic neuroendocrine cancer reported rarely. According to my statistics, from 1994 to 2007, domestic only reported 24 cases of liver primary neuroendocrine carcinoma in patients aged 15 to 84 years, with an average age of 47.5 years, women slightly more than men, 1.2:1, incidence and foreign similar to that reported . Since the hepatic neuroendocrine cancer incidence rate is low, the lack of typical clinical symptoms, easily missed, misdiagnosed, and the high degree of malignancy, more than in the early stage of intrahepatic metastasis or regional lymph node metastasis, and therefore a poor prognosis, early diagnosis, treatment, help to extend The survival of patients.
2.1 the traditional view of the characteristics of the disease, hepatic neuroendocrine carcinoma originated in ectopic pancreatic tissue or intrahepatic adrenergic organization. However, studies have shown that the greater the possibility of the formation of the disease from neuroendocrine cells of the intrahepatic bile duct proliferation . Often in the right lobe of the liver neuroendocrine cancer, may be in the form of single or multiple lesions, often without cirrhosis in the liver tissue. Non-specific clinical symptoms, early small tumors can be free of any signs and symptoms when the tumor grows to a certain extent, in the right upper quadrant palpable mass, or abdominal discomfort, loss of appetite, fatigue, bloating, weight loss and other symptoms . The vast majority of cases do not appear abnormal neuroendocrine product number of clinical manifestations, may be related to the insufficient number of neuroendocrine product or quality defects can not activate the target organ and play a biological role . Histological features, the cancer is small, polygonal shape or cube, arranged in a glandular or flake, nested, increased mitotic activity, nuclear pleomorphism, accompanied by bleeding and necrosis. Electron microscope, with special neuroendocrine granules in the cytoplasm, the particles round or oval, the membrane surrounding sizes . Immunohistochemical markers CgA (chromogranin A) and Syn (synaptophysin) is highly specific neuroendocrine markers, the positive expression of the exact basis of the diagnosis of the disease. Imaging studies lack of specificity of the diagnosis of the disease, CT showed mostly uneven low-density mass in the liver, often within the necrotic liquefaction zone, the extensive tumor hemorrhage and necrosis, the formation of huge solid and cystic mass; dynamic enhanced scan early tumor as inhomogeneous enhancement, advanced tumors gradually into such as density and low-density .
The 2.2 differential diagnosis of the disease to be associated with primary liver cancer, liver hemangioma differentiated. Primary liver cancer more than a history of hepatitis and cirrhosis of the liver, often accompanied by splenomegaly and portal vein widened, elevated alpha-fetoprotein (AFP); histopathology showed mostly beam-like arrangement of sinusoids lack interstitial. With primary liver cancer, hepatic neuroendocrine carcinoma is rarely associated with a history of hepatitis and cirrhosis, alpha-fetoprotein nor specifically elevated, histopathological and immunohistochemical examination can help identify. Hepatic hemangioma mostly single, can occur in the liver in various parts of the CT scan showed low density placeholder, of intratumoral little liquefaction necrosis area, seen early enhanced low-density area was peripheral enhancement, and gradually increasing extends to the central delay of contrast agent dispersion showed concentric initially enhance the density of the part at the same time gradually decreases, and the lesion partially or completely changed was high density. The specificity of MRI, the diagnosis of hepatic hemangioma showed homogeneous low signal on T1-weighted images, and a clear edge; conventional T2-weighted images showed a characteristic “light bulb" sign-like high signal . Hepatic neuroendocrine carcinoma occurred in the right lobe of the liver, CT showed low density lesions, central necrosis cystic substantial part of the continued strengthening enhanced central necrosis bleeding area no enhancement, but ultimately needed with the pathology and immunohistochemistry of checking identification.
2.3 Treatment (1) surgery: The disease is mainly the treatment of liver resection. Even if the tumor has been transferred, it should be possible with surgery to remove the primary tumor, metastases, and lymph node dissection, in order to reduce the tumor burden and improve the survival rate of patients. (2) the hepatic arterial chemoembolization (TACE): unresectable hepatic neuroendocrine carcinoma, TACE have a certain effect. Chemotherapy drug commonly used cis-platinum, mitomycin, doxorubicin, fluorouracil, etc.. 1 interval of 4 to 6 weeks, repeated many times better . (3) radiation therapy: hepatic neuroendocrine cancer radiation therapy is not sensitive, but have a certain effect for brain metastases pain caused by bone metastases, radiotherapy. (4) systemic chemotherapy,: unresectable or TACE is not suitable for the patient, you can choose to systemic chemotherapy. However, the disease is currently no standard chemotherapy regimens. Commonly used chemotherapy drugs: fluorouracil, cisplatin, dacarbazine, doxorubicin, the streptozocin (Streptozocin), cyclophosphamide. Efficiency of less than 30%  single-agent chemotherapy, combination chemotherapy can improve the efficiency of the treatment of neuroendocrine tumors. As Moertel et al  reported the cisplatin plus relying on the etoposide treatment poorly differentiated metastatic neuroendocrine tumors have a higher response rate.  reported Kouvaraki such as fluorouracil, doxorubicin Star streptozocin treatment of pancreatic neuroendocrine tumors up to 39% efficiency. (5) The biological response modifier therapy: somatostatin analogs such as octreotide somatostatin receptors (SSTR) and neuroendocrine tumor cell surface binding, inhibiting the release of the polypeptide, can significantly improve the neuroendocrine clinical symptoms, but its role in inhibiting tumor growth there is a big controversy. Study , interferon and somatostatin analogues combination therapy of neuroendocrine tumors synergistic additive effect, but yet large-scale, prospective, multi-center study further confirmed. (6) molecular targeted therapy: neuroendocrine tumors is rich in blood vessels of solid tumors, the tumor cell surface expression of VEGF and VEGFR . Studies have shown that neuroendocrine tumors in patients with blood levels of VEGF prompted the progress of the disease . VEGF-mediated angiogenesis play an important role in the the neuroendocrine tumor recurrence transfer process. Of monoclonal antibodies and tyrosine kinase inhibitors for the treatment of neuroendocrine carcinoma is becoming a hot spot. 2005 ASCO meeting released a bevacizumab (Bevacizumab) treatment of carcinoid tumors with interferon randomized controlled phase Ⅱ clinical trial results showed that after 18 weeks of treatment, 44 patients with metastatic carcinoid tumor or the surgery patients, shellfish the bevacizumab group progression-free survival of 95%, the the interferon group to 68% . Phase II clinical trials are ongoing in H.Lee Moffitt Cancer Research Center, in combination with bevacizumab fluorouracil, doxorubicin Star and streptozocin chemotherapy drugs to treat neuroendocrine tumors . Many foreign research institutions are other angiogenesis inhibitors such as Sorafenib, Sunitinib, Vatalanib treatment of this disease randomized controlled multi-center study may angiogenesis inhibitors will become the standard treatment for this disease programs.
2.4 prognosis of survival and the survival of primary hepatic neuroendocrine carcinoma, both at home and abroad have no relevant reports. Its prognosis depends on the histological type, tumor size, metastasis and treatment on a variety of factors. Is generally believed that the prognosis is poor, but better than other primary liver cancer .
The patients, hepatic single large lesions, the initially pathological diagnosis of adenocarcinoma, consultation, and after the outer court combined immunohistochemical results confirmed primary hepatic neuroendocrine carcinoma. Improve the rate of early diagnosis of the disease, is the key to obtain a good effect. Combined with the diagnosis and treatment of cases through the experience as follows: (1) no hepatitis, history of cirrhosis of liver lesions, especially CT showed a large low-density lesions, the central see large areas of liquefaction necrosis area, enhanced substantial part of continuing to strengthen , central necrosis bleeding no enhancement should consider the possibility of this disease; (2) on the basis of pathological diagnosis, immunohistochemical examination of CgA, Syn on the diagnosis of the disease is important; (3) should do a comprehensive inspection except extrahepatic primary lesion. The patients were 2 more than a month that multiple intrahepatic metastasis, tumor burden is too large may be an important reason, after the comprehensive treatment of interferon, focused ultrasound, the body heat of chemotherapy, biological immune therapy, get 1 3 month period of stable disease. Currently, there is no domestic pharmaceutical treatment of the disease reported. Progress after the patient’s condition, we use Chinese medicine treatment for 6 more than a month, patients are generally in good condition, free of any symptoms and signs, periodic review of CT suggestive of liver lesions stable, has narrowed abdominal lesions compared with stable condition, the display of Chinese medicine disease may have some effect, and is worthy of further explored.