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ORIGINAL ARTICLE
Year : 2014  |  Volume : 10  |  Issue : 8  |  Page : 276-280

Clinical analysis of gastroenteropancreatic neuroendocrine tumor with liver metastasis, compared with primary hepatic neuroendocrine tumor


Department of Liver Surgery, Zhongshan Hospital, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China

Date of Web Publication17-Feb-2015

Correspondence Address:
J Zhou
Department of Liver Surgery, Zhongshan Hospital, Liver Cancer Institute, Fudan University, 180 Feng Lin Road, Shanghai 200032
China
N Ren
Department of Pathology, Zhongshan Hospital, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai 200032
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.151532

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 > Abstract 

Objective: The objective was to study the clinicopathologic features, grading, treatment protocols, and prognostic of gastroenteropancreatic neuroendocrine tumor (NET) with liver metastasis and primary hepatic NET.
Materials and Methods: The clinical data of 34 patients with hepatic NET were retrospectively reviewed. According to the primary tumor location and 2010 World Health Organization classification, the cases were categorized to analyze the clinicopathologic features, treatment condition, and prognostic factors.
Results: There was a marked male predominance either in gastroenteropancreatic NET liver metastasis group or primary group. Primary hepatic NET is mostly single nodule located in the right lobe of liver, and the metastatic hepatic NET is mostly from pancreas with multiple nodules and metastasizes to both lobes of the liver, with a high degree of malignancy and poor prognosis. There are 17 cases (50%) of NET and 17 cases (50%) of neuroendocrine carcinoma (NEC) in all the 34 patients of this study. The mitotic figure and Ki-67 proliferation index are both higher in NEC group than in NET group, which indicated highly malignancy of the NEC. The 5-year disease-free survival (DFS) rates for primary group and metastatic group were 30% and 40%, respectively (P > 0.05), while the 5-year survival rates were 35% and 66%, respectively (P > 0.05). Different tumor grade was found closely associated with 5-year DFS (P < 0.05) and overall survival (OS) (P < 0.05) in both groups. Furthermore, we found 5-year DFS of patients with primary site of the tumor located in the gastrointestinal tract was much lower than that located in pancreas (P < 0.05), while the 5-year OS showed no significant differences between two groups (P > 0.05).
Conclusions: Surgery is an effective method for the treatment of hepatic NET; tumor grading is an important determinant factor of prognosis.

Keywords: Immunohistochemistry, liver metastasis, neuroendocrine tumor, prognosis


How to cite this article:
Shen Y H, Chen S, Zhang W T, Ji Y, Yu L, Sun H C, Qiu S J, Ren N, Zhou J. Clinical analysis of gastroenteropancreatic neuroendocrine tumor with liver metastasis, compared with primary hepatic neuroendocrine tumor. J Can Res Ther 2014;10, Suppl S4:276-80

How to cite this URL:
Shen Y H, Chen S, Zhang W T, Ji Y, Yu L, Sun H C, Qiu S J, Ren N, Zhou J. Clinical analysis of gastroenteropancreatic neuroendocrine tumor with liver metastasis, compared with primary hepatic neuroendocrine tumor. J Can Res Ther [serial online] 2014 [cited 2019 Jun 16];10:276-80. Available from: http://www.cancerjournal.net/text.asp?2014/10/8/276/151532


 > Introduction Top


Neuroendocrine tumor (NET) is one kind of heterogeneous tumor that derived from peptidergic neuron and neuroendocrine cell, which occur in all neuroendocrine organs and tissues. [1] Primary hepatic NET is relatively rare, [2] there were only about 100 cases reported since 1958. [3],[4],[5] Most of the hepatic NETs are metastasized from pancreas and gastrointestinal tract.

This research retrospectively reviewed the clinic information of patients suffer from gastroenteropancreatic NET with liver metastasis, compared with those suffer from primary hepatic NET, discussed the clinical and pathological features, grading, treatment protocols, and prognosis of hepatic NET. This research is envisioned to provide a theoretical and practical evidence of the treatment of hepatic NET.


 > Materials and methods Top


Patients and clinical data

Thirty-four patients with hepatic NETs which were surgical resected and pathological confirmed in Zhongshan Hospital, Fudan University from 2008 to 2014 were enrolled. Among which, 19 cases were metastasis from gastroenteropancreatic NET (metastatic group), and 15 cases were primary hepatic NETs (primary group). There was a marked male predominance either in the metastatic group (11/19) or primary group (9/15). The mean age was 55.1 with a range of 40-69 years in the metastatic group, while in the primary group, the mean age was 55.5 with a range of 38-79 years. Most of the patients (13/19) had symptoms caused by tumor oppression in the metastatic group, while in the primary group, only 5/15 cases had abdominal discomfort or diarrhea and one case had slight fever as a chief complaint. Other patients had no symptoms and were detected incidentally by medical check-up.

Nine (47%) cases were single nodule and 10 (53%) cases were multiple nodules in the liver in the metastatic group. Among which, the nodules located in the right lobe of the liver in 13 (68%) cases, located in the left lobe of the liver in 3 (16%) cases, and involving both lobes in 3 (16%) cases. In the primary group, 14 (93.3%) cases were found single nodule and only 1 (6.7%) cases were multiple nodules. Among which, 6 (40%) cases located in the left lobe, 8 (53.3%) cases located in the right lobe, another 1 (6.7%) cases involving both lobes. The mean diameter of the tumor in the liver was 5 cm with a range of 0.5-20 cm.

The primary sites of the tumor in the metastatic group were showed in [Table 1]. The basic information and clinical data were collected, and the clinicopathological features of hepatic NET were analyzed retrospectively.
Table 1: Primary site of the tumor in the metastatic group

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Diagnosis and classification criteria

According to World Health Organization classification of tumors of the digestive system, [6] the NETs are classified into two groups: (1) NET: NET G1 and NET G2. In G1, mitotic figure <2/10 high power field (HPF) (1 HPF = 2 mm 2 ), Ki-67 proliferation index (PI) <2%; in G2, mitotic figure is 2-20/10 HPF, Ki-67 PI = 3-20%. (2) Neuroendocrine carcinoma (NEC), mitotic figure >20/10 HPF, Ki-67 PI > 20%.

Immunohistochemistry

All the tumor samples were fixed by 4% Formaldehyde, conventional dehydrated, embedded by paraffin and sliced into 4 μm. Streptavidin peroxidase method is used for staining, color development is by 3,3'-diaminobenzidine and counter stain is by hematoxylin. Four antibodies include Syn, CgA, NSE, and CD56 were marked, with negative and positive control.

Statistical analysis

The statistical analysis was performed with SPSS software version 17.0 (SPSS Inc., Chicago, IL, USA) software. Fisher exact test was used to compare quantitative data. Survival curves were estimated according to the method of Kaplan-Meier and Log-rank test. A P < 0.05 was considered significant.


 > Result Top


Classification and immunohistochemistry

There were 17 cases (50%) of NET G2 and 17 cases (50%) of NEC in all 34 patients. In the primary group, there were seven cases (46.7%) of NET G2, with mitotic figure 5-10/10 HPF, and eight cases (53.33%) of NEC, with mitotic figure >20/10 HPF. In the metastatic group, there were 10 cases (52.6%) of NET G2, with mitotic figure 3-7/10 HPF, and nine cases (47.4%) of NEC, with mitotic figure >20/10 HPF.

The immunohistochemistry result was shown in [Table 2]. As it can be seen, in the primary group, positive rates of Syn, CgA, NSE, andCD56 were 80% (12/15), 86.67% (13/15), 80% (12/15), and 80% (12/15). In the metastatic group, the positive rates were 78.9% (15/19), 84.2% (16/19), 78.9% (15/19), and 63.2% (12/19). There was no significant difference found between NET group and NEC group either in the primary group (P > 0.05) or metastatic group (P > 0.05).
Table 2: The immunohistochemistry result of the NETs

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Treatment and follow-up

All the 34 patients received surgical operation. In the metastatic group, 10 cases receive liver resection coordinate with tumor resection of the primary site. The other nine cases were liver metastasis patients 1 (2 cases), 2 (4 cases), 4 (1 cases) or 7 (2 cases) years after tumor resection of primary site, they received liver resection only. In the primary group, 15 cases received liver resection, in which there was one case of partial hepatectomy combined with choledochojejunostomy.

All the 34 patients gave informed consent and were followed up till the study with a range from 2 to 75 months (median follow-up time 47.6 months). The 5-year disease-free survival (DFS) rates for primary group and metastatic group were 30% and 40%, respectively (P > 0.05), while the 5-year survival rates were 35% and 66%, respectively (P > 0.05) [Figure 1]a and b.
Figure 1: (a) The 5-year disease-free survival rates for the primary group and metastatic group. (b) The 5-year overall survival rates for the primary group and metastatic group

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We found the prognosis of NET group was better than NEC group different tumor grade was found closely associated with 5-year DFS and overall survival (OS) either in primary group (P < 0.05, P < 0.05) or in metastatic group (P < 0.05, P < 0.05) [Figure 2]a-d. Furthermore, we found 5-year DFS of patients with primary site of the tumor located in the gastrointestinal tract was much lower than that located in pancreas (P < 0.05), while the 5-year OS showed no significant differences between two groups (P > 0.05) [Figure 3]a and b.
Figure 2: (a) The 5-year disease-free survival rates for neuroendocrine tumor and neuroendocrine carcinoma in the primary group. (b) The 5-year overall survival rates for neuroendocrine tumor and neuroendocrine carcinoma in the primary group. (c) The 5-year disease-free survival rates for neuroendocrine tumor and neuroendocrine carcinoma in the metastatic group. (d) The 5-year overall survival rates for neuroendocrine tumor and neuroendocrine carcinoma in the metastatic group

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Figure 3: (a) The 5-year disease-free survival of patients with the primary site of the tumor located in the gastrointestinal tract and located in the pancreas. (b) The 5-year overall survival of patients with the primary site of the tumor located in the gastrointestinal tract and located in the pancreas

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 > Discussion Top


Previously research suggested that NET is rare, but the pathological analysis indicates that there is an increase of this tumor at a speed of 3.65/100,000 person/year. Most of the hepatic NETs are metastasized from pancreas and gastrointestinal tract, primary hepatic NET is reported accounts for 0.8-4% of the NET. [7] But in our Department, as a center for surgical treatment for liver neoplasms, the rate of primary hepatic neuroendocrine is higher to 50%. To better understand the clinicopathologic features of hepatic NET metastasized from pancreas and gastrointestinal tract and compared with primary hepatic neuroendocrine is significantly meaningful for its prevention and treatment strategies.

We found a marked male predominance either in metastatic group or in primary group in the study, and the mean age was about 55-year-old, this further support the suggestion that the elder men should have physical examination regularly especially those with abdominal discomfort, which can be a method to screen and prevent the NET liver metastasis.

We found primary hepatic NET is mostly single nodule located in the right lobe of liver, and the metastatic hepatic NET is mostly from pancreas with multiple nodules and metastasize to both lobes of the liver, with a high degree of malignancy and poor prognosis, this result is accordant with previous report. [8],[9],[10],[11],[12]

There are 17 cases (50%) of NET and 17 cases (50%) of NEC in all the 34 patients of this study. The mitotic figure and Ki-67 PI are both higher in NEC group than in NET group, which indicated highly malignancy of the NEC. The size, grading, mitotic figure and Ki-67 PI of tumor can affect patient's survival rate, which has significant value of guiding the malignancy assessment and predicting prognosis of hepatic NET. Immunohistochemistry has important value to the diagnosis of hepatic NET. The joint detection of Syn and CgA shows high specificity and has been provisions for compulsory makers of immumohistochemical staining to diagnose NET. Our result of this study shows the high positive rate of markers of NET such as Syn, CgA, and NSE either in the metastatic group or primary group.

Most of the gastroenteropancreatic NETs will metastasis to the liver, and lobectomy of liver is still the best treatment for hepatic NET. For those with good health condition, liver resection coordinate with tumor resection of the primary site is advised. If the physical condition of the patient is unable to tolerant simultaneous resection, it is suggested to resect the primary lesion first and leave the metastases to the second stage of resection. In addition, for primary hepatic NET patients with poorer liver functions, liver transplantation is much better than simple excision of the tumor. [13] Rosenau et al. [14] reported that the survival rate of 19 cases of hepatic NET patients who received liver transplantation was higher to 87%.

Eighty-five percent patients diagnosed hepatic NET could be treated by radical surgical resection, with a 5-year recurrence rate of 18-40% and 5-year survival rate of 74-78%. [15] In this study, the 5-year recurrence rates for the primary group and metastatic group were 70% and 60%, the 5-year survival rates were 35% and 66%. The result is poor than reports, maybe because of the high proportion of NEC (50%) or later diagnosis of the disease.

We found the prognosis of NET group was better than NEC group, confirmed the association between the tumor grade with prognosis.

Relevant research [9] showed that pancreatic NET with poor prognosis, but we found patients with primary site of the tumor located in the gastrointestinal tract still showed high tendency of recurrence, and the 5-year OS showed no significant differences between two groups.


 > Conclusion Top


Hepatic NET is a disease without specific clinical manifestation, but tumor grading could be a significant factor of prognosis. Thus, early diagnosis and treatment is meaningful, active surgical treatment is still effective whether for primary hepatic NET or gastroenteropancreatic NET with liver metastasis.

 
 > References Top

1.
Oberg K. Neuroendocrine tumors (NETs): Historical overview and epidemiology. Tumori 2010;96:797-801.  Back to cited text no. 1
    
2.
Yalav O, Ülkü A, Akçam TA, Demiryürek H, Doran F. Primary hepatic neuroendocrine tumor: Five cases with different preoperative diagnoses. Turk J Gastroenterol 2012;23:272-8.  Back to cited text no. 2
    
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Fenoglio LM, Severini S, Ferrigno D, Gollè G, Serraino C, Bracco C, et al. Primary hepatic carcinoid: A case report and literature review. World J Gastroenterol 2009;15:2418-22.  Back to cited text no. 3
    
4.
Shetty PK, Baliga SV, Balaiah K, Gnana PS. Primary hepatic neuroendocrine tumor: an unusual cystic presentation [J]. Indian J PatholMicrobiol 2010; 53:760-762.  Back to cited text no. 4
    
5.
Gravante G, De Liguori Carino N, Overton J, Manzia TM, Orlando G. Primary carcinoids of the liver: A review of symptoms, diagnosis and treatments. Dig Surg 2008;25:364-8.  Back to cited text no. 5
    
6.
Rindi G, Arnold R, Bosman F. Nomenclature and classification of neuroendocrine neoplasms of the digestive system. In: Bosman FT, Carneiro F, Hruban RH, editors. WHO classification of tumours of the digestive system. Lyon: IARC Press; 2010. p. 13-4.  Back to cited text no. 6
    
7.
Chinese pathologic consensus group for gastrointestinal and pancreatic neuroendocrine neoplasms. Standardization in diagnosis of gastrointestinal and pancreatic neuroendocrine neoplasms: The Chinese consensus. Zhonghua Bing Li Xue Za Zhi 2013;42:691-4.  Back to cited text no. 7
    
8.
Ihse I, Persson B, Tibblin S. Neuroendocrine metastases of the liver. World J Surg 1995;19:76-82.  Back to cited text no. 8
    
9.
Pape UF, Berndt U, Müller-Nordhorn J, Böhmig M, Roll S, Koch M, et al. Prognostic factors of long-term outcome in gastroenteropancreatic neuroendocrine tumours. Endocr Relat Cancer 2008;15:1083-97.  Back to cited text no. 9
    
10.
Lawrence B, Gustafsson BI, Chan A, Svejda B, Kidd M, Modlin IM. The epidemiology of gastroenteropancreatic neuroendocrine tumors. Endocrinol Metab Clin North Am 2011;40:1-18, vii.  Back to cited text no. 10
    
11.
La Rosa S, Klersy C, Uccella S, Dainese L, Albarello L, Sonzogni A, et al. Improved histologic and clinicopathologic criteria for prognostic evaluation of pancreatic endocrine tumors. Hum Pathol 2009;40:30-40.  Back to cited text no. 11
    
12.
Gupta S, Yao JC, Ahrar K, Wallace MJ, Morello FA, Madoff DC, et al. Hepatic artery embolization and chemoembolization for treatment of patients with metastatic carcinoid tumors: The M.D. Anderson experience. Cancer J 2003;9:261-7.  Back to cited text no. 12
    
13.
Alekseev D, Goralczyk A, Lorf T, Ramadori G, Obed A. Ten years survival with excellent outcome after living donor liver transplantation from 70 years old donor for primary hepatic neuroendocrine carcinoma: Case report. Int J Surg Case Rep 2012;3:34-6.  Back to cited text no. 13
    
14.
Rosenau J, Bahr MJ, von Wasielewski R, Mengel M, Schmidt HH, Nashan B, et al. Ki67, E-cadherin, and p53 as prognostic indicators of long-term outcome after liver transplantation for metastatic neuroendocrine tumors. Transplantation 2002;73:386-94.  Back to cited text no. 14
    
15.
Huang YQ, Xu F, Yang JM, Huang B. Primary hepatic neuroendocrine carcinoma: Clinical analysis of 11 cases. Hepatobiliary Pancreat Dis Int 2010;9:44-8.  Back to cited text no. 15
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2]



 

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