Primary hepatic neuroendocrine tumor (NET) or metastatic ileal NET – that is the question

A 65 year old male presented with recurrent epigastric pain, loose stools, flushing of face and breathing difficulty for 1 year. He had undergone right hepatectomy elsewhere for primary hepatic neuroendocrine tumor (NET) 12 years ago. His hematologic and biochemical investigations were within normal range except for raised urine 5 Hydroxyindolacetic acid (HIAA) levels (309 ng/24 hours).

Abdominal contrast enhanced computed tomography studies for liver (triple phase study) and bowel (enterography) were performed. Figure 1 A shows peripheral hyper enhancing lesion in hepatic segment III. Previous right hepatectomy with hypertrophy of remnant liver is noted. There was a markedly enhancing intraluminal polypoidal mass in the ileum (Figure 1 B).

Figure 1. Contrast enhanced computed tomography scan of abdomen

The patient underwent liver mestastatectomy with segmental bowel resection. The 'cut open section' of the resected small bowel revealed a stenosing tumor and a large draining lymph node (Figure 2). Histopathology revealed a well differentiated, intermediate grade NET (WHO; G2). Cytoreductive surgery together with initiation of long acting octreotide analogue resulted in symptomatic control of carcinoid syndrome.

 Figure 2. Segemental ileal resection showing small tumor with large mesenteric lymph node

Primary hepatic NETs are exceedingly rare and such diagnosis should be made only after a thorough clinical and radiological evaluation to exclude an elusive primary elsewhere (usually in the small intestine).¹ Primary ileal NET are often detected late and long term follow up therefore is essential. This is the most likely scenario in the present case also. A revised diagnosis of primary ileal NET with liver metastasis and carcinoid syndrome thus was made.

Aggressive surgery in metastatic NET in the form of removal of small bowel primary together with involved draining lymph nodes is reported to provide significant reduction in tumor related symptoms and improves survival. 

For liver secondaries, even a 70 % cytoreduction by means of parenchyma sparing debulking has been reported to improve progression free and overall survival.² Liver transplantation may be offered to select patients with: well-differentiated NET (Ki-67 <10 %), age <55 years, absence of extrahepatic disease, primary tumor removed before transplantation, stable disease for at least 6 months before LT, and <50% liver involvement.³

 References

1. Fenwick SW, Wyatt JI, Toogood GJ, Lodge JP. Hepatic resection and transplantation for primary carcinoid tumors of the liver. Ann Surg 2004;239(2):210-219.

2. Maxwell JE, Sherman SK, O'Dorisio TM, Bellizzi AM, Howe JR. Liver directed surgery of neuroendocrine metastases: what is the optimal strategy? Surgery 2016;159(1):320-333.

3. Rossi RE, Burroughs AK, Caplin ME. Liver transplantation for unresectable neuroendocrine tumor liver metastases. Ann Surg Oncol 2014;21(7):2398-405.

Authors:

Dr Nitin Vashistha, MS, FIAGES, FACS

Dr Dinesh Singhal, MS, FACS, DNB (Surg Gastro)

Department of Surgical Gastroenterology,
Max Super Speciality Hospital, Saket, New Delhi, India
E mail: gi.cancer.india@gmail.com

www.gicancerindia.com

Management of Neuroendocrine Liver Metastases (NELM) due to Pancreatic Neuroendocrine Tumors (PNET)

Background

A recent multicenter study from 7 major hepato-biliary centers in the USA & Europe reported that 421 patients underwent curative hepatectomy for NELM over 24 years (1990-2014).¹ At our center over last 7 years (2013 -2020), we managed 18 patients with digestive tract NET (Table 1).

Table 1.  Digestive tract NET patients (2013 – 2020)

S.no	Primary Site	Number of Patients	NELM
1.	Pancreas (Non functional)	4	2
2.	Pancreas (Functional)	3	0
3.	Ampulla of Vater	2	0
4.	First part of duodenum	5	0
5.	Small intestine	4	2
	Total	18	4

In the following sections we present our experience with PNET undergoing treatment for NELM at our center.

Representative Case Report

A 53 year old woman was investigated for pain left upper quadrant. Following investigations which included contrast enhanced abdominal CT scan, serum chromogranin levels (within normal limits) and DOTA – PET, a diagnosis of PNET was made. She underwent laparoscopy assisted distal pancreatectomy with splenectomy (Figure 1). 

Figure 1. Laparoscopic view showing large tumor in distal pancreas

Biopsy details are provided in Table 1. During follow up (abdominal CT scan, DOTA –PET), 14 months later she was found to have solitary large liver metastasis in segment 2& 3 (Figure 2) for which left lateral segmentectomy was done.

Figure 2. CT scan abdomen depicting large NELM in segments II & III of liver

Subsequently after 1 year, she developed multiple (at least 8 in number) NELM in segments 4,5,6,7,8 (Figure 3)for which transarterial chemoembolization (TACE) has been done.

Figure 3. CT scan abdomen revealing multiple NELM (marked by arrow)

During last 7 years, we have managed 6 other patients with PNET. The details of all the 7 patients are summarized in Table 2.

Table 2. PNET patients and their follow up

No.	Age & Sex	Presentation	Diagnosis	Tumor location & size (cm)	Procedure	AJCC Stage	Tumor grade	Ki-67 (%)	FU
1	61yr, Male	Weight loss 10 kg in 1 yr	Nonfunctional PNET	Proximal body 4x3 cm	Distal pancreatectomy+ splenectomy (DP + S)	pT1N1	G2	3%	NELM 22 mo PO
2.	60 yr, Female	Incidentally detected	Nonfunctional PNET	Distal body 1.5x1 cm	Distal pancreatectomy	pT1N0	G1	<1%	5 yr Well
3. *	53 yr, Female	Pain abdomen	Nonfunctional PNET	Distal body 9x6 cm	DP + S	pT1Nx	G2	6 -8%	NELM 14 mo
4.‡	28yr Male	Recurrent hypoglycemia	Insulinoma	Distal body 3x2 cm	DP + S	pT2N0	G 1	<1%	6 yr Well
5.**	37yr	Recurrent hypoglycemia	Insulinoma	Body  3x2.8 cm	DP + S	pT2N0	G1	<2%	5 yr Well
6. **	60 yr	Recurrent hypoglycemia	Insulinoma	Proximal body  2x2 cm	Enucleation	pT1Nx	G1	<2%	4 yr Well
7.	51 yr	Incidentally detected	Nonfunctional PNET	Body  3x2 cm	DP+S	pT2N0	G1	<2%	6 yr Well

‡ Vashistha N, Aggarwal B, Singhal D Gastroenterology2016;151:43-44

* Details provided in case report

** https://gicancerindia.blogspot.com/2020/03/benign-insulinoma-enucleation-or.html

Discussion

Of the patients presenting with NELM, non PNET primary (e.g. small bowel, rectum, and bronchus) source is more common as compared to PNET.¹

Resection with curative intent is currently the treatment of choice. However almost half of the patients are likely to develop recurrent disease. Risk factors for early (defined in one study as < 3 years) recurrence include PNET, lymph node positive primary tumor and R1 resection.² The same study reports that re –treatment with curative intent provides significant survival advantage when compared to non curative treatment.

For patients with unresectable NELM, parenchyma sparing procedures (ablation, enucleation, wedge resections) with target threshold of 70% debulking with resection of primary is reported to improve progression free and overall survival.³

In the surgical series, PNETs are more common in 6^th decade, in females and in body and tail of pancreas and more likely to be nonfunctional.^1,4,5 Nonfunctional  PNETs are more likely to present with NELM.¹ In a study involving 542 patients who underwent resection for PNET, the median time to recurrence was 19 (range 0.8 – 236.3) months, overall recurrence rate was 13.7% with liver being the most common site of recurrence. The 5 and 10 year survival in this study was 86.4 % and 81.3% respectively.⁶

The independent predictor for recurrent disease for PNET include non functioning tumors, tumor grade, node positive primary and vascular invasion.⁵ A recent study of NELM in small (< 3 cm) well differentiated PNET reported that molecular alterations such as DAXX mutations, chromosomal gains and alternative lengthening of telomeres (ALT) are associated with increased risk of metastasis.⁷

References
 1.      Spolverato G, Bagante F, Aldrighetti L et al. Neuroendocrine liver metastasis: Prognostic implications of primary tumor site on patients undergoing curative intent liver surgery. J Gastrointest Surg 2017;21(12): 2039-2047

      2.      Zhang XF, Beal EW, Chakedis J et al. Early recurrence of neuroendocrine liver metastasis after curative hepatectomy: Risk factors, prognosis and treatment J Gastrointest Surg 2017;21:1821-1830

      3.      Maxwell JE, Sherman SK, O'Dorisio et al. Liver directed surgery for neuroendocrine metastases. What is the optimal strategy? Surgery 2016;159(1):32-33

      4.      Zhou B, Duan J, Yan S et al. Prognostic factors of long term outcome in surgically resectable pancreatic neuroendocrine tumors. Oncol Lett 2017;13(3): 1157-1164

      5.      Landoni L, Marchegiani G, Pollini T et al. The evolution of surgical strategies for pancreatic neuroendocrine tumors: Time trends and outcome analysis from 587 consecutive resections at a high volume institution. Ann Surg 2019;269(4):725-732

      6.      Kim H, Song KB, Hwang DW et al. Time trend and recurrence analysis of pancreatic neuroendocrine tumors. Endocr Connect 2019;8(7):1052- 1060

      7.       Pea A, Yu J, Marchionni L et al. Genetic analysis of small well differentiated pancreatic neuroendocrine tumors identifies subgroups with differing risks of liver metastases. Ann Surg 2020;271(3): 566-73

Authors:

Dr Nitin Vashistha, MS, FIAGES, FACS

Dr Dinesh Singhal, MS, FACS, DNB (Surg Gastro)

Department of Surgical Gastroenterology,
Max Super Speciality Hospital, Saket, New Delhi, India
E mail: gi.cancer.india@gmail.com

www.gicancerindia.com

Insulinoma: Enucleation or Segmental Pancreatic Resection?

Insulinoma is a rare neuroendocrine tumor arising from insulin producing β-cells of the pancreas. Insulinoma patients present with history of abnormally low blood sugar levels associated with hypoglycemic symptoms such as visual disturbances, confusion, weakness, abnormal behaviour, sweating or palpitations. In severe cases patient may develop seizures, loss of consciousness or may go into coma. The triad of any of these symptoms on fasting together with hypoglycaemia (blood sugar < 40 mg%) and relief of symptoms on intake of sugars is known as Whipple’s triad, which is suggestive of insulinoma. Diagnosis of insulinoma is confirmed by evocative testing, when fasting blood sugar is ≤ 40 mg% is associated with hyperinsulinemia (> 23µU/ml) and raised C-peptide levels (> 4.4 ng/ml).¹

Once a diagnosis of insulinoma has been made the next most important is to localize the tumor within the pancreas for surgical planning. Owing to hyper-vascular nature, on contrast enhanced CT scan (Figure 1), insulinoma typically appear as hyperattenuating nodule with clear margins and avid enhancement in comparison to normal pancreatic parenchyma on post-contrast arterial or pancreatic phase images ². 

Figure 1. Abdominal contrast enhanced computed tomography scan (Arrow head pointing towards insulinoma)

While in the past preoperative localization of insulinoma was difficult but now with modern high-resolution, multi-phase contrast enhanced thin slice cross sectional-imaging (CT scan, MRI) and endoscopic ultrasonography high preoperative localization rates are feasible. In rare instances when preoperative localization of tumor is unsuccessful then intraoperative ultrasound is a useful adjunct for localization of the tumor.

Insulinoma are mostly sporadic (94%), benign (87%) and solitary (90%) and are mostly smaller than 20 mm in diameter (84%).³ Surgery is curative for patients with insulinoma and resection of localized insulinoma results in biochemical cure in 98% patients with 6% chances of recurrence at 10 years.⁴ The two surgical options for benign insulinoma include enucleation or segmental resection. Both the surgical procedures are safe and for an individual patient choice of the surgical procedure is based on the size & location of the tumor.

Enucleation (Figure 2) is commonly performed procedure because of its advantage of preserving pancreatic parenchyma. 

Figure 2. Enucleated insulinoma (tumor from Figure 1)

Complete removal of the insulinoma is important for preventing recurrence.⁵ Enucleation is safe for small lesions which are > 2 mm away from the main pancreatic duct.⁶ Enucleation is associated with less blood loss, shorter hospital stay and lower rates of exocrine & endocrine insufficiency in comparison to segmental resection. Although rate of postoperative pancreatic fistula (POPF) is reported to be higher after enucleation but increased POPF rates are not associated with higher mortality or morbidity.⁷

Segmental resection of pancreas i.e. pancreaticoduodenectomy, central pancreatectomy or distal pancreatectomy (Figure 3) is indicated for lesions in close proximity to the main pancreatic duct, deeply situated tumors in pancreas and when there is suspicion of malignancy. In various reports rate of segmental resection of pancreas for insulinoma is reported to be indicated in around 50% of the patients.⁸

Figure 3. Distal pancreatectomy specimen

In summary surgery is curative for benign insulinoma and outcomes of both enucleation and segmental resection are comparable. Wherever feasible enucleation may be preferred over segmental resection. Enucleation is associated with improved exocrine and endocrine function but with a higher rate of POPF without increased mortality or overall morbidity rates.

References

1.       Vashistha N, Aggarwal B, Singhal D. Young adult with multivisceral lesions and hypoglycaemia. Gastroenterology. 2016;151(1): 43-44

2.       Zhu L, Xue H, Sun H et al. Insulinoma Detection With MDCT: Is There a Role for Whole-Pancreas Perfusion? Am J Roentgenol. 2017;208: 306-314

3.       Mehrabi A, Fischer L, Hafezi M et al. A Systematic Review of Localization, Surgical Treatment Options, and Outcome of Insulinoma. Pancreas.2014;43(5):675–686, JULY

4.       Howe JR, Merchant NB, Conrad C et al. The North American Neuroendocrine Tumor Society Consensus Paper on the Surgical Management of Pancreatic Neuroendocrine Tumors. Pancreas. 2020; 49(1):1-33

5.       Mathur A, Gorden P, Libutti SK. Insulinoma. Surg Clin North Am. 2009; 89(5): 1105–1121

6.       Brient C, Regenet N, Sulpice L et al. Risk factors for postoperative pancreatic fistulisation subsequent to enucleation. J Gastrointest Surg. 2012;16(10):1883-7

7.       Huttner FJ, Koessler EJ, Hackert T et al. Meta-analysis of surgical outcome after enucleation versus standard resection for pancreatic neoplasms. Br J Surg. 2015;102 (9), 1026-36

8.       Crippa S, Zerbi A, Boninsegna L et al. Surgical Management of Insulinomas Short- and Long-term Outcomes After Enucleations and Pancreatic Resections. Arch Surg. 2012;147(3):261-266

Authors:

Dr Nitin Vashistha, MS, FIAGES, FACS

Dr Dinesh Singhal, MS, FACS, DNB (Surg Gastro)

Department of Surgical Gastroenterology,
Max Super Speciality Hospital, Saket, New Delhi, India
E mail: gi.cancer.india@gmail.com

www.gicancerindia.com