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

Serous Oligocystic Cystadenoma (SOA)

A 50 year lady presented with history of dull ache in left upper abdomen of 2 months duration. Her abdominal examination was unremarkable. The abdominal ultrasound was suggestive of cystic lesion in the body and tail of pancreas. The carbohydrate antigen 19-9 (CA 19-9) was 21 units/milliliter. Her other hematological & biochemical parameters were within prescribed normal range.  Subsequently she underwent abdominal contrast enhanced computed tomography (CT) scan and then magnetic resonance cholangiopancreatography (MRCP) and contrast enhanced magnetic resonance imaging (MRI) scan (Figure A, B & C).   In view of the typical imaging findings (vide infra) a diagnosis of SOA was made.

Figure A: Contrast enhanced abdominal computed tomography scan

Figure B: Contrast enhanced abdominal magnetic resonance imaging scan

Figure C: Magnetic Resonance Cholangio-Pancreatography 

In line with current recommendation for surgery for pancreatic serous cystadenoma, resection was proceeded with due to symptomatic, large (> 4 cm) tumor.¹

The patient underwent laparoscopy assisted distal pancreatectomy with splenectomy. At laparoscopy there was a large (approximately 9 x 7cm) multiloculated exophytic tumor in the body and tail region of pancreas that was adherent to the mesocolon and left branch of the middle colic artery (Figure D). She had an uncomplicated postoperative period and was discharged on 8^th day following surgery. Histopathology revealed cysts lined by single layer of cuboidal epithelial cells filled with clear cytoplasm.

Figure D: Distal pancreatectomy + splenectomy specimen showing

multiple thin walled cysts

Discussion

Serous oligocystic cystadenoma is a subgroup of pancreatic serous cystadenoma (SA) characterized by image findings described above.² In comparison with SA, they are uncommon and can sometimes be difficult to diagnose due challenging overlap of image findings with other cystic lesions.

In the following sections, we present differentiating features with other pancreatic cystic neoplasms:

A.      Solid pseudopapillary neoplasm (SPN)

B.      Branch chain intraductal papillary mucinous neoplasm (IPMN)

C.      Mucinous cystic neoplasm (MCN)

In our patient, the contrast enhanced abdominal computed tomography scan shows a lobulated cystic neoplasm with septations in the body and tail of pancreas with thin (< 2 mm) non enhancing walls. The cystic spaces (6 in number) are > 2 cm (Figure A). These findings are better appreciated in contrast enhanced abdominal magnetic resonance imaging scan (Figure B). At magnetic resonance cholangio-pancreatography (MRCP), the main pancreatic duct (MPD) is not dilated in its entire course and there was no duct – cyst communication (Figure C). Hence a diagnosis of SOA was made.³

Mucinous cystic neoplasms usually are unilocular or mildly septated and have a smooth contour.^3,4 The cyst wall is thick and enhances at contrast enhanced MR imaging.⁴

Branch chain IPMN was ruled out as the MPD was of normal caliber at MRCP and the cystic tumor did not have communication with the main pancreatic duct (Figure B).

Solid pseudopapillary neoplasms typically appear in young women and on contrast enhanced abdominal CT or MRI scan appear as well defined, encapsulated, heterogeneous solid and cystic tumor with areas with hemorrhagic degeneration.⁵ These findings are not consistent with those in Figures A and B from our patient. Therefore SPN was also ruled out.

References

1.       Tseng JF, Warshaw AL, Sahani DV et al. Serous Cystadenoma of the pancreas: tumor growth rates and recommendations for treatment. Ann Surg.2005;242(3):413-419

2.       Lee JH, Kim JK, Kim TH et al. MRI features of serous oligocystic adenoma of the pancreas: differentiation from mucinous cystic neoplasm of the pancreas. Br J Radiol. 2012;85:571-576

3.       Kim SY, Lee JM, Kim SH et al. Macrocystic neoplasms of the pancreas: CT differentiation of serous oligocystic adenoma from mucinous cystadenoma and intraductal papillary mucinous tumor. AJR. 2006;187:1192-1198

4.       Kalb B, Sarmineto JM< Kooby DA et al. MR imaging of cystic lesions of the pancreas. RadioGraphics 2009;29:1749-1765

5.       Cantisani V, Mortele KJ, Levy A et al. MR imaging features of solid pseudopapillary tumor of the pancreas in adult and pediatric patients. AJR. 2003;181:395-401

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