Mucinous Cystic Neoplasm (MCN) of Pancreas

A woman in her 8^th decade presented with 2 months history of dull aching pain in the upper abdomen.  She was in good health and there was no serious comorbidity though she had hypertension that was well controlled on medication. Her physical examination was unremarkable except for obesity (BMI 31kg/m²). An initial abdominal ultrasound done elsewhere was suggestive of large cystic lesion in the body of pancreas.

The patient was further investigated with contrast enhanced abdominal magnetic resonance imaging (MRI) of the abdomen which showed a well defined, large (> 5 cm) unilocular cystic lesion with thick enhancing capsule located centrally in the body of pancreas. There was no duct – cyst communication (Figure 1 & 2).

Figure 1

Figure 2

A diagnosis of mucinous cystic neoplasm (MCN) was made. A subsequent endoscopic ultrasound revealed a large multiseptated cyst with solid components in the pancreatic body raising the possibility of mucinous cystadenocarcinoma. The cyst fluid CEA was 47788 IU.

In view of large, centrally placed lesion, a hybrid procedure i.e. laparoscopy assisted lateral to medial mobilization of pancreas and spleen with open transection of the pancreas was proceeded with. The postoperative period was uncomplicated.

At histopathology there was 7x5 cm MCN with low grade dysplasia.

The patient is well 3 years after surgery

Discussion

1.       Pseudocyst or MCN

2.       Surgery for MCN

These are sequentially discussed below:

1.       Pseudocyst or MCN: Prior to any intervention for cystic tumors of the pancreas, pseudocyst needs to be conclusively ruled out. In patients where doubt persists after all investigative modalities have been utilized it is best to follow the surgical dictum ‘it is better to resect a pseudocyst than to drain a cystic tumor’. The salient features for differentiating MCN and  pseudocyst are summarized in table 1

Table 1. Pseudocyst versus MCN¹

Parameter	MCN	Pseudocyst
History of acute pancreatitis	Absent. (c.f. 10% patient may present with acute pancreatitis)2,3	Present
Contrast MRI with MRCP	Cyst wall enhancing Main pancreatic duct – cyst communication absent (Figure 3)	Cyst wall nonenhancing Main pancreatic duct – cyst communication present (Figure 4)
EUS guided cyst fluid aspiration	Cyst fluid amylase – CEA  +++	Cyst fluid +++ CEA -

 

Figure 3. Main pancreatic duct – cyst communication absent

Figure 4. Main pancreatic duct – cyst communication present

2. Mucinous cystic neoplasms are characterized by presence of ovarian stroma and lack of communication with main pancreatic duct.² They occur most frequently in women (95%), in distal pancreas (97%) and are always a single lesion.³ The risk of malignancy is reported to be 17%.² The clinical and imaging parameters associated with malignancy include older age, presence of mural nodules and cyst diameter of ≥ 60 mm.²

Resection should be considered in all patients with MCN.² This is most commonly in the form of distal pancreatectomy. In low risk MCN (≤ 4 cm, no mural nodules) non radical resections are appropriate

References

1.       Singhal D, Kakodkar R, Sud R et al. Issues in management of pancreatic pseudocysts. JOP 2006;7(5):502-7

2.       Crippa S, Salvia R, Warshaw AL et al. Mucinous cystic neoplasm of the pancreas is not an aggressive entity: lessons from 163 resected patients. Ann Surg 2008;247(4):571-9

3.       Farrell JJ, Castillo F. Pancreatic cystic neoplasms: management and unanswered questions Gastroenterology 2013;144:1303-15

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