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

Colon cancer: Generalized peritoneal pigmentation - rare sequel of India ink tattooing

Colonoscopic tattooing of colorectal neoplasms with India ink is currently the preferred technique for tumor localization during subsequent laparoscopic resections. It is safe (complications 0.22%) and accurate (90.5 - 97.9%).^1,2,3 Dye spillage occurs in 2.4 – 13 % patients and is usually asymptomatic.⁴

Tattooing may sometimes result in rare findings that cause diagnostic dilemma during surgery.

A 65 year old male presented with history of weight loss, recent onset constipation and bleeding of bright red per rectum for 1 year. His general physical and abdominal examination was unremarkable as was digital rectal examination and proctoscopy.

Colonoscopy revealed large polypoidal sigmoid colon tumor which was tattooed with India ink. Admittedly the tumor in our patient was large and may well have been localized without tattooing also.

Endoscopic biopsy suggested well differentiated adenocarcinoma.  Contrast enhanced abdominal computed tomography scan showed large, non obstructing tumor involving distal sigmoid colon (Figure 1).  

Figure 1: Contrast enhanced abdominal computed tomography scan showing large enhancing tumor in distal sigmoid colon

The patient was planned for laparoscopy assisted radical sigmoid colectomy.  At initial laparoscopy there were dark pigmented macules diffusely present over peritoneal cavity raising suspicion of metastatic malignant melanoma (Figure 2). 

Figure 2: Laparoscopy showing multiple pigmented patches over peritoneum with minimal free fluid

Frozen section from multiple such lesions did not reveal tumor deposits and was proceeded with. Final histopathology staging was pT2N0M0. On Hematoxylin & Eosin (H & E) staining, pigmented lesions were due to black pigment (presumably carbon from India ink) laden macrophages. Negative immunohistochemistry (IHC) for HMB45 & Melan A ruled out melanocytes as causative for pigmentation (Figure 3).

Figure 3: Microphotograph: H & E stain - showing black pigment laden macrophages; IHC HMB45 - negative for melanocytes

 The postulated mechanisms for such findings include intraperitoneal spillage of India ink or via pigment laden macrophages.⁵

Awareness of this entity is important for surgeons to avoid misinterpretation of peritoneal findings at laparoscopy.

References

1.       Nizam R, Siddiqi N, Landas SK, Caplan DS, Holtzapple PG. Colonic tattooing with India ink: Benefits, risks and alternatives. Am J Gastroenterol 1996;91(9):1804-08

2.       Acuna SA, Elmi M, Shah PS, Coburn NG, Quereshi FA. Preoperative localization of colorectal cancer: A systematic review and metanalysis. Surg Endosc 2017;31(6):2366-2379

3.       Cho YB, Lee WY, Yun HR, Lee WS, Yun SH, Chun HK. Tumor localization for laparoscopic colorectal surgery. World J Surg 2007;31(7):1491-5

4.       Trakarnsanga A, Akaraviputh T. Endoscopic tattooing of colorectal lesions: Is it a risk free procedure ? World J Gastrointest Endosc. 2011;3 (12):256-60

5.       Cappell MS, Courtney JT, Amin M. Black macular patches on parietal peritoneum and other extra intestinal sites from intraperitoneal spillage and spread of India ink from preoperative endoscopic tattooing: an endoscopic, surgical, gross pathologic and microscopic study. Dig Dis Sci 2010;55(9):2599-2605

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

Why is pancreatic cancer so aggressive?

The term pancreatic cancer is synonymously used for pancreatic ductal adenocarcinoma (PDAC) - one of the most aggressive of all cancers. Accounting for >80% of pancreatic cancers, PDAC is currently the third leading cause of cancer related deaths in USA and is projected to become second leading cause by 2025. The overall 5-year survival in PDAC for localized cancer (no spread beyond pancreas) is 37%, regional cancer (spread to nearby structures or regional lymph nodes) is 12% and for metastatic cancer (spread to distant parts of body such as liver, lungs of bones) the 5-year survival is 3%.

However, PDAC is not the only type of cancer pancreas and there are several other types of cancers arising from the pancreas. In a recent study using National Cancer Database of USA, survival analysis of different histologic types of pancreatic cancers reported median overall survival of 20.2 months for PDAC. In contrast median survival for cystic mucinous neoplasms with an associated invasive carcinoma was 52.6 months while median survival was not reached for neuroendocrine tumors, with 5-year overall survival rates of 84%¹. For this reason, biological behavior of PDAC is considered to be entirely different and more aggressive in comparison to other malignant pancreatic tumors.

The biological factors responsible for this aggressive nature of PDAC are not fully understood.

This article briefly summarizes some of the proposed mechanisms responsible for aggressive nature of PDAC.

Metastasis (i.e. spread to distant organs such as liver, lung or bone) is the most common cause of death in cancer patients. This holds particularly true for PDAC because most of the patients are diagnosed late with metastasis. The factors that may be responsible for this aggressive nature of PDAC may include

·         Late diagnosis

·         Early metastasis

·         Minimally effective systemic therapy

The proposed time for progression from the initiating event that began pancreatic cancer genesis until development of the cancer clone is an average of 11.7 years. Further it takes an average of 6.8 years for development of metastatic subclones and patients dying an average of 2.7 years later. Unfortunately, most patients with PDAC are diagnosed late towards the end of this 21-year average time span, indicating that the poor prognosis may be due to late diagnosis in the natural history of the disease².

Many studies have proposed that epithelial to mesenchymal transition (EMT) contributes to early dissemination of cancer cells and plays important role in invasion and metastasis of PDAC³. Several EMT inducing transcription factors such as Snail, Twist and Zeb1 have been studied. For the sake of simplicity, the current discussion is restricted to recently proposed Zeb1 factor which controls ability of cells to migrate and survive in early embryonic development. The Zeb 1 is blocked in normal cells but its re-activation in cancer cells leads to early dissemination of cancer cells throughout the body and quick adaptation of these cancer cells to the changing conditions in their new environment.  This leads to easier dissemination of cancer cells and early development of metastases⁴.  

In summary, PDAC is associated with limited survival with current therapies and further improvement in survival is likely to come with advancements either in diagnostic modalities for early detection of cancer or effective systemic therapy i.e. chemotherapy / immunotherapy, against metastases.

References

1.       Pokrzywa CJ, Abbott DE, Matkowskyj KA et al. Natural History and Treatment Trends in Pancreatic Cancer Subtypes. J Gastrointest Surg. 2019

2.       S Yachida and CA Iacobuzio-Donahue. Evolution and dynamics of pancreatic cancer progression. Oncogene 2013

3.       Zheng X, Carstens JL, Kim J et al. EMT program is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 2015

4.       Krebs AM, Mitschke J, Lasierra Losada M, Schmalhofer O et al. The EMT activator ZEB1 is a key factor for cellular plasticity and promotes metastasis in pancreatic cancer. Nat Cell Biol 2017

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

Solid Pseudopapillary Tumor / Neoplasm: Pitfalls in Management of Cystic tumor of Pancreas

A 13 year girl presented with history of mild upper abdominal pain of 6 years duration. The pain had increased in intensity for 1 month. However there was no history of use of intravenous analgesics or of hospitalization for pain relief. She was evaluated and diagnosed to have pancreatic pseudocyst and an open cystoenterostomy was attempted elsewhere. However operative findings at exploration precluded internal drainage. She had an uneventful recovery and was subsequently referred to higher center for further management.

On examination at our centre, she was found to be thin built with stable vitals. Abdominal examination was unremarkable except for well healed midline laparotomy scar.

All routine hematologic and biochemical investigations were within the prescribed normal range. A contrast enhanced computed tomography (CECT) scan of the abdomen was performed (Figure 1 & 2).

Figure 1.

Figure 1 of abdominal CECT shows a 6 cm tumour of the body and tail of the pancreas with solid and cystic components. 

Figure 2.

Figure 2 reveals an air pocket in the tumour at the site of previous biopsy.

 In view of young female patient with an indolent history and aforementioned image features, a diagnosis of solid pseudopapillary tumour (SPT) was made and distal pancreatectomy with splenectomy performed (Figure 3). Histopathology was confirmatory of SPT.

Our report reiterates that when managing cystic lesions of pancreas, a careful evaluation of history, biochemical investigations and imaging is essential to differentiate pseudocyst from cystic tumors. In most instances, the latter can be easily identified by an absence of documented episode of acute pancreatitis and cross sectional imaging depicting thick walled multilocular lesion with septae or solid components. Cyst fluid analysis (preferably endoscopic ultrasound guided) may be helpful when doubt exists in diagnosis. The features indicative of PC include high amylase content, inflammatory cytology and tumor markers (CEA, CA19-9, CA 72-4) within the specified normal range.¹

First described by Frantz in 1959, SPT of the pancreas is a rare neoplasm comprising of 1-2% of all pancreatic tumors.² This entity is encountered almost exclusively in young females in their second or third decade with male to female ratio of 1 is to 9. The tumor may be asymptomatic or associated with vague symptoms such as abdominal pain/discomfort, nausea or loss of appetite. Consequently SPTs often attain large size (3-16cms) by the time a diagnosis is made. At imaging, the characteristic CECT features include a large heterogeneous mass with solid and cystic components and areas of hyperattenuation representing hemorrhage.

With an increased understanding of the biological behavior [low malignant potential (15%) and excellent long-term prognosis in patients with metastatic disease the surgical management of SPTs has evolved over the last decade. The essence of management of primary tumor is on organ preservation. For the tumors in the pancreatic head, pylorus preserving pancreaticoduodenectomy and for the body and tail tumors into a spleen preserving distal pancreatectomy are acceptable procedures. However in patients with large tumors, spleen preservation may not always be feasible. Central resections for body tumors should only be performed at high volume centers. Due to a low incidence of lymph node involvement (<2%) a formal lymphadenectomy is not indicated. The currently available evidence supports metastectomy with 1 cm margin for liver metastases and debulking for peritoneal deposits. Overall 5-year survival is as high as 100% in patients undergoing surgical resection.³ Extended survival is still possible even with extensive disease with debulking surgery.

References

1.       Brugge WR, Lauwers GY, Sahani D, Fernandezdel,Castillo C, Warshaw AL. Cystic neoplasms of the pancreas. N Engl J Med 2004, 351:1218-26

2.       Frantz VK. Papillary tumors of the pancreas: Benign or malignant? Tumors of the pancreas. In: Atlas of Tumor Pathology, Section 7, Fascicles 27 and 28.Washington, DC, USA: Armed Forces Institute of Pathology, 1959:32-3.

3.       de Castro S. M. M, Singhal D, Aronson DC, Busch OR,TM van Gulik, Obertop H, D Gouma et al. Management of Solid-pseudopapillary Neoplasms of the Pancreas: a Comparison with Standard Pancreatic Neoplasms. World J Surg. 2007; 31(5): 1130–1135

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