Neuroendocrine Cancer: Fibrosis – an unsolved mystery?

What happened to me?

Since I was diagnosed in 2010, I’ve always known about a fibrosis issue in my retroperitoneal area.  It was identified on the very first CT scan which triggered my diagnosis.  Here’s how the radiologist described it – “There is a rind of abnormal tissue surrounding the aorta extending distally from below the renal vessels. This measures up to 15mm in thickness”.  Followed by a statement saying that it was “almost certainly malignant”.  The second and third scans would go on to describe as “retroperitoneal fibrosis” and “a plaque-like substance”.  Interestingly the fibrosis itself does not appear to ‘light up’ on nuclear scans indicating it might not be cancerous.  Nonetheless it doesn’t sound like a fun thing to have given that it can potentially impact the kidneys and impinge on vital structures such as the aorta, Inferior Vena Cava (IVC) and the ureters!

I really didn’t know what to make of this issue at diagnosis but I knew the aorta was pretty important!  Fortunately, I had a surgeon who had operated on many NET patients and had seen this issue before. In fact after my first surgery, he described it as a “dense fibrotic retroperitoneal reaction encircling his aorta and cava (inferior vena cava (IVC))”.  Fortunately, my surgeon was known for difficult and extreme surgery, so as part of the removal of my primary, he also spent 3 hours dissecting out the retroperitoneal fibrosis surrounding these important blood vessels and managed 270-degree clearance. The remnant still shows on CT scans. Some of the removed tissue was tested and found to be benign, showing only florid inflammation and fibrosis (thankfully).  Other than a delay in my liver surgery (due to lack of time to address this at the same time as my primary removal), the removal of some of this fibrosis presented some stability at the time. That said, the abstract papers below have led me to believe that my retroperitoneal fibrosis is clinically significant.

Fast forward to routine surveillance in 2018 which coincided with a change of oncologist,  it was noted on my surveillance scan that the retroperitoneal fibrosis was potentially impinging on important vessels in this area, particularly the left ureter but including some blood vessels. I had a mini workup following that observation.  Included in that was my first Ga68 PET which confirmed potentially active lymph nodes in the retroperitoneal area that might be contributing to continued or new fibrosis growth.  In order to further assess the risk to my kidneys, I had a different nuclear scan known as a Renal MAG3. This scan looks at the blood supply, function, and flow of urine from the kidneys. The output informed my MDT and surgical team to look at treatment options to counter the risk of damage and the timing of potential surgery to correct the issue. I’m happy to report that the MAG3 scan confirmed there are no blockages to my kidneys or bladder. It did confirm my right kidney is doing 60% of the work, the suspected left one is covering the remaining 40% effort.  Apparently, it’s pretty normal that it isn’t exactly 50/50.  Surgery is now on the back burner (phew!).  The kidney function will be monitored closely going forward.

Background

It has long been observed that certain Neuroendocrine Tumours (NETs) are often associated with their ability to secrete hormones and these substances are thought to be responsible for the collection of symptoms which lead to clinical syndromes.  The issue of fibrosis is normally related to the most common NET syndrome known as carcinoid syndrome.

One of the lesser-known aspects of this disease is the development of fibrosis, both local and distant. They can also result in incidental diagnoses of NETs after causing abdominal obstructions. These fibrotic complications may lead to considerable morbidity in 3 main areas.

The most well-known form of fibrosis is ‘Hedinger Syndrome’ (so-called Carcinoid Heart Disease) tightly associated with midgut NETs and will not be covered further. However, mesenteric fibrosis is actually more common and also associated with midgut NETs.  There are other less common locations involved including retroperitoneal fibrosis, pleural and pulmonary fibrosis and skin fibrosis.

The mesentery and retroperitoneum areas

The mesentery and retroperitoneum are complex to describe but think of the mesentery as something holding the small intestine together with all its folds and the retroperitoneum describes the part of the abdomen that is generally closer to your backbone than to your belly button, i.e. behind the intestines.  According to a paper (abstract linked below) by Professor Martyn Caplin (et al) regarding mesenteric fibrosis, “it often has a characteristic appearance of a mesenteric mass with linear soft tissue opacities radiating outward in a “wheel spoke” pattern associated with distortion of the surrounding tissues”  (see graphics below).  This is similar the findings on my diagnostic scans and I have seen this same presentation numerous times in my patient group.

Often labelled ‘Desmoplasia’, it is easily spotted on CT and MRI scans and is one of the unusual features of NETs vs other types of cancer.  Some examples are below:

What causes it, what effect does it have and how can it be treated?

As with Hedinger Syndrome, which mostly causes right-sided fibrosis in the heart, mesenteric and retroperitoneal fibrosis (and others) is thought to be caused by the excess secretion of serotonin (5-HT) from NETs. I say ‘thought’ but no one really knows for sure.  But it appears to be a result of lymph node metastases in the mesentery (as shown  in the diagrams above) and there is some suggestion that retroperitoneal fibrosis may just be an extension of mesenteric fibrosis that overlaps/extends into the retroperitoneal cavity.  This would fit with the anatomic layout of that area i.e. the mesenteric root sits directly anterior to the retroperitoneum. When fibrosis becomes bulky, it can encase vessels, tether bowel, extend posteriorly and compress retroperitoneal structures (Reference 7).

There are a few quite a few studies (some recent) on the subject which I’ll provide abstracts for here.

Uppsala Hospital Sweden. In one study entitled “Clinical signs of fibrosis in small intestinal neuroendocrine tumours” first published in November 2016 by Uppsala Hospital Sweden, it said that it was caused by serotonin and other cytokines released from tumour cells and which may induce fibrosis, leading to carcinoid heart disease and abdominal fibrotic reactions. A cohort study of patients with SI NETs diagnosed between 1985 and 2015 was carried out – a total of 824 patients. Clinically significant abdominal signs and symptoms of fibrosis occurred in 36 patients. Of these, 20 had critically symptomatic central mesenteric fibrosis causing obstruction of mesenteric vessels, and 16 had retroperitoneal fibrosis causing obstructive uropathy with hydronephrosis (the swelling of a kidney due to a build-up of urine).  Extensive fibrosis causing mesenteric vessel obstruction and/or obstructive uropathy was more often associated with symptomatic and advanced disease encompassing lymph node metastases in the mesenteric root, para‐aortic lymph node metastases, as well as liver metastases and peritoneal carcinomatosis. Palliative intervention in terms of superior mesenteric vein stenting or resection of central mesenteric metastases and/or percutaneous nephrostomy and J stent treatment was beneficial in the majority of the patients. They concluded by saying that extensive abdominal fibrosis associated with clinically significant symptoms of intestinal ischaemia and/or obstructive uropathy was linked to advanced disease in patients with SI NETs. Prompt recognition and minimally invasive intervention were effective in disease palliation.

Royal Free Hospital. In another paper entitled “Neuroendocrine tumours and fibrosis: An unsolved mystery?, published by Professor Martyn Caplin of the Royal Free (and others), where this issue is discussed alongside the role of serotonin, growth factors, and other peptides in the development of NET related fibrotic reactions.  They also suggested serotonin as the main culprit in both CHD fibrosis and in mesenteric/retroperitoneum and expressed many of the factors above.  This study suggested that up to 50% of SI NET patients may be involved but looking at both reports together indicates that the first study above only isolated clinically significant cases whereas Royal Free looked for signs in all cases.

Another paper (a paid subscription) from Royal Free (Caplin et al) indicated that the severity of mesenteric desmoplasia did not seem to demonstrate a statistically significant effect on overall survival or long-term outcome (taken from a study of 147 patients at Royal Free London). Sounds like good news but there are clearly consequences that could arise from the issue.

I do not have access to all the full texts above, only the abstracts which I’ve linked above.

One older publication authored by a known UK NET endocrinologist, covered some of the above issues but added that fibrosis in the pleural/pulmonary areas and the skin could also be associated.   For ease of reference, the following extracts are cited to Fibrosis and carcinoid syndrome: from causation to future therapy Maralyn Druce, Andrea Rockall and Ashley B. Grossman Druce M. et al. Nat. Rev. Endocrinol. 5, 276–283 (2009); doi:10.1038/nrendo.2009.51

“Mesenteric fibrosis and carcinoid syndrome.  Intestinal fibrosis in a series of 37 patients with jejunoileal carcinoid tumors, 8 of 12 patients with bowel obstructions had evidence of fibrosis or kinking of the bowel.6 among 36 patients with carcinoid syndrome who were seen at Yale University, 15 either had fibrosis at the time of surgery or developed it subsequently. In a surgical series of 121 patients with midgut carcinoid tumors, 75 required laparotomies, due to abdominal pain; of these patients, 59 were noted to have marked mesenteric fibrosis at the time of surgery. Spread of the primary tumor into the mesentery and peritoneum can result in a marked fibrotic reaction. This fibrosis can mat together multiple loops of bowel and result in kinking, ischemia, volvulus and obstruction.

Retroperitoneal fibrosis. True retroperitoneal fibrosis is a rare clinical entity, in which inflammation results in fibrosis throughout the retroperitoneum. In two-thirds of patients, this condition is idiopathic. The majority of cases that are not idiopathic are associated with drugs, such as antihypertensive agents and methysergide. Although retroperitoneal fibrosis is not commonly seen in the context of carcinoid syndrome and has not been reported in any recent, major review, several cases have been reported in literature.

Note:  some sources suggested that NET related retroperitoneal fibrosis may be mesenteric fibrosis that has grown into the retroperitoneal cavity.  I’m looking for an authoritative reference.

Pleural and Pulmonary Fibrosis. In a review of 50 patients with carcinoid tumors who presented to a single unit over 9 years and were examined using CT, 14 patients had pleural thickening, and in 9 of these cases, no other attributable cause was established. All 14 patients had developed this pleural thickening within 2 years of being diagnosed as having carcinoid syndrome, and 7 of the 9 patients also had fibrosis elsewhere, for example, in the heart valves, skin, or mesentery. Carcinoid syndrome has rarely been described as a cause of alveolar fibrosis, but fibrosis elsewhere in the lung occurs more frequently. in a series of 25 patients known to have peripheral carcinoid tumors of the lung, 19 displayed hyperplasia of neuroendocrine cells elsewhere in the lung, and 8 patients (25%) had lesions of obliterative bronchiolitis, including 2 with asymptomatic obstruction of airflow. These data suggest that bronchiolar fibrosis is not uncommon, although it is usually subclinical.

Skin fibrosis. Dermal fibrosis may be primary or secondary to peripheral vasospasm, which occurs in response to vasoconstrictor substances that are secreted by the tumor. Carcinoid syndrome associated with scleroderma has been reported: in one series, its prevalence was 2 cases in 25 individuals. This complication of carcinoid syndrome is usually a late feature and may be attenuated by the use of cyproheptadine hydrochloride, parachlor phenylalanine and prednisolone, which suggests a causative role for tryptophan metabolism and 5-HT”

Update as at 3rd Feb 2021

Thanks to a grant from the NET Research Foundation, a team led by leading NET specialist Professor Martyn Caplin of Royal Free London and experts in Erasmus Centre in Netherlands, will explore the underlying molecular cause of mesenteric fibrosis, as well as develop new diagnostic and imaging tools to treat the condition. This is great news.  Read more here.  Read some of the output from the research here (warning – a bit technical)

Update as at 13th May 2023

Every day is a school day. See update of an incidental finding of a hydrocele first noticed Jan 2010 and then picked up on diagnosis in July 2010 ……… or was it more than just incidental?  Now I think it was a side effect of retroperitoneal fibrosis. Click here to read more.  I would  like to hear from anyone with a small intestine NET with fibrosis and who also presented with a hydrocele before or after the official diagnosis.

Update as at 27th December 2025

Some more references added:

• NET RF poster – see above update 3rd Feb 2021
• In this 2025 review,  there is no progress further than above.  There is no effective medical therapy to treat or reverse this phenomenon. Further research into the pathophysiology of this desmoplastic reaction should provide insights into future development of targeted anti fibrotic therapies for SINEN-associated desmoplasia.  Spyroglou, A., Violetis, O., Iliakopoulos, K. et al. Mesenteric Fibrosis in Neuroendocrine Neoplasms: a Systematic Review of New Thoughts on Causation and Potential Treatments. Curr Oncol Rep 27, 642–655 (2025). See Reference 6 below. 
• A 2024 article which is quite technical but suggests potential targets for research.  Graf SD, Keber CU, Hattesohl A, Teply-Szymanski J, Hattesohl S, Guder M, Gercke N, Di Fazio P, Slater EP, Jesinghaus M, Denkert C, Bartsch DK, Lehman B. Mesenteric fibrosis in patients with small intestinal neuroendocrine tumors is associated with enrichment of alpha-smooth muscle actin-positive fibrosis and COMP-expressing stromal cells. J Neuroendocrinol. 2024 Feb;36(2):e13364. doi: 10.1111/jne.13364. Epub 2024 Jan 21. PMID: 38246597.  See Reference 7 below. 

Summary

These issues need to be identified early on in diagnostics, preventative treatment considered, and then monitored going forward.  Potential complications may include (but not be limited to) bowel and blood vessel obstructions.  NET related Retroperitoneal fibrosis also needs to be monitored as potential complications may include (but not be limited to) obstructive uropathy.

For those worried about this issue, please note that when you look at the statistics from Uppsala, only 4.5% of cases are classed as clinically significant and with the retroperitoneal area, the figure reduces to 2%.

Resources used:

1. Retroperitoneal Fibrosis – StatPearls – NCBI Bookshelf (nih.gov)
2. Fibrosis and carcinoid syndrome: from causation to future therapy | Nature Reviews Endocrinology
3. Neuroendocrine tumors and fibrosis: An unsolved mystery? – Laskaratos – 2017 – Cancer – Wiley Online Library
4. Prognostic Factors for Survival among Patients with Small Bowel Neuroendocrine Tumours Associated with Mesenteric Desmoplasia | Neuroendocrinology | Karger Publishers
5. Clinical signs of fibrosis in small intestinal neuroendocrine tumours | British Journal of Surgery | Oxford Academic (oup.com)
6. Mesenteric Fibrosis in Neuroendocrine Neoplasms: a Systematic Review of New Thoughts on Causation and Potential Treatments
7. Mesenteric fibrosis in patients with small intestinal neuroendocrine tumors is associated with enrichment of alpha‐smooth muscle actin‐positive fibrosis and COMP‐expressing stromal cells – Graf – 2024 – Journal of Neuroendocrinology – Wiley Online Library
8. NET RF poster – here

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