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 include (but not limited to) diarrhea, flushing and wheezing.  One of the lesser known aspects of this disease is the development of fibrosis, both local and distant. These fibrotic complications may lead to considerable morbidity. They can also result in incidental diagnoses of NETs after causing abdominal obstructions.

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.

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 graphic below).

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.

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:

Axial CT image of a patient with a metastatic neuroendocrine tumor that demonstrates retroperitoneal thickening and fibrosis (arrow).

What causes it, what problems does it cause 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.  There’s a few quite recent studies on the subject which I’ll provide abstracts 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 was effective in disease palliation.

Royal Free Hospital. In another fairly recent paper entitled “Neuroendocrine tumors 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 recent paper (also 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 texts above, only the abstracts which I’ve linked above (all only available from paid subscriptions).

One older publication authored by known UK NET expert 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 laparotomy, 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. 

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”

What happened to me?

Since I was diagnosed in 2010, I’ve always known I’ve had a fibrosis issue in the retroperitoneal area, as it was actually identified on my 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”.  He went on to describe that “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 was not cancerous (see below).

I really didn’t know what to make of this issue at diagnosis, although I did know the aorta was pretty important!  Fortunately I had a surgeon who had operated on many NET patients and has seen this issue before.  After my first surgery, he described it as a “dense fibrotic retroperitoneal reaction encircling his aorta and cava (inferior vena cava (IVC))”. 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).  That said, the abstract papers above has led me to believe that my retroperitoneal fibrosis is clinically significant.

Routine surveillance in 2018 has picked up that retroperitoneal fibrosis is potentially impinging on important vessels in this area, particularly the left ureter but including some blood vessels. A follow up Ga68 PET confirms active lymph nodes in the retroperitoneal area that might be contributing to continued or new fibrosis growth.

In order to further assess risk to my kidneys, I had a different nuclear can known as a Renal MAG3. This scan looks at the blood supply, function and flow of urine from the kidneys. The output will inform my MDT and surgical team looking 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.

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.  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%.

Neuroendocrine Cancer is normally slow growing BUT …..

Thanks for reading