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Gluteal Nodules in Patients with Metastatic Midgut Carcinoid Disease Treated with Depot Somatostatin Analogs

Unit of Endocrinology and Department of Radiology, University of Sheffield, Royal Hallamshire Hospital, Sheffield S10 2JF, United Kingdom

Address all correspondence and requests for reprints to: Dr. John Newell-Price, Unit of Endocrinology, University of Sheffield, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF, United Kingdom. E-mail: j.newellprice{at}sheffield.ac.uk.

	Abstract

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Context and Objectives: We were referred a patient with metastatic well-differentiated endocrine tumor of the small intestine (midgut carcinoid) in whom asymptomatic sc gluteal nodules had been identified on routine abdominal computed tomography and labeled as metastases. This prompted us to assess the prevalence and cause of these nodules.

Design and Setting: This was a retrospective, cross-sectional study at a university teaching hospital.

Methods: Routine abdominal computed tomography scans of 56 patients with metastatic midgut carcinoid were analyzed by two independent radiologists, blinded to treatment status (depot somatostatin analogs).

Main Outcome Measures: Number of patients with nodules, number of injections, and duration and total cumulative dose per patient were assessed.

Results: No nodules were detected in 13 patients not on depot somatostatin therapy. Nodules were found in 29 of 43 patients (67%) on somatostatin analog therapy: 16 of 22 patients on lanreotide Autogel, five of 12 patients on octreotide LAR only, and eight of nine patients who had been treated with both somatostatin analogs. There was no difference in the clinical state of those with or without nodules. Per patient, the average number was seven, and average size was 1 cm. Presence of nodules was significantly associated with total number of injections (P = 0.024), duration on treatment (P = 0.022), and cumulative dose of lanreotide Autogel (P < 0.001). Nodules underwent involution on follow-up imaging.

Conclusion: Patients with metastatic midgut carcinoid tumors have large numbers of asymptomatic sc nodules in the gluteal area when on either depot somatostatin analog, but these resolve over time. This clear observation gives reassurance to patients and those managing them that such nodules are unlikely to represent metastases.

	Introduction

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Well-differentiated endocrine tumors of the small intestinal tract (hereafter referred to as midgut carcinoids) are typically slow-growing tumors, which frequently present with metastases, especially to the liver (1). Disease stage has a significant influence on prognosis with the best 5-yr survival of 93% in localized disease, falling to 74% in regional disease (2). The presence of metastases is an important predictor of death (3), and the lowest survival is found in patients with more than five distinct liver metastases and the presence of the carcinoid syndrome (4).

Somatostatin analogs play a key role in the management of patients with active carcinoid syndrome, are highly effective in control of symptoms (5, 6, 7), and may have an antiproliferative effect on tumor growth (8). Commercially available somatostatin analogs exert their effects through interaction with somatostatin receptors (predominantly SST2 and SST5) expressed on tumors. The two main long-acting depot analogs used are the slow-release im formulation of octreotide, octreotide LAR (dose 10–30 mg), and the slow-release depot deep sc preparation lanreotide Autogel (dose 60–120 mg), both usually administered every 4 wk in the gluteal area.

Computed tomography (CT) is the main means of imaging used for surveillance in patients with these tumors to aid determination of extent of disease, plan for palliative or potentially curative surgery, and monitor response to treatment (9, 10). We had been referred a patient with carcinoid syndrome with sc gluteal nodules identified on surveillance CT, which were not clinically apparent but that had been labeled as metastases (Fig. 1A). If these represented metastatic disease, it would have important implications for future management. However, metastases to the skin are reported as a late manifestation of neuroendocrine tumors, are rare, and may become extremely painful (11). Because of the uncertainty as to whether these were sc metastatic deposits or nodules secondary to depot somatostatin analogs, we decided to investigate the prevalence of these nodules in patients with metastatic midgut carcinoid.

View larger version (69K): [in this window] [in a new window]   FIG. 1. A, Representative axial CT scan showing the presence of sc nodules in the gluteal area of a patient with metastatic midgut carcinoid diagnosed with sc metastases. B, Resolution of nodules with time: i and ii, nodules appear to shrink and disappear with time; nodules in a patient on lanreotide Autogel (i), and 6 months later (ii), note involution of size; iii and iv, a nodule in a patient on octreotide LAR (iii) and 1 yr later (iv), note disappearance of nodule.

	Patients and Methods

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Two independent radiologists (L.-Q.H. and A.B.) blinded to clinical and treatment status assessed the scans of these patients. A unique coding number identified each patient. The CT scans were all interpreted on a digital workstation with total freedom for window and level adjustments and for the magnification of each image at the time of the analysis. The radiologists were aware that all the patients were suffering from a midgut carcinoid tumor and that all scans had to be assessed for the presence of sc nodules in the gluteal area. A patient was considered positive when at least one nodule was detected. Scans difficult to interpret were discussed by both radiologists to reach a final decision.

For each patient, the first scan showing sc nodules was analyzed further by assessing number, position, and size of nodules. These characteristics were assessed on follow-up scans.

The sample was divided into four groups: group A, never on treatment with somatostatin analogs; group B, on lanreotide Autogel; group C, on octreotide LAR; and group D, had received both treatments. The mean number of weeks on somatostatin analogs, the mean number of injections, and the total cumulative dose of the particular analog used by each patient were calculated.

Statistical analysis

Demographic data for the sample are presented. Descriptive statistics are given as means with 95% confidence intervals (CI). Pearson correlation statistic was used to analyze data based on the presence or absence of nodules vs. treatment and to evaluate the effect of different treatments on development of sc nodules. To make between-group comparisons on continuous-type variables for two groups separated by absence or presence of nodules, the independent-sample t test was used. Multiple regression analysis was used to assess for confounders. A significant result was taken as P < 0.05.

	Results

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Patients

A total of 131 patients attended the gastroenteropancreatic Neuroendocrine Tumor Clinic in Sheffield from 2004–2007. In all, 59 patients had known metastatic midgut carcinoid. Three patients were excluded because their scans, having been done in other hospitals, were not available for review. Fifty-six patients, who had been imaged on the same CT scanner, had their scans analyzed by two blinded independent radiologists. Demographic data are given in Table 1.

None of the patients in group A (never treated, n = 13) had nodules. Overall, a total of 29 of 43 patients (67%) who had received somatostatin analogs were found to have sc nodules, (Fig. 2A). Of these, 16 of 22 patients (73%) in group B (lanreotide Autogel only), five of 12 patients (42%) in group C (octreotide LAR only), and eight of nine patients (89%) in group D (had received both treatments) had nodules (Fig. 2B). By correlation analysis, there was a nonsignificant trend toward group B (lanreotide Autogel only) having nodules, compared with either group C (octreotide LAR only) or D (both treatments) (P = 0.055). This was corroborated by comparison with group A (never treated); those on lanreotide Autogel had a stronger association with the presence of sc nodules (P < 0.001) than did the group on octreotide LAR (P = 0.015).

View larger version (18K): [in this window] [in a new window]   FIG. 2. Relationship between somatostatin analogs and sc nodules. A, Twenty-nine of 43 patients (67%) on somatostatin analog treatment developed sc nodules, whereas in those patients who had never received a somatostatin analog no one (zero of 13) developed nodules (P < 0.001); B, both Lanreotide Autogel (group B) and octreotide LAR (group C) cause nodules, 73 and 42%, respectively. The tendency is greater with lanreotide Autogel (P < 0.001 vs. no treatment). Eighty-nine percent of those who had received both treatments (group D) had nodules.

As a group, those on depot somatostatin therapy had a significantly increased likelihood of nodules with a greater number of injections (P = 0.024) and longer duration of treatment period (P = 0.022). For those on lanreotide Autogel alone, those who had nodules, compared with those without, had on average received 25 more injections (95% CI, 11–40) and had received these for 94 more weeks (95% CI, 50–138). There was a significant relationship between the mean cumulative dose of lanreotide Autogel and sc nodules (P < 0.001), with an average higher dose of 1876 mg (95% CI, 937-2814). In contrast, there were no significant differences in dose and duration of treatment for those on octreotide LAR alone between those with and without nodules; those patients with nodules had on average received 89 mg more of octreotide LAR (95% CI, –366 to 544; P = 0.68). Multiple regression analysis did not reveal any significant influence of age (P = 0.34) or gender (P = 0.54) on the development of nodules.

Nodule characteristics

The mean size of the nodules was 1 cm (95% CI, 0.9–1.1), with no difference in size between lanreotide Autogel and octreotide LAR groups. In 96% of patients who had nodules, these were multiple, usually bilateral, and found at different levels. Only one patient had a solitary nodule. The average number of nodules was seven (95% CI, 5–9). Eighty-three percent of all nodules in those on lanreotide Autogel were closer to the surface, whereas 17% were closer to the muscle layer. On the other hand, only 57% of those nodules associated with octreotide LAR therapy were close to the surface, whereas 43% were closer to the muscle layer. There was no evidence that the nodules were more prevalent in those with less sc fat. Ten index nodules in patients receiving either analog were randomly selected, and the characteristics were assessed on follow-up scans. In all (100%), they had either disappeared or decreased in size after 1 yr (Fig. 1B).

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
Our data show, for the first time, that the presence of sc gluteal nodules in a large number of patients with midgut carcinoid disease is associated with the use of somatostatin analogs. Importantly, none of the patients in the control group (no somatostatin analog) had any gluteal nodules, although all had metastases elsewhere. These nodules were detected by routine CT scanning rather than by being clinically apparent and otherwise had no impact on the clinical state of the patients. Such nodules may, however, be apparent if specifically sought on clinical examination. Surgical resection of hepatic metastases has been associated with improvement in survival and symptomatic improvement (13). The presence of metastases elsewhere may influence the decision for surgery or choice of other medical therapy. Moreover, there is the potential for great anxiety when results of CT scans are discussed with patients and sc nodules considered to be potential metastases.

Octreotide LAR and lanreotide Autogel are the two commonly used extended-release formulations. We cannot state for certain as to the etiology of the nodules but did not find any nodules in other sc areas. Although there is an increased tendency to develop nodules on lanreotide Autogel, compared with octreotide LAR, the difference between groups was not significant, although the relatively small subgroup numbers will have limited the power to detect any differences. There was no difference in the radiological characteristics of the nodules between the two drugs, although there was a difference in position. Nodules associated with use of octreotide LAR tended to be closer to the muscle layer, whereas those caused by lanreotide Autogel were mainly closer to the surface. The most likely reason for this is that lanreotide Autogel is given sc (deep), whereas octreotide LAR is injected im. The majority of patients receive their injections in the community, and thus we are unable to comment directly on the influence of injection technique on the presence of nodules, but this is a likely factor because there did not appear to be a relationship with cumulative dose of octreotide LAR and the presence of nodules. Repeated injections may also cause induration and hardening of the sc area, making it harder for healthcare professionals to inject both sc and im. It is surprising that we found nodules in the sc layer in patients on octreotide LAR, and this may highlight this problem.

Another explanation for these nodules is a granulomatous reaction to the drug. Lanreotide may cause foreign-body granulomas, as shown in a single patient on biopsy (14). Granuloma formation has also been reported in a patient on octreotide LAR, which was detected by [¹¹¹In]octreotide scintigraphy (15). We did not perform biopsies of the nodules in our patients, and given our data, we feel that this is not indicated and would not be a reasonable investigation, especially because the nodules appear to resolve with time.

Because it is not routine clinical practice to perform abdominal CT scans on patients with acromegaly, we are unable to comment as to whether they too have nodules disclosed on CT when on somatostatin analogs, but it seems likely.

In conclusion, development of sc gluteal nodules should be anticipated in patients with midgut carcinoid treated with depot somatostatin analogs, especially with a longer duration of treatment, and our data strongly suggest that these are not metastases and that patients can be reassured of this.

	Footnotes

 
Disclosure Information: All authors have nothing to declare.

First Published Online February 26, 2008

Abbreviations: CI, Confidence interval; CT, computed tomography.

Received January 4, 2008.

Accepted February 15, 2008.

	References

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Debono, M. Articles by Newell-Price, J. Search for Related Content PubMed PubMed Citation Articles by Debono, M. Articles by Newell-Price, J. Related Collections Endocrine Oncology