Renal Neuroendocrine Neoplasms: A Single-center Experience

Journal Pre-proof Renal neuroendocrine neoplasms: a single-center experience Patrick W. McGarrah, M.D., Gustavo F.M. Westin, M.D., M.P.H., Timothy J. Hobday, M.D., Joseph A. Scales, M.D., Johann P. Ingimarsson, M.D., Bradley C. Leibovich, M.D., Thorvardur R. Halfdanarson, M.D. PII:

S1558-7673(19)30354-4

DOI:

https://doi.org/10.1016/j.clgc.2019.11.003

Reference:

CLGC 1395

To appear in:

Clinical Genitourinary Cancer

Received Date: 13 July 2019 Revised Date:

26 November 2019

Accepted Date: 27 November 2019

Please cite this article as: McGarrah PW, Westin GFM, Hobday TJ, Scales JA, Ingimarsson JP, Leibovich BC, Halfdanarson TR, Renal neuroendocrine neoplasms: a single-center experience, Clinical Genitourinary Cancer (2020), doi: https://doi.org/10.1016/j.clgc.2019.11.003. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc.

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Renal neuroendocrine neoplasms: a single-center experience Patrick W. McGarrah, M.D.1, Gustavo F. M. Westin, M.D., M.P.H.,2,3, Timothy J. Hobday, M.D.2, Joseph A. Scales, M.D.4,5, Johann P. Ingimarsson, M.D.,4,6, Bradley C. Leibovich, M.D.4 Thorvardur R. Halfdanarson, M.D.2 1

Department of Internal Medicine, 2Division of Medical Oncology, 3University Cancer & Blood Center, 3320 Old Jefferson Road, Building 700, Athens, GA 30607, 4Department of Urology Mayo Clinic, 200 First Street SW, Rochester, MN 55905, 5Urology Clinics of North Texas, 6124 W. Parker Road, Suite 434, Plano, Texas 75093, 6Maine Medical Partners Urology 100 Brickhill Avenue, South Portland, ME 04106. Corresponding author: Thorvardur Halfdanarson, MD [email protected] Mayo Clinic 200 First Street SW Rochester, MN 55905

Running title: Renal neuroendocrine neoplasms at Mayo Clinic

Keywords: renal carcinoid, kidney carcinoid, renal neuroendocrine carcinoma, horseshoe kidney, somatostatin analog, everolimus, rare cancers

Word count: 3551

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Conflict of Interest Dr. Halfdanarson declares research support from: Ipsen, Thermo Fisher Scientific, Agios, and ArQule; consultancy (advisory boards) with Lexicon, Advanced Accelerator Applications, Novartis, and Curium. Dr. McGarrah, Scales, Hobday, Ingimarsson, Leibovich, and Westin declare no conflicts.

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MicroAbstract: Renal neuroendocrine neoplasms are rare, with little to no data available on prognosis and treatment outcomes. We present the largest single-institution series of 17 patients, with a median follow-up of 62.8 months. After aggressive resection, the median time to recurrence was 18 months, and median overall survival was 143 months. Somatostatin analogs provided disease stability in 4 of 9 patients.

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malignancies and the available literature is very limited. The natural history and response to

13

treatments is not well characterized.

Abstract

Background: Primary neuroendocrine neoplasms (NENs) of the kidney are exceedingly rare

14 15

Objective: We aimed to describe the presenting features, demographics, tumor characteristics,

16

and treatment outcomes of patients with renal NENs.

17 18

Methods: We performed a retrospective analysis of all Mayo Clinic patients with a tissue

19

diagnosis of a primary renal neuroendocrine neoplasm. Baseline patient and surgical pathologic

20

features were collected, as well as treatment modalities. Time to recurrence after resection and

21

overall survival were estimated with survival analysis. SEER data was used to estimate

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population-wide incidence and overall survival.

23 24

Results: Seventeen patients were included with a median follow-up of 62.8 months. Distant

25

metastasis was present in 29 percent at diagnosis, with 76 percent experiencing distant metastasis

26

at any point. Twenty-four percent had horseshoe kidney. Fourteen of 17 patients had surgical

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resection with no evidence of disease after surgery. Ten of these patients had documented

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recurrence. The median time to recurrence was (TTR) 18 months (95% CI 9 - 46). Only one

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patient out of ten had a radiographic response to systemic therapy. Four out of 9 patients had

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stable disease with somatostatin analogs (SSA). The median overall survival (OS) was 143

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months (95% CI 50 - 143).

32 33

Conclusion: Renal NENs are rare malignancies affecting mostly middle-aged patients, with

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distant metastasis being common. About half of patients experience stable disease with SSAs.

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The OS is usually greater than 5 years.

36 37 38

Introduction Primary renal NENs are exquisitely rare neoplasms with only a handful of reports

39

available in the literature describing their behavior. Most reviews estimate that approximately

40

90-100 cases have been described in the literature.1-3 Many series are compilations of case

41

reports from multiple institutions, the largest of which described 56 cases.4 Several series of

42

single institution experiences have been published, including 7 cases from Cleveland Clinic, 9

43

from MD Anderson Cancer Center, and most recently 5 from the University of Minnesota.2, 5

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Certain findings are consistent across the series. Nearly every study mentions an association of

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roughly 20-30% of cases arising from horseshoe kidneys. Carcinoid syndrome is rare and few

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tumors were considered functional. Metastasis is common, usually to regional lymph nodes and

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to the liver. Most series focus on “carcinoid” tumors that are well-differentiated; however the

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series from MD Anderson and Cleveland Clinic also described poorly differentiated large and

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small cell carcinomas. These, as expected, behaved much more aggressively. For the well-

50

differentiated NENs, survival was prolonged to several years despite resistance to chemotherapy

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and aforementioned frequent metastasis. Given the rarity of renal NENs, few if any reports have

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offered summary statistics regarding OS and TTR following resection. There is even less data to

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quantify response rates to systemic therapy as most reports published to date do not offer

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information on the results of systemic therapy. Korkmaz et al describe a single patient with a

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renal carcinoid who achieved stable disease for 7 months on octreotide.6 A review of 22 case

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reports in the literature of renal small cell carcinoma by Majhail et al found that patients who

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received platinum-based therapy survived longer than those who did not (20 vs 8 months).7 Our

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series of 17 patients is the largest single-institution series to date, and we attempted to fill in

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some of the knowledge gaps regarding the characteristics of this rare entity as well as the

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outcomes of both surgical and systemic therapy.

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Methods

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We performed a retrospective analysis of all patients at Mayo Clinic diagnosed with a

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primary renal NEN between 1997-2017. The project was approved by an independent ethical

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committee in the form of the Mayo Clinic Institutional Review Board (IRB). Data were extracted

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from the electronic medical record. All biopsy specimens had been read internally. Pathology

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was reviewed to verify the diagnosis of a renal NEN. Histologic grade, Ki-67 proliferative index,

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and the degree of differentiation were recorded when available. Tumor stage was occasionally

69

reported, but not collected as there is no official staging system for renal NENs.8

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The primary endpoints were time to recurrence and overall survival. Time to recurrence

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was defined as interval between a complete surgical resection of all known disease (including

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primary tumor bed resection, lymphadenectomy, and hepatic metastasectomy) and radiographic

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evidence of tumor recurrence. Overall survival was defined as the interval between time of tissue

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diagnosis and death of any cause. Response to systemic or radiation therapy was assessed by

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reviewing imaging studies and reports and assigning the result as response, stable disease, or

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progression.

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In an attempt to characterize the epidemiology of renal NENs, we analyzed data from the

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Surveillance, Epidemiology and End Results registry. We searched for cases of primary renal

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malignancy with a tumor type of “carcinoid” or “neuroendocrine carcinoma.” Incidence and

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survival were estimated using the SEER*Stat 8.3.2 software. Survival was estimated with the

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Kaplan-Meier method using JMP 14.

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Results Seventeen patients were included in our series with a median duration of follow-up of

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62.8 months. Basic demographics and initial presentations are detailed in Table 1. The median

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age at diagnosis was 47, with a range of 21-82. Pain was the most common symptom prompting

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evaluation and eventual diagnosis, present in 59 percent of patients. Three patients had

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functional tumors defined by symptoms of flushing or diarrhea suggestive of carcinoid

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syndrome.

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Sixteen patients underwent surgical resection, and in 13 patients this included lymph

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node dissection. Twelve of these 13 had node involvement. Five patients had distant metastasis

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at diagnosis manifesting as either bone (in two patients) or liver metastases. Seventy-six percent

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of patients had distant metastasis at any point during follow-up (Table 1). Four patients (24%)

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had horseshoe kidneys. All eight patients who underwent functional imaging of somatostatin

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receptor avidity (either with somatostatin receptor scintigraphy or 68Ga-DOTATATE PET

7 96

imaging) showed positive radiotracer uptake indicating presence of somatostatin receptors on the

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surface of the tumor cells.

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Nine patients had tumors that were well-differentiated, with no differentiation comment

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present in 6 cases. The other two were well- and well- to moderately differentiated, respectively.

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No tumor was poorly differentiated or reported as small or large cell neuroendocrine carcinoma.

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Reported tumor grades were variable as some were in older grading scales using 4 grades. Five

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tumors were grade 2 of 3, and one tumor was grade 1 of 3. Most tumors were not evaluated for

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Ki-67 proliferative index, of those that were, 2 were simply reported as less than 5 percent. Three

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tumors fell in the range of 4-8 percent. One tumor was reported out as 10-15 percent Ki-67

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positive.

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All but one patient underwent surgical resection. Treatment modalities are detailed in

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Table 2. These were radical nephrectomies except for one patient who had a partial nephrectomy.

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Eighty-eight percent of patients had no residual disease after resection. Ten of these 14 patients

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had documented recurrence during follow-up, and 4 were lost to follow-up. Fourteen patients

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received systemic therapy, with 10 receiving it for recurrence after total resection. Of the patients

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receiving systemic therapy for a reason other than recurrence after total resection: one patient

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was not resected, two had residual disease after resection, and one received adjuvant 5-FU

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concurrently with external beam radiation therapy as a radiosensitizer. Somatostatin analogs

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were by far the most common agents used. Eight patients received systemic therapy beyond first-

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line due to progression, with everolimus being used in half of these. Five patients received

116

palliative radiotherapy to metastases and one patient received adjuvant chemoradiation to the

117

tumor resection bed.

8 118

Therapeutic responses are outlined in Table 3. Only one patient who received

119

simultaneous everolimus and SSA in the first-line setting showed a documented radiographic

120

regression of disease. Of the other 9 patients who received SSAs, 4 had stable disease and 5 had

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progression. Two patients had stable disease on second-line everolimus and two progressed.

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Three of 6 patients who received radiation had a response and 3 had stable disease

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Status at last follow-up and primary end-points are summarized in Table 4. Survival

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curves are shown in Figures 1 and 2 for TTR and OS. Figure 1 includes 14 total patients as out of

125

17 in our series, one was not resected and two had residual disease after resection. At last follow-

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up, 6 patients were deceased, 5 had stable disease, 5 had no evidence of disease, and one had

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progression. While most patients did not meet the OS endpoint, the Kaplan-Meier estimate of

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median OS was 143 months (95% CI 50 – 143). The median time to recurrence after complete

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surgical resection was 18 months (95% CI 9 – 46).

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A review of SEER data estimated the annual incidence of primary renal neuroendocrine

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neoplasms to be 0.13 per million persons. A total of 117 cases were documented between 2000

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and 2013. The median age at diagnosis was 57, with 26% having distant metastasis at diagnosis.

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The proportions of carcinoid tumors and neuroendocrine carcinoma were almost equal in the

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SEER registry, 47% and 53%, respectively. Twenty-six percent of patients had stage IV disease

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at diagnosis and in 60% staging was not known or not reported. Among the remaining patients,

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2%, 3% and 9% had stages I, II and III respectively. The median overall survival among the

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patients in the SEER cohort was 84 months. Patients with neuroendocrine carcinoma had a

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significantly decreased median survival compared with patients with carcinoid tumors (14

139

months vs. not estimable, p < 0.0001).

9 140

141 142

Discussion Neuroendocrine neoplasms (NENs) of the genitourinary tract are considered rare and

143

owing to the rarity of this disease, the literature on the topic is very limited, and mostly in the

144

form of small case series and single case reports.6 While high-grade neuroendocrine carcinoma

145

originating in the prostate and bladder is not infrequently seen, NENs of the kidney seem to be

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extremely rare and their pathophysiology is incompletely understood. Most renal NENs express

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neuroendocrine markers on immunohistochemical staining such as synaptophysin, chromogranin

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and CD56.6, 9 Loss of heterozygosity on chromosome 3p21 has been reported but no studies

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using more current genomic analyses such as next generation sequencing have been reported.9

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We have reported the largest institutional series of renal NENs and correlated the

151

findings with data from the SEER registry showing that patients with renal NENs can have a

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relatively favorable outcome with long survival following resection. Previous reports that have

153

approached this number of patients have relied on aggregation of unconfirmed pathology reports

154

from many different institutions. Hansel et al. also had internally confirmed pathology and a

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relatively large (N = 15) series of patients with available follow-up data, and Aung et al.

156

described 11 cases.9, 10 However, no literature has previously reported outcomes with as long of a

157

follow-up period and with enough treatment outcome data to allow for statistical analysis. The

158

patient demographics and presenting features in our series were largely comparable to previous

159

reports. The median age of 47 years at diagnosis with roughly equal proportions of men and

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women is similar to previous observations.1, 6, 10, 11 Only two of our 17 patients were

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asymptomatic at presentation, with common symptoms being abdominal or flank pain and

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hematuria. This is consistent with the findings of the larger case reviews by Romero et al.,

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Korkmaz et al., and Murali et al.4, 6, 11 By contrast, Hansel et al. and Aung et al. only reported

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symptoms in 12 of 32 combined patients, but of those the symptoms were similar.9, 10

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Most of our patients (92 percent) had regional lymph node involvement at diagnosis. This

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is equal to the percentage reported by the Hansel et al. series but higher than the 30 – 40 percent

167

reported in the aggregated case series.4, 6, 10 It is possible that the higher figure is a reflection of a

168

referral bias for tertiary institutions likely to see patients with more advanced disease. We found

169

liver and bone to be the most common sites of distant metastases, with most of our patients

170

eventually developing distant metastatic disease. This is similar to the Hansel et al. series but

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slightly higher than the other case reports. An important finding not previously available is that

172

while only 29 percent of our patients had distant metastasis at diagnosis, 76 percent had distant

173

disease at any point during the follow-up period.

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The majority of the tumors in our series were morphologically well-differentiated. Only

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one was reported as moderately differentiated and none as poorly differentiated. Most of the

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literature on renal NENs specifically describes “carcinoids,” so by definition this describes well-

177

differentiated neoplasms. However, poorly differentiated primary renal neuroendocrine

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neoplasms were described by both Teegavarapu et al. and Lane et al. with mostly small cell

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carcinomas and one large cell neuroendocrine carcinoma reported.3, 5 Not surprisingly, these

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tumors exhibited aggressive clinical courses as seen in other extrapulmonary neuroendocrine

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carcinomas.

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Surgical resection was the initial treatment of choice in our series which is consistent with all previous literature. Fourteen of 16 resected patients achieved a complete resection of all

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visible disease. This included lymphadenectomies and resections of hepatic metastases. Because

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of the rarity of primary renal NENs, it is unknown if such an aggressive surgical strategy leads to

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a survival advantage. There is some evidence that hepatic debulking in gastroenteropancreatic

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NENs leads to improved survival.12 This series by Croome et al. included patients with both

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bone and hepatic metastases, which were the two sites of distant disease most common in our

189

series and in previous literature.4, 6, 10 Given the high rate of successful total resection in our

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patients and evidence of improved outcome in other metastatic neuroendocrine neoplasms, an

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aggressive surgical approach should be considered in primary renal NENs. Based on a

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radiographic response in 3 of 6 patients, it also seems reasonable to consider radiotherapy for

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palliation of symptomatic metastases.

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Ten of the 14 patients in our series who had complete resection eventually suffered

195

recurrence. The other four patients were lost to follow-up. Thus, it seems primary renal NENs

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are unlikely to be cured despite aggressive surgical management. Half of the patients remained

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disease-free for at least 18 months. Prior literature has not reported on time to recurrence to

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compare to the median we found of 19 months, but Romero et al. found that 53% of patients in

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published case reports with lymph node involvement had recurred at mean follow-up of 43

200

months.4 Hansel et al. reported that 7 of 15 patients with median follow-up of 36 months were

201

disease-free. While our median TTR was shorter than these intervals, the data are not directly

202

comparable as our figure is a result of survival analysis of the entire cohort using censoring

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versus reporting outcomes only on patients with extended follow-up. The use of survival analysis

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and censoring in our cohort likely provides a more accurate estimate of median TTR, as previous

205

literature may be biased by only reporting outcomes for patients known to survive for an

12 206

extended period. That said, as in all renal NEN cohorts, the sample size in our analysis was small

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(N = 17) and a referral bias is always present for a single-institution analysis.

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As seen by other investigators, we confirmed that renal NENs are strongly associated

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with horseshoe kidneys, present in 4 of our 17 patients.6, 11, 13-16 The incidence of horseshoe

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kidney in the general population is estimated at approximately 1 in 10,000 live births.17

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Interestingly, horseshoe kidney is also associated with Wilms tumor, with one large series

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finding a horseshoe kidney present in 0.48% of patients with Wilms tumor.18 NENs arising in

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horseshoe kidneys have been reported by others to have a more indolent clinical behavior but we

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were not able to confirm that observation.11, 19

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There are several limitations to our study. There is no agreed-upon grading or staging

216

system for renal NENs and given the time period studied, the tumor grade was assigned using

217

different methods over time. The grading of the tumors was not routinely done according to the

218

2010 WHO classification of digestive tumors, a grading system commonly used in NENs outside

219

of the gastrointestinal tract. Ki-67 proliferative index was only applied in a minority of patients

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within our institutional series. Renal NENs seem to be predominantly of low tumor grade. A

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retrospective multicenter study of 21 cases showed that mitotic count was 2 mitoses/10 high-

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power fields in 90% of patients.10 Most reported studies in the past have not included tumor

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grading using Ki-67 proliferative index but Kim et al. recently reported 6 cases of well-

224

differentiated renal NENs where 3 of the cases demonstrated more aggressive behavior and in

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those cases, the Ki-67 index and mitotic count were increased as compared to the more indolent

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NENs and others have reported similar findings albeit in very small numbers.9, 19 Therefore, it is

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recommended that in new cases the neoplasm should be graded in accordance to the grading

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standards for other NENs.

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Using the SEER registry is particularly challenging for studies of rare malignancies as

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there is no central pathology review and therefore, no quality control regarding the accuracy of

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the diagnosis. Furthermore, the SEER data included staging, but as previously mentioned there is

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no official AJCC staging system for renal NENs. In our analysis, the cases identified using

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SEER were of two categories: “carcinoid tumors” and “neuroendocrine carcinoma,” with the

234

latter cohort exhibiting a much shorter survival. Although this cannot be confirmed, we surmise

235

that the patients with a diagnosis of a renal carcinoid tumor more closely represent the cohort

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included in our study while the patients identified as neuroendocrine carcinoma likely have a

237

malignancy of a higher grade and therefore more likely to have a more aggressive natural history

238

and inferior survival. Also, data from SEER will only provide information on overall survival

239

and not disease-specific survival. Acknowledging the limitations of the SEER, renal NENs

240

appear to be exceptionally rare.

241

No previous study has reported on aggregated outcomes of specific systemic therapies.

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Fourteen patients received systemic therapy in our series, with only one documented treatment

243

response. This was in a patient with residual skeletal metastases following primary tumor

244

resection, subsequently found to have hepatic metastases as well. Everolimus and octreotide

245

were started simultaneously with mild regression of the hepatic lesions at 3 months. The lesions

246

then progressed at interval scan at 7 months.

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Given the rarity of this disease, there are no universally accepted treatment standards, but

248

patients have been treated similarly to patients with gastrointestinal NENs. Complete resection,

249

although eventually followed by metastatic recurrence in most patients, seems to be associated

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with prolonged survival. However, no data exists to compare survival in patients who undergo no

251

surgery, incomplete, or less aggressive resections. Somatostatin analogs including octreotide and

14 252

lanreotide are frequently used but their efficacy remains unproven in this rare NEN type.

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Somatostatin analogs are expected to at least result in disease stability, possibly for several years,

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as most of the tumors expressed somatostatin receptors. Randomized clinical trials in patients

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with metastatic gastroenteropancreatic NENs have shown that somatostatin analogs substantially

256

prolong progression-free survival, but objective responses are rare.20, 21 In the absence of better

257

data, it is reasonable to consider somatostatin analogs as first-line therapy for patients with

258

advanced well-differentiated renal NENs expressing somatostatin receptors as seen on receptor

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imaging studies such as 68Ga-DOTATATE PET or somatostatin receptor scintigraphy.

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In our series, everolimus was used in one patient as first-line therapy and in an additional

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four patients as second-line therapy. There was disease stability in two of the second-line

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patients and progression in the other two patients. Given that everolimus has been shown in

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randomized controlled clinical trials to prolong progression-free survival in patients with

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metastatic pancreatic NENs as well as patients with metastatic nonfunctional pulmonary or

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gastrointestinal NENs, everolimus is a reasonable second-line therapy choice for patients who

266

have progressed on first-line somatostatin analog therapy or as first-line therapy for patients with

267

renal NENs who do not express somatostatin receptors.22, 23

268

Peptide receptor radionuclide therapy (PRRT) utilizes therapeutic radionuclides attached

269

to somatostatin analogs and is increasingly being used for patients with NENs.24, 25 PRRT with

270

lutetium-177 (177Lu)-DOTATATE was recently approved for therapy of gastroenteropancreatic

271

NENs following progression on somatostatin analog therapy based on the results of a phase 3

272

randomized clinical trial in patients with small bowel NENs.26 PRRT has also been extensively

273

used in patients with pancreatic and thoracic/pulmonary NENs, albeit without data available

274

from randomized clinical trials. In this setting PRRT seems to be effective, often resulting in

15 275

durable responses, mostly in the form of disease stability.27-29 Although no data exist regarding

276

the utility of 177Lu-DOTATATE PRRT in patients with renal NENs, it can certainly be

277

considered in patients with well-differentiated renal NENs expressing somatostatin receptors as

278

seen on 68Ga-DOTATATE PET imaging.

279

280

Conclusions Renal NENs are exceedingly rare tumors affecting mostly middle-aged patients, and

281 282

almost always metastasize and recur despite aggressive surgical resection. However, most

283

patients experience at least a 1.5-year disease-free interval following resection and the clinical

284

course appears to be indolent. In addition, most patients live well over five years even though

285

cure is generally not possible. True responses to chemotherapy have not been observed, but

286

SSAs stabilized the disease in almost half of the patients. Given this and the overall good safety

287

profile of SSAs, it seems to be a very reasonable choice for treatment of metastatic renal NENs.

288

In the era of PRRT, it will be important to review treatment experiences with this modality in

289

renal NENs that are positive on somatostatin receptor imaging due to the very limited systemic

290

therapeutic options.

291

292

293 294

Clinical Practice Points •

Renal NENs are known to be rare, with no previous summary data available on treatment outcomes or prognosis

16 295

•

overall survival of 143 months; most patients eventually developed distant metastases

296 297

The median TTR after aggressive surgical resection was 18 months, with a median

•

Somatostatin analogs should be considered for first-line systemic therapy; palliative

298

radiation should be considered for symptomatic metastases; PRRT can be considered as

299

most tumors express somatostatin receptors, although data is not available

300

Figure Legends

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Table 1. Baseline patient characteristics

302

Table 2. Treatment modalities; *everolimus and octreotide started simultaneously

303

Table 3. Treatment responses

304

Table 4. Patient outcomes

305

Figure 1. Kaplan-Meier curve of time to recurrence after initial surgical resection. Tick marks

306

represent censored events.

307

Figure 2. Kaplan-Meier curve of overall survival from time of diagnosis. Tick marks represent

308

censored events.

309

Figure 3. Kaplan-Meier curve of overall survival from time of diagnosis created from SEER

310

data, comparing primary renal carcinoid and primary renal neuroendocrine carcinoma.

311

312

Funding Sources

17 313

This publication was supported by Grant Number UL1 TR002377 from the National Center for

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Advancing Translational Sciences (NCATS). Its contents are solely the responsibility of the

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authors and do not necessarily represent the official views of the NIH. References

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Number of patients (n = 17)

%

Age (years) Median

47

Range

21 - 82

Sex Male

7

41

Female

10

59

Pain

10

59

Hematuria

2

12

Asymptomatic

2

12

Flushing

1

6

Other

2

12

3

18

Present

12

92

Not present

1

6

Not assessed

4

24

Distant metastasis at diagnosis

5

29

Distant metastasis at diagnosis or subsequently

13

76

Liver metastasis

9

53

Bone metastasis

9

53

Other distant metastasis

3

18

Horseshoe kidney

4

24

8

47

Presenting feature

Additional clinical features Clinically functional (e.g. diarrhea, flushing) Regional lymph node involvement at diagnosis

Diagnostics Functional imaging

Somatostatin receptor avidity

8

100

Not measured

13

76

Elevated at diagnosis

0

0

Not reported

6

35

1 of 3

1

6

2 of 3

5

29

2 of 4

4

24

3 of 4

1

6

Not reported

6

38

Well-differentiated

9

53

Well- to moderately differentiated

1

6

Moderately differentiated

1

6

Poorly differentiated

0

0

Not reported

11

69

“< 5”

2

12

4–8

3

19

>8

1

6

Serum chromogranin A

Pathology Grade

Differentiation

Ki-67 %

Number of patients (n = 17)

%

No resection

1

6

Radical nephrectomy

15

88

Partial nephrectomy

1

6

14/16

88

Documented recurrence

10

71

Lost to follow-up

4

29

14

82

Somatostatin analogs

11

79

Everolimus

1*

7

Platinum-etoposide

2

14

Platinum-irinotecan

1

7

5-FU (radiosensitizer)

1

7

8

47

Everolimus

4

50

CAV

1

13

Docetaxel

1

13

Temozolomide

1

13

Capecitabine-temozolomide

1

13

6

35

Surgical treatment

No residual disease after resection

Systemic therapy First-line

Second-line

Radiation therapy

Best response Response SSA platinum-etoposide cisplatin-irinotecan SSA-everolimus sunitinib docetaxel CAV everolimus temozolomide capecitabine-temozolomide radiation therapy

Stable disease 4

Progression 5 2

1 1 1

2 1

1 1 2 1

3

3

Number of patients (n = 17) Last known status

%

Deceased

6

35

Disease progression

1

6

Stable disease

5

29

No evidence of disease

5

29

Median duration of follow-up (months)

62.8 95% CI

Median overall survival

143

50 - 143

Median time to recurrence (months)

18

9 - 46

Figure 1

Figure 2

Figure 3 1.0

Log-Rank: p < 0.001

0.8

0.6

0.4

0.2

0.0 0

20

40

60 80 100 120 Overall Survival (months)

140

160

180