ENDOCRINE PRACTICE Rapid Electronic Article in Press
Original Article
EP-2020-0368
CLINICAL HETEROGENEITY OF THE ECTOPIC ACTH SYNDROME: A LONG-TERM FOLLOW UP STUDY
Ana Laura Espinosa-de-los-Monteros, MD, Claudia Ramírez-Rentería, MD and Moisés Mercado, MD, FRCP(C)
Running title: Long-term outcome of ectopic ACTH syndrome
From the Endocrine Service and the Research Unit in Endocrine Diseases, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, IMSS, Mexico City.
Corresponding address: Moisés Mercado, Av. Cuauhtémoc 330, Col de los Doctores, Mexico City 06720, Mexico.
Email: mmercadoa@yahoo.com, moises.mercado@endocrinologia.org.mx
Abstract
Background and objective: The ectopic ACTH syndrome (EAS) is a heterogeneous condition, caused by neuroendocrine neoplasms (NEN) located in the lungs, thymus or pancreas. Our purpose was to evaluate the long-term outcome of these patients.
Design: Retrospective study at a referral center.
Methods: The charts of 164 patients with Cushing syndrome, followed at our center from 1993 to 2019 were analyzed.
Results: EAS was found in 16 patients (9.75%, 9 women, mean age 36.01 years), who had been followed for a median of 72 months. The source of EAS was a NEN in 10 patients (8 bronchial and 2 thymic carcinoid tumors) and a mixed corticomedullary tumor, consisting of a pheochromocytoma and an adrenocortical carcinoma in one patient. In two of the 6 patients initially considered to have occult EAS, the source of the ACTH excess became apparent after adrenalectomy, whereas in the remaining 4 (25%) it has remained occult. Of the 11 patients in whom resection of the NEN was attempted, 10 patients achieved an early remission (91%) but 4 (25%) of these had a recurrence during follow up (biochemically and clinically silent in 2). Three patients have died (18.75%): the young woman with the mixed corticomedullary tumor, a man with a thymic NEN that evolved into a neuroendocrine (NE) carcinoma after 11 years of follow up and a woman with a bronchial NEN.
Conclusions: The course of EAS varies according to tumor type and grade. Some patients have a protracted course whereas others may evolve into NE carcinomas.
Key words: Cushing syndrome, ectopic ACTH secretion, neuroendocrine neoplasm, bronchial carcinoid, thymic carcinoid
Abbreviations:
ACTH= Adrenocorticotropic hormone; BIPSS= Bilateral inferior petrosal sinus sampling; CS= Cushing syndrome; CgA= Chromogranin A; CT= Computarized tomography; CV= Coefficient of variation; DDAVP= Desmopressin; DXM= Dexamethasone; EAS= Ectopic ACTH syndrome; HDDST= High dose dexamethasone suppression test; IQR= Interquartile range; MRI= Magnetic resonance imaging; NE= Neuroendocrine; NEN= Neuroendocrine neoplasm; Octreotide LAR= Octreotide Long-Acting-Repeatable; RIA= Radioimmunoassay; SCCL= Small cell carcinoma of the lung; SNP= Synaptophysin; SPECT= Single- photon emission computerized tomography; TSS= Transsphenoidal surgery; XRT= External radiotherapy; UFC= Urinary free cortisol; ULN= Upper limit of normal.
Introduction
Ectopic ACTH (adrenocorticotropic hormone) syndrome (EAS) is a rare condition with an incidence of 1.4 new cases per 10 million inhabitants per year, representing less than 20% of all ACTH-dependent Cushing syndrome (CS) cases (1). The first description of EAS is attributed to Meador and Liddle who in 1962 demonstrated ACTH biological activity in bronchopulmonary carcinoid tumors (2-3). ACTH-secreting neuroendocrine neoplasms (NEN) are usually located in the thymus, lungs or endocrine pancreas. Information regarding the long-term clinical behavior of NEN causing EAS is scarce, mainly due to the relative rarity of the condition. Some of the few published series are
fundamentally oncological in nature and focus on surgical outcomes and survival (4-10), whereas others are characterized by a more functional-endocrinological approach (11- 15). Not infrequently, these neoplasms linger-on over several years sometimes changing their biological and functional characteristics as they evolve from being relatively well- differentiated tumors into highly aggressive neuroendocrine carcinomas (1). The purpose of this study was to analyze the clinical and biological characteristics of our patients with EAS followed over a long period of time, trying to find patterns that would allow better diagnostic and therapeutic strategies.
Patients and Methods:
Patients and Cushing syndrome protocol: The medical records of all the patients with CS who have been diagnosed and followed at Hospital de Especialidades, Centro Médico Nacional S.XXI between 1993 and 2019 were reviewed. The project was approved by our Hospital’s scientific and ethics committees and all subject signed an informed consent upon enrolment in the Clinic. All patients had been evaluated according to the same diagnostic protocol, as follows: upon clinical suspicion of Cushing syndrome, the presence of endogenous hypercortisolism was established by an elevated 24-hour urinary free cortisol level (UFC) along with the lack of serum cortisol suppression to less than 1.8 ug/dL (49.66 nmol/L) after 1 mg of dexamethasone (DXM) the night before. ACTH dependency was established by measuring an elevated or inappropriately normal plasma ACTH level. The pituitary origin of ACTH-dependent Cushing syndrome was excluded by a less than 68% suppression of serum cortisol upon an overnight HDDST (16), a normal pituitary MRI and a central-to-peripheral ACTH gradient < 2 at baseline or < 3 after desmopressin stimulation, upon bilateral inferior petrosal sinus sampling (BIPSS).
Imaging: After biochemical confirmation of ectopic ACTH secretion, imaging studies were carried out to identify the source. Periodic imaging using conventional computerized tomography (CT) was used prior to 2008 and a triple-phase, multi-detector CT of the neck, chest, abdomen, and pelvis using a special protocol for NEN, were performed in all patients since 2008. Octreotide scintigraphy was performed in most cases by administering 6 mCi (222 mBq) of 111In-DTPA-D-Phe1-octreotide obtaining planar anterior-posterior and lateral scintigrams at 24 hours with a large field of view gamma camera and a medium energy collimator. For the past 8 years, such planar images have been fused with single photon emission computerized tomography (SPECT) to allow a better anatomical localization (17).
Hormonal measurements: Hormone determinations were carried out using various commercially available immunoassays throughout the years that the patients had been followed. From 1993 to 2000, serum and urinary cortisol were measured by a polyclonal RIA with a detection limit of 1.6 ug/dL (44.13 nmol/L) and intra- and inter-assay coefficients of variation (CV) of 5.4% and 7.3%, respectively. From 2000 until 2008, all hormonal determinations were performed using a solid-phase, two-site, chemiluminescent enzyme immunometric assay with the aid of an automated analyzer (IMMULITE 2000, Diagnostic Products Corp, Los Angeles, CA). Detection limits were 0.2 ug/dL (5.51 nmol/L) for cortisol and 5 pg/mL (1.1 pmol/L) for ACTH; intra- and inter-assay CVs are 7.2% and 4% for cortisol and 9.6% and 8.8% for ACTH, respectively. For the past 11 years we’ve been using the following assays: For serum cortisol we use a highly sensitive automated electrochemiluminescent assay with a detection limit of 0.018 ug/dL
(0.49 nmol/L) and intra- and inter-assay CVs of 1.2% and 1.5%, respectively (Cobas [Roche], Mannheim, Germany). For urinary cortisol, the same electrochemiluminescent assay is used after extraction with dimethyl chloride; the intra- and inter-assay CVs were 2.4% and 2.9%, respectively and the normal range was 36-137 ug/day (0.49 nmol/L). ACTH was determined by means of an automated electrochemiluminscent assay with an analytical sensibility of 1.6 pg/mL (0.352 pmol/L) and intra- and inter-assay CVs of 7.4% and 7%, respectively (DiaSorin-Liaison, Saluggia, Italy). As of 2017 urinary free cortisol is measured by a competitive chemiluminescent assay (Abbot Architect, IL), with a sensitivity of < 0.8 mg/dL (< 22 nmol/L) with intra- and inter-assay CVs below 3%.
Statistical analysis: Categorical variables were compared between groups using X2 or Fisher’s exact test according to the numbers in each category. Continuous variables were compared using Mann-Whitney U test or one-way analysis of variance as appropriate. All analyses were generated with IBM SPSS Statistics for Windows v21.0. A p-value of <0.05 in a two-sided test was considered to be statistically significant. Results are expressed in means + standard deviation or median and interquartile ranges (IQR), depending on the distribution of data.
Results
· Patients:
Of 164 patients with CS of different etiologies diagnosed and treated at our center between 1993 and 2019, 16 (9.75%, 9 women and 7 men) were found to have EAS. Mean age at diagnosis was 36.1 + 10.8 years (Table 1). Five patients had been previously DOI:10.4158/EP-2020-0368 C 2020 AACE.
treated at another center: two with transsphenoidal surgery (TSS), one with TSS and radiotherapy (XRT), and two with unilateral adrenalectomy. Median follow up time of the 16 patients was 78 months (range 2-228) (Table 1). All patients presented with the classical signs and symptoms of CS; diabetes mellitus and hypertension were present in 64.2% and 92.8% of the cases, respectively (Table 1).
· Diagnosis of EAS:
All patients had elevated 24-h UFC levels at diagnosis (median 9.8 x ULN [IQR 4.3-14]) and morning serum cortisol levels above 1.8 ug/dL (49.6 nmol/L) after having received 1 mg dexamethasone the night before (Table 1). Median plasma ACTH levels were 108 (IQR 75-143) pg/mL (23.76 [IQR 23.7-31.4] pmol/L) (Table 1). Median percent cortisol suppression upon HDDST was 17% (IQR 0-49) (Table 1). In all cases, the ACTH central- to-peripheral ratio during BIPSS was less than 3 after desmopressin stimulation (mean 1.2 ±0.1) (Table 1).
CT-scan was performed in all cases and octreotide scintigraphy in 13. Upon the initial evaluation, the source of ectopic ACTH secretion was identified in 10 patients: in 3 by CT-scan (all bronchial), in one by octreotide scintigraphy (bronchial) and in 6 by both, CT- scan and octreotide scintigraphy (3 bronchial and 2 thymic NEN, one mixed corticomedullary adrenal tumor) (Figure 1). The source of ACTH secretion could not be identified at the initial evaluation in six patients (Figure 1). Adrenalectomy was performed in order to control hypercortisolism in all six of them. In two of these six patients, a bronchial ACTH-secreting NEN became apparent by both, CT-scan and octreotide scintigraphy two and 9 years, respectively, after they underwent adrenalectomy and were
categorized as having covert EAS (Figure 1). Two other patients with occult EAS were lost after 6 and 18 months of follow-up, respectively. The remaining two patients have been followed for 7 and 17 years, respectively with periodic neck, chest and abdomen CT scans as well as with 111In-octreotide scintigraphy and the source of the ACTH is still occult (Figure 1). Thus, upon last evaluation, the source of EAS remained occult in four patients, whereas 12 had an identified NEN (10 overt and 2 covert) (Figure 1).
· Treatment, pathological findings and outcome:
Surgical resection of the identified ACTH-secreting lesion was performed in 11 of the 12 patients. Most of these patients were started on ketoconazole at an average dose of 200 mg twice a day in preparation for surgery. The remaining patient, a woman with a 1.4 x 2.2 cm left lung tumor identified by CT and octreotide scintigraphy, who had been previously subjected to unilateral adrenalectomy, declined surgery and was lost to follow up. Eight patients had bronchial NEN, two had thymic NEN and one had a mixed corticomedullary adrenal tumor in which an ACTH-secreting pheochromocytoma was intermingled with a cortisol-secreting adrenocortical carcinoma. The histopathology of the 10 patients with bronchial and thymic NEN confirmed the presence of low to intermediate grade neuroendocrine tumors (G1 and G2, according to the 2010 WHO classification); positive ACTH immunostaining was documented in all of them. Ten of the 11 patients went into clinical and biochemical remission after surgical resection of their DOI:10.4158/EP-2020-0368 C 2020 AACE.
primary NEN. The median follow-up of the 11 patients who underwent surgical resection was 72 months (IQR 20-132); 7 of these patients had been followed for more than 60 months and 4 for more than 120 months.
The NEN recurred in 4 of the 10 patients (40%) (in 3 patients with bronchial NEN and in the patient with a mixed cortico-medullary carcinoma) in whom an initial remission had been documented, 1-13 years after surgical resection. In three patients the histopathology of the recurring lesion was consistent with a G1 NEN. In 2 patients (both with bronchopulmonary NEN) recurrences occurred more than once. Structural recurrences with neither clinical nor biochemical evidence of hypercortisolism were documented in two patients who had not been subjected to adrenalectomy. The first of these cases is that of a currently 67-year-old male who presented with EAS due to a left bronchial NEN documented by CT scan. The lesion was resected, and he went into clinical and biochemical remission that lasted 11 years, when follow up CT-scan revealed a right pulmonary lesion that was positive on octreotide scintigraphy as well, yet he remained totally asymptomatic with normal UFC and ACTH levels. The right pulmonary lesion was resected and proved to be a G1 NEN that positively immunostained for ACTH, chromogranin A (CgA) and synaptophysin (SNP), with a Ki-67 < 1%. The second case is that of a currently 46-year-old woman with a clinically and biochemically evident EAS due to a left bronchial NEN who was successfully operated. Eight years later she was found to have an enlarged mediastinal lymph node without clinical or biochemical evidence of hypercortisolism. The lymph node was resected, and the histopathology was consistent with metastasis of a NEN which positively immunostained for ACTH and with
a Ki-67 of 1%. Three years later and again, with no evidence of hypercortisolism, she developed another enlarged lymph node, documented by CT and octreotide scintigraphy, but this time the lymph node was not surgically removed (patient declined the procedure), and she was started on octreotide LAR with which it remains stable.
In one of the two patients with a thymic NEN, complete resection of the lesion was not possible, although he showed a significant clinical improvement and reduction of UFC but his ACTH level persisted elevated. Over the course of 5 years his NEN relapsed several times despite repeated debulking surgeries and treatment with octreotide LAR, lanreotide autogel and even subcutaneous pasireotide and everolimus. The histopathology of the excised lesions evolved from a well-differentiated, ACTH- and CgA-positive lesion, with relatively low Ki-67 to a poorly differentiated neuroendocrine carcinoma, with a very high proliferation index and negative immunostaining for ACTH and other sympathochromaffin biomarkers. He underwent bilateral adrenalectomy and in a matter of months, the tumor grew and became metastatic (liver, lung, vertebrae, peritoneum); the patient died shortly after, despite having received chemotherapy with temozolomide and cisplatinum/etoposide.
In total, three patients (18.75%) have died with metastatic disease as of the writing of this manuscript: a woman with a bronchial NEN who died 3 years after diagnosis, a man with a metastatic thymic NEN 11 years after diagnosis and a young woman with a mixed corticomedullary adrenal carcinoma 18 months after diagnosis.
Discussion
The EAS is a clinically, biochemically and histopathologically heterogeneous condition. Whereas the median duration of follow up among published series is 59 months (range 33 to 126), our patients had been followed for a median of 84 months (7 years), which allowed us to analyze in detail the broad clinical spectrum and therapeutic outcome of the EAS. Like in other reported series, the known female predominance seen in patients with Cushing disease (over 90% in our center) is absent in patients with EAS (56% in the current study) (1). Although in most cases symptoms and signs of hypercortisolism are the same as in other forms of CS, patients with EAS have been reported to have more severe osteoporosis and hypokalemia (1). In this regard, the prevalence of hypokalemia among our patients with EAS was 42.8%, considerably higher than the prevalence rate in our patients with CD (8-10%, unpublished data), but somewhat lower than figures reported by the large series from the National Institutes of Health (11) and St. Bartholomew Hospital in London (12).
The functional and anatomical diagnosis of EAS constitutes a major challenge in clinical endocrinology. Not infrequently, patients are misdiagnosed as having Cushing disease and are even subjected to pituitary surgery prior to referral to a tertiary care center where the source of ACTH excess is finally established as ectopic (1). Three of our patients (18.75%) had been subjected to TSS at a different hospital before they were referred to our institution because they were thought to have Cushing’s disease. This is also reported by other series albeit at a somewhat lower rate (10-14%) (11-12). In some instances, we found patients with clear evidence of ectopic ACTH excess and yet, no
tumor can be found even after performing repeated imaging studies such as high- resolution CT scanning and radiolabeled octreotide scintigraphy. The term “occult” EAS has been coined to define this scenario and has been observed to occur in 10-20% of cases (11-15, 18). In a subset of these patients with occult EAS the origin of the ACTH excess is eventually found upon long-term follow up and have been categorized as having covert EAS (11-12). In the present series, 6 of our patients were initially categorized as having occult EAS. In two of these patients the source of ACTH secretion was identified several years after the initial diagnosis, but in the other four subjects the EAS remains occult after 0.5, 1.5, 7 and 17 years of follow up, respectively. Interestingly, in the two patients with covert EAS, the origin of the NEN responsible for the ACTH excess was discovered 2 and 9 years, respectively after bilateral adrenalectomy was performed in order to control hypercortisolism. This observation prompts us to speculate that a Nelson- like phenomenon may be taking place in these patients, whereby invisible tumors grow to become detectable by currently available imaging techniques after having lost the negative feedback control previously exerted by the massive hypercortisolism. Furthermore, in another of our patients with overt EAS due to a thymic NEN, the tumor became widely metastatic right after bilateral adrenalectomy. Despite these clinical observations, we cannot prove that a Nelson-syndrome in fact took place in these patients. Taken together, these observations highlight the importance of identifying and treating the original source of the ACTH excess in order to offer the individual patient a greater probability of a long-lasting remission. Newer imaging techniques such as 68Ga- SSTR-PET/CT have been reported to have a 100% sensitivity in identifying covert lesions, yet they are not widely available and thus, are not frequently used (19).
Overall, 10 out of the 11 (91%) patients with overt and covert EAS who underwent surgical resection of the primary NEN achieved an early biochemical remission. Unfortunately, 4 of these patients experienced recurrences over the course of several months and years so the long-term remission rate in our series was 54.5%. Similar to our findings, early remission rates reported by other series ranges from 70% to 100% (4-9, 12, 15, 20). In one of the largest EAS series published to date, 65 out of 90 patients underwent surgical resection of the primary tumor and 40 of these 65 patients (61.5%) were considered to be cured; after a follow up time that went from 1 month to up to 16 years, 5 patients relapsed, so the long term remission rate dropped to 54% (11). In another large EAS series, only 12 out of 40 patients had a potentially resectable single tumoral lesion (12). Surgical resection resulted in a complete remission in 10 of these patients, whereas two had a partial remission, yet, no precise information is provided regarding the long-term outcome of these patients (11). Ascertaining the long-term remission rate in other series is not a simple task with only 10 published studies actually reporting recurrence rates (4- 9, 11, 15, 20). Recurrence rates vary according to the anatomical location of the tumor, from 0-40% in patients with bronchial NEN (4-9), to 70% in patients with thymic NEN (19) and to 80-100% in patients with small cell carcinoma of the lung (SCCL) (21). Of the 4 relapsing patients in our series, two recurred clinically as well as biochemically with imaging studies revealing metastatic disease. The other two relapsing patients, however, were totally asymptomatic and biochemically eucortisolic and the recurrence was discovered by CT and octreoscan and corroborated histopathologically and immunohistochemically (positive ACTH immunostaining) upon surgical resection of the
lesion. Thus, some patients with EAS due to NEN may develop over the course of their disease, clinically and biochemically “silent” metastasis, underscoring the heterogeneous biological behavior of these tumors and the need to perform periodic imaging surveillance, particularly in patients who have undergone bilateral adrenalectomy for hypercortisolism control.
Mortality rate in patients with EAS varies according to the type, grade and location of the tumor. Patients whose ACTH excess resulting from a SCCL, extrathoracic NEN, thymic NEN, medullary thyroid carcinomas and gastrinomas frequently have metastatic disease when they are first diagnosed and thus, most of them are dead after two years of follow up (10,12, 15). At the other end of the spectrum, patients with bronchial NEN are less likely to be metastatic at diagnosis and over 80% are alive after 10 years of follow up (4- 8). Thus, series including a large number of patients with SCCL such as the one from St. Bartholomew Hospital in London report an overall mortality rate of 87.5%, whereas series with a relatively limited number of patients with SCCL (less than 4% of the total number of patients) have an overall mortality rate of 18-30% after long term follow up (11, 21). No patients with SCCL were included in our study, hence our mortality rate of 18.7%. Death occurred 1.5-11 years after diagnosis in 3 patients; one had a bronchial NEN, another one had a thymic NEN and the third one had a mixed corticomedullary adrenal tumor, consisting of an ACTH-producing pheochromocytoma and an adrenocortical carcinoma (recently published as a case report) (22).
The main limitations of our study are the relatively small sample size and its retrospective nature, while the principal strength is the detailed and long follow up of the patients, who are diagnosed, treated and monitored according to the same pre-established protocol. We conclude that the long-term course of patients with EAS is hard to predict and varies widely, according to tumor type and grade. Typical bronchial NEN have a relatively good prognosis with most of the patients being alive 10 years after diagnosis, whereas the outlook for higher grade lesions such as SCCL is much worse. Some of these patients have a protracted course over many years and may evolve from harboring relatively well- differentiated NEN to true neuroendocrine carcinomas. Complete surgical resection of the tumor causing the EAS is achieved in 35-70% of the patients, depending on the series. Recurrence rate ranges 24-40% and sometimes, relapses are occasionally biochemically and clinically silent, only being discovered upon follow up imaging. The need to perform bilateral adrenalectomy in order to control life-threatening CS by, abolishing the negative feedback control exerted by the massive hypercortisolism on the primary neoplasm, may result in its unrestricted growth which in turn may lead to a) the discovery of a previously occult NEN, b) the induction of tumor recurrences, and c) the emergence of metastasis.
Declaration of conflict of interest: All authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported
Funding: This work did not receive any specific grant from any funding agency in the public, commercial or non-for-profit sector.
Authors contribution statement: Drs. Espinosa de los Monteros and Mercado conceived the idea, Drs. Espinosa de los Monteros and Ramirez-Rentería gathered the data and all three authors analyzed the information and prepared the manuscript
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Legends for figures:
16 patients
10 overt EAS
2 covert EAS (moved from occult to overt)
4 occult
1 patient with pulmonary tumor refused surgery
Surgical resection of the NET N=11
Early remission
Persistence
N=10: 8 bronchial carcinoids 1 thymic carcinoid
N=1: thymic carcinoid
1 mixed adrenocorticomedullary carcinoma
Late remission
Recurrences
N=6: 5 bronchial carcinoids 1 thymic carcinoid
N=4: 3 bronchial carcinoids 1 mixed adrenocorticomedullary carcinoma
| Occult EAS | Overt EAS | Total group | p | |
|---|---|---|---|---|
| N (Women/Men) | 4 (3/1) | 12 (6/6) | 16 (9/7) | 0.585 |
| Age, mean ± SD | 35.2 ± 14.5 | 36.4 ± 10 | 36.1 ± 10.8 | 0.882 |
| Median F/U (IQR) | 51 (9-174) | 84 (16-141) | 78 (2-128) | 0.684 |
| Diabetes mellitus, % | 66.6 | 63.6 | 64.2 | 0.999 |
| Hypertension, % | 100 | 91 | 92.8 | 0.999 |
| Prior treatments: | --- | 4 (33.3) | 4 (25) | |
| · Transsphenoidal surgery, n (%) | 0.994 | |||
| · Bilateral adrenalectomy, n (%) | --- | 2 (16.6) | 2 (12.5) | 0.874 |
| Median UFC, x ULN (IQR) | 4.6 (2.6-4.3) | 10.4 (4.3-14) | 9.8 (4.3-14) | 0.753 |
| Median ACTH, pg/mL (IQR) | 107 (68-139) | 108 (75-143) | 108 (75-43) | 0.753 |
| SI units pmol/L | 23.5 (15-30) | 23.7 (16-31) | 23.7 (16-31) | |
| Median % suppression on HDDST (IQR) | 29 (6-57.2) | 0 (0-49) | 17 (0-49) | 0.343 |
| Central-to-peripheral ACTH gradient on petrosal sinus sampling, mean ± SD | 1.2 ±0.06 | 1.2 ±0.2 | 1.2 ±0.1 | 0.927 |
| Positive CT scan, n (%) | --- | 11 (91.6) | 11 (68.7) | 0.333 |
| Positive octreoscan, n (%) | --- | 7 (77.7) | 7 (43.7) | 0.232 |
| Ilias. JCEM 2005;90:4955 | Isidori. JCEM 2006;91:371 | Davi. EJE 2017;176:453 | Our study 2020 | |
|---|---|---|---|---|
| N (M/F) | 90 (42/48) | 40 (19/21) | 110 (46/64) | 16 (7/9) |
| Main locations | Bronchial 38.9% GEPNET 22.2% Gastrinoma 6.6% Thymus 5.5% Pheochr 5.5% SCCL 3.3% | Bronchial 30% SCCL 17.5% MTC 7.5% PanNET 7.5% Thymus 5% Pheochr 2.5% | Bronchial 41% PanNET 15.5% Pheochr 6.4% Thymus 5.5% SCCL 3.6% MTC 1.8% | Bronchial 56.2% Thymus 12.5% Pheochr 6.25%* |
| Occult | 18.8% | 12.5% | 22.7% | 25% |
| Surgical resection | 65/90 (72.2%): Cure 42 (64.6%) Persistence 23 (35.4%) | 12/40 (30%) cure Complete 10 (83.3%) Partial 2 (16.6%) | 60/110 (54.5%): Cure 56.6% Persistence 43.3% | 11/16 (68.7%): Cure 91% Persistence 9% |
| Recurrence | ??? | ??? | 8/34 (23.5%) | 4/10 (40%) |
| Adrenalectomy | 33/90 (36.6%) | 12/40 (30%) | 31/110 (28.2%) | 7/16 (43.7%) |
| Death | 16/90 (18%) | 35/40 (87.5%) | 33/110 (30%) | 3/16 (18.7%) |