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The incidence of endogenous Cushing’s syndrome in the modern era
Sofie Wengander (1), Penelope Trimpou (1, 2), Eleni Papakokkinou (1, 2), Oskar Ragnarsson (1,2)
(1) Department of Internal Medicine and Clinical Nutrition, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden, (2) Department of Endocrinology, Sahlgrenska University Hospital, Gothenburg, Sweden.
Correspondence and reprint requests: Oskar Ragnarsson, Department of Endocrinology, Sahlgrenska University Hospital, Blå Stråket 5, SE-413 45 Göteborg, Sweden. Tel: +46-31-342-1000, E-mail: oskar.ragnarsson@medic.gu.se
Short title: Incidence of Cushing’s syndrome
Key words: Cushing’s syndrome; incidence; prevalence; epidemiology; diagnostic codes
Funding: The Gothenburg Society of Medicine and The Health and Medical Care Committee of the Regional Executive Board (Region Västra Götaland).
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/cen.14014
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Disclosure summary: PT has received lecture fees from Novo Nordisk. OR has received lecture fees from Novo Nordisk, Ipsen, Sandoz, and Pfizer; an unrestricted research grant from HRA-pharma, and consultancy fees from Novartis and HRA-pharma. SW and EP have nothing to disclose.
Abstract
Introduction: Epidemiological studies on the incidence of Cushing’s syndrome (CS) are few and most often includes only patients with the most common form, i.e. Cushing’s disease (CD).
Objective: To analyse the incidence of endogenous CS in an unselected cohort of patients from western Sweden between 2002 and 2017.
Methods: Medical records from patients who had received a diagnostic code for CS and adrenocortical carcinoma in the Västra Götaland County between 2002 and 2017 were reviewed. Eighty-two patients had been diagnosed with endogenous CS in the region during the study period, and were included in this analysis.
Results: Thirty-nine patients (48%) had CD, 21 (26%) had ectopic ACTH-producing tumour, 17 (21%) had a benign adrenal CS and 5 (6%) had cortisol producing adrenocortical carcinoma. Nine of 21 (43%) patients with ectopic CS had an ACTH-producing lung tumour, 4 had a neuroendocrine pancreas tumour and 5 had an occult tumour. The annual incidence of endogenous CS was 3.2 cases per million per year; 1.5 for CD, 0.8 for ectopic CS, 0.7 for benign adrenal CS, and 0.2 for adrenocortical carcinoma.
Conclusions: Approximately three new cases of endogenous CS, per one million inhabitants, were diagnosed annually between 2002 and 2017. Compared to previous reports,
proportionally more patients had ectopic CS. The reason for this is unclear although increased awareness of hypercortisolism in patients with malignant tumours in the modern era is a possible explanation.
Introduction
Cushing’s syndrome (CS) is a rare endocrine disorder caused by a prolonged exposure to elevated cortisol levels (1). Due to its rarity, and heterogeneity, epidemiological studies on the incidence of CS are few and most often only includes patients with the most common form, i.e. Cushing’s disease (CD) (2-7). In fact, only two population-based studies have evaluated the incidence of other aetiologies (8, 9). A nationwide Danish study including 166 patients diagnosed with endogenous CS between 1985 and 1995 found an incidence for CD of 1.2 cases per million/year, 0.6 cases per million/year for cortisol producing adrenal adenoma, 0.3 cases per million/year for “cancer associated CS”, and 0.2 cases per million/year for adrenocortical carcinoma (9). A study from New Zeeland including 253 patients, excluding adrenocortical carcinoma and malignant ectopic CS, estimated the incidence of CS between 1960 and 2005 to be 1.8 per million per year (8). Thus, data on the incidence on all subtypes of endogenous CS, especially in the modern era, is needed.
The primary aim of this study was to analyse the incidence of endogenous CS in an unselected cohort of patients from western Sweden between 2002 and 2017.
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Methods
Design
This was a retrospective study on patients diagnosed with all subtypes of endogenous CS in the Västra Götaland County in Sweden between 2002 and 2017. At the beginning of the study (January 1, 2002), the county had a population of 1,500,857, and at the end of the study 1,690,782 (December 31, 2017; National database of statistics, Sweden, SCB).
Identification of patients
All patients with suspected CS in the Västra Götaland County are referred to the Sahlgrenska University Hospital, Gothenburg, Sweden, for evaluation and treatment. In Sweden, diagnostic codes, provided during all hospital visits, are registered according to the diagnosis- related group (DRG) registry. To identify patients with CS, a search in the DRG-registry at the Sahlgrenska University Hospital was performed by using the following ICD-10 codes: a) Pituitary-dependent CS (E24.0), b) Nelson’s syndrome (E24.1), c) Iatrogenic CS (E24.2), d) Ectopic ACTH-syndrome (E24.3), e) Alcohol-induced CS (E24.4), f) Other specified CS (E24.8), g) Unspecified CS (E24.9), and h) adrenocortical carcinoma (C74.0).
Collection of data and validation of the CS diagnosis
Medical records for identified patients at all hospitals in the Västra Götaland County (including the hospitals in Göteborg, Borås, Trollhättan, Skövde, Uddevalla, Alingsås and Lidköping that are available through the electronic journal at the Sahlgrenska University Hospital), were reviewed.
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To validate the diagnosis of CS, clinical features, biochemical data, imaging and histopathological diagnosis of all patients were evaluated by the authors through review of medical records. In general, the diagnosis of CS, and it’s aetiology, was determined by an experienced endocrinologist in accordance with recommended diagnostic criteria (10, 11). Mild autonomous cortisol secretion in patients with adrenal incidentaloma was defined as a pathological dexamethasone suppression test (serum cortisol >50 nmol/L), low ACTH concentrations in plasma, and urinary free cortisol within the normal reference range, in the absence of typical clinical signs and symptoms of CS. Patients with adrenocortical carcinoma were considered to have endogenous CS if they presented with typical symptoms and signs, as well as biochemical features, characteristic for CS.
Patients
In total, 234 patients had received a diagnostic code for CS between 2002 and 2017 (Figure 1). One-hundred-and-fifty-one (65%) patients had endogenous CS, of whom 80 were diagnosed between 2002 and 2017 in the Västra Götaland County, and were included in the study. Excluded were 54 patients with endogenous CS who had been diagnosed before the year 2002, and 17 patients with endogenous CS not living in the Västra Götaland County (10 not from Sweden and 7 from other regions in Sweden). Also excluded were 24 patients with iatrogenic CS due to long-term treatment with glucocorticoids, 21 patients with adrenal incidentaloma and mild autonomous cortisol secretion (previously called subclinical CS), 11 patients who had been evaluated due to suspected CS that was ruled out after clinical and biochemical evaluation, 18 patients with other endocrine diagnoses, 7 with other non- endocrine diagnoses and two patients with unavailable medical charts. Patients who had received the CS diagnosis in the Västra Götaland County before 2002, and were alive at the end of the study, were, however, included in the analysis of prevalence.
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Thirty-four patients living in the Västra Götaland County had been diagnosed with adrenocortical carcinoma during the study period. Excluded from the analysis were 23 patients without hypercortisolism and 6 patients with inappropriately high serum cortisol following dexamethasone administration (serum cortisol >50 nmol/L) but without clinical features supporting CS. Five patients presented with symptoms and signs, as well as biochemical features, characteristic for CS. Three of these patients had already been identified by using the diagnostic code for CS. The two additional patients were included in the study. Thus, the final cohort consisted of 82 patients with endogenous CS. 250-420
Ethics
The ethical committee of the University of Gothenburg, Göteborg, Sweden approved the study (reference number 814/18; approved 16 November 2018). The study was conducted according to the Declaration of Helsinki.
Statistics
Descriptive data are presented as mean ± SD or median (interquartile range; range). For comparison between two groups, unpaired t-test was used for normally distributed data and Mann-Whitney U-test for non-normally distributed data. For proportions, Pearson Chi-square or Fishers exact test were used. A P-value <0.05 was considered statistically significant. Statistical analyses were performed using SPSS version 25.
According to the national database of statistics in Sweden (SCB) the population of Västra Götaland County was 1,500,857 on January 1, 2002 and 1,690,782 on December 31, 2017. The incidence rates of endogenous CS were calculated by dividing the number of patients diagnosed with CS, with the mean population rate in the region during the study period.
Calculations on incidence were performed separately for CD, ectopic CS, benign adrenal CS [including cortisol producing adrenal adenoma, macronodular hyperplasia and primary pigmented nodular adrenocortical disease (PPNAD)], and cortisol producing adrenocortical carcinoma.
Prevalence was estimated by dividing the number of patients diagnosed with CS between 2002 and 2017, as well patients diagnosed with CS before 2002, who were alive at the end of the study, with the population rate of Västra Götaland County at December 31, 2017.
Results
Of 82 patients diagnosed with endogenous CS between 2002 and 2017, 39 had CD, 21 had ectopic ACTH-producing tumour, 17 had a benign adrenal disease and 5 had cortisol producing adrenocortical carcinoma (Figure 1).
Cushing’s disease
Thirty-nine patients were diagnosed with CD, 38 (26 women and 12 men) with ACTH- secreting pituitary adenoma and one female patient with an aggressive ACTH-secreting pituitary tumour. The mean age at diagnosis in patients with CD was 48±17 years. Twenty- eight (72%) patients had hypertension at diagnosis and 10 (26%) had diabetes mellitus.
Twenty-five (64%) patients had an ACTH-producing microadenoma (<10 mm). Of these, 24 (96%) had the aetiology confirmed preoperatively through an inferior petrosal sinus sampling and 21 (84%) postoperatively with a histopathological examination. Fourteen (36%) patients had a macroadenoma (≥10 mm), of whom 7 (50%) had the diagnosis confirmed with a preoperative inferior petrosal sinus sampling and 12 (86%) with a histopathological examination. All 14 patients with macroadenoma had clinically overt CS. The median (IQR)
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plasma ACTH was lower in patients with micro- compared to patients with macroadenoma [17 (7-24) versus 37 (13-48) pmol/L; P=0.025]. Serum cortisol following 1 mg over-night dexamethasone suppression [470 (166-685) versus 425 (248-583) nmol/L; P=0.7], urinary free cortisol times the upper limit of normal [3.1 (1.9-7.2) versus 2.3 (1.6-4.4); P=0.2] and serum cortisol at midnight [513 (375-885) versus 590 (390-670) nmol/L; P=0.9] did not differ between patients with micro- and macroadenoma.
The primary treatment was transsphenoidal pituitary surgery in all but one patient (treated with pituitary radiation therapy). Twelve of 38 (32%) patients initially treated with transsphenoidal pituitary surgery needed additional treatment due to persistent hypercortisolism, 5 of 25 (20%) patients with microadenoma and 7 of 13 (53%) of patients with macroadenoma.
Ectopic Cushing’s syndrome
Twenty-one patients were diagnosed with ectopic CS. Nine (43%) patients had a lung tumour,
4 with histologically confirmed small cell lung cancer and one with ACTH-positive neuroendocrine lung tumour (carcinoid). Four more patients had been diagnosed with lung cancer based on imaging. Three of these had liver metastases on imaging and one had a histologically confirmed brain metastases from a neuroendocrine tumour.
Four patients had a histologically confirmed pancreatic neuroendocrine tumour with liver metastases. One patient had a histologically confirmed neuroendocrine tumour in the thymus with skeletal metastases, and one patient had a histologically confirmed small intestine neuroendocrine tumour with multiple metastases. The primary tumour in one patient with a disseminated disease was assumed to be a prostate cancer.
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In 5 patients, the localization of the ACTH-secreting tumour was unknown despite extensive biochemical, imaging and histopathological examinations (occult ectopic CS). Two of these patients had a metastatic disease on imaging. Ectopic origin was presumed in three patients without metastases after inferior sinus petrosal sampling (conducted two times in two of these three patients), showing an absence of significant peripheral increase in ACTH after corticotrophin-releasing hormone (CRH) stimulation, as well as a non-significant central to peripheral gradient, both before and after CRH administration. After a 3-, 4- and 6-year follow-up, none of these patients had developed a visible tumour despite repeated imaging studies covering the pituitary gland, neck, thorax, abdomen and pelvis, nor had they developed Nelson syndrome.
The mean age at diagnosis in patients with ectopic CS was 59±18 years. Thirteen of 21 (62%) patients were women. Seventeen (81%) of the patients had hypertension at diagnosis and eleven (52%) had diabetes mellitus (Table 1).
Patients with ectopic CS, compared to patients with CD and patients with cortisol-producing adrenal adenoma, were older at diagnosis, had higher serum cortisol at midnight and following dexamethasone administration, and had higher urinary free cortisol.
Benign adrenal Cushing’s syndrome
Fourteen of 17 (82%) patients with benign adrenal CS had a unilateral cortisol producing adrenal adenoma (13 women and one man), histologically confirmed in 13 patients (missing in one patient) (Table 1). The mean age at diagnosis was 46±15 years. Ten (71%) had hypertension at diagnosis and five (36%) had diabetes mellitus.
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Eleven of 14 (79%) patients with benign adrenal CS were initially referred to our department due to suspected CS and three (21%) due to an adrenal incidentaloma. All three patients with adrenal incidentaloma had clinical stigmata in accordance with CS. Serum cortisol at midnight [210 and 250 nmol/L (not measured in one)] and following 48-hr dexamethasone (260, 340 and 470 nmol/L, respectively) were elevated, and urinary free cortisol was higher than the normal reference range in two of three patients (0.9, 1.1 and 1.2 times the upper limit of normal, respectively). Plasma ACTH was 2.1, 2.3 and 2.7 pmol/L, respectively (normal reference range 2-11 pmol/L).
Two female patients had PPNAD, 11 and 38 years old, and one 56-year-old man had bilateral macronodular hyperplasia. All three patients were referred to our clinic due to typical features of CS and had significantly elevated urinary free cortisol (3.5, 3.7, and 11 times higher levels than the normal reference range) and elevated serum cortisol after over-night 1 mg dexamethasone suppression test (680, 820, and 830 nmol/L, respectively). The diagnosis in all three cases was confirmed by histopathological examination.
Adrenocortical carcinoma
Five patients had histologically confirmed adrenocortical cancer, three men and two women, aged 29, 32, 43, 46, and 54 years, respectively. All presented with typical symptoms and signs characteristic for CS. Plasma ACTH was low, serum cortisol following 1 mg over-night dexamethasone suppression was high (range 585-810 nmol/L), and urinary free cortisol times the upper limit of normal was high (range 2.3-10.3) in all 5 patients.
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Incidence and prevalence
The total incidence of endogenous CS between 2002 to 2017 was 3.2 cases per million/year. The number of new cases with endogenous CS varied over the years, with the lowest rate in 2003 when only one patient was diagnosed, compared to 2013 when 11 new cases were diagnosed (Figure 2). The incidence of CD was 1.5 cases per million per year, 0.8 cases per million/year for ectopic CS, 0.7 cases per million/year for benign adrenal CS (0.5 cases per million/year for cortisol producing adrenal adenoma) and 0.2 cases per million/year for cortisol producing adrenocortical carcinoma. By excluding the three patients with overt CS, who presented initially as an adrenal incidentaloma, the total annual incidence of endogenous CS was 3.1 cases per million and the annual incidence for benign adrenal CS was 0.5 cases per million.
At the end of the study, 5 of 54 patients who were diagnosed with endogenous CS before 2002 were not living in the Västra Götaland County and 10 had died. Thus, 39 patients who were diagnosed before 2002, and who were alive at the end of the study, were included in the prevalence analysis, but not in the analysis of incidence.
Of 82 patients diagnosed with CS between 2002-2017, 4 patients were not living in the region and 24 patients had died by the end of the study (18 patients with ectopic CS, 4 patients with adrenal carcinoma and two patients with CD). Thus, in total, 93 patients with endogenous CS were alive and living in the Västra Götaland County resulting in a prevalence of 57 cases per million.
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The use of the diagnostic codes in patients with CS
All 39 patients with CD had received the diagnostic code for pituitary-dependent CS (E24.0). However, 17 patients, without CD, had also received the code, including two patients with ectopic CS and one with iatrogenic CS.
Thirteen of 21 (62%) patients with ectopic CS had received a correct diagnostic code (E24.3) Two patients received the code for pituitary-dependent CS, three for other specified CS (E24.8) and three patients for unspecified CS (E24.9).
Eight patients with benign adrenal CS had received a diagnostic code for other specified CS and 9 for unspecified CS.
All 5 patients with cortisol producing adrenocortical carcinoma received the diagnostic code for adrenocortical cancer (C74.0). Two received the code for other specified CS and one for unspecified CS. Two patients did not receive a diagnostic code for CS.
Discussion
In this study, on an unselected cohort of patients with all forms of endogenous CS, we found an overall annual incidence rate of 3.2 cases per million/year. Of 82 patients diagnosed between 2002 and 2017, 39 (48%) had CD, 21 (26%) had ectopic CS, 17 (21%) had benign adrenal disease and 5 (6%) had cortisol-producing adrenocortical cancer.
The incidence of CD in our study (1.5 cases per million/year) is in line most previous studies (2-9). Similarly, the incidence of cortisol-producing adrenal adenoma (0.5 cases per million/year) is close to the incidence reported in the two studies that have included patients with various forms of CS, not only CD (0.3 and 0.6 cases per million per year, respectively;
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Table 2) (8, 9). On the contrary, we found a considerably higher incidence of ectopic CS (0.8 cases per million per year) than the two previously mentioned studies (0.1 and 0.3 cases per million per year, respectively) (8, 9). In highly cited review articles on endogenous CS (1, 12), the proportion of patients with ectopic CS is typically considered to be 10%. Also, in one of the largest study on ectopic CS published today (13), 14% of patients with ACTH- dependent CS had ectopic CS, compared to 35% in our cohort. Furthermore, in the European registry on CS (ERCUSYN), an even lower proportion of patients (5%) had ectopic CS (14). The differences in the incidence of ectopic CS in the current study, compared to previous reports, can possibly be explained by increased awareness of hypercortisolism in patients with malignant tumours, but also by variations in the diagnostic process and management of these patients. In some countries, and/or hospitals, patients with ectopic CS may be managed solely by oncologists and not endocrinologist. In such cases, it is likely that the patients receive a diagnostic code for their malignant disease but not ectopic CS. Furthermore, the course of ectopic CS is often rapid, sometimes with a fatal outcome within weeks from diagnosis, increasing the risk of not receiving the correct diagnostic code.
In a recent study from USA, Broder et al. reported an exceptionally high annual incidence rate of 49 cases per million for all endogenous CS and 8 cases per million/year for CD (15). The study was based on data on patients younger than 65 years of age from a large insurance database where the diagnosis was based on diagnostic codes for CS and the medical records were not reviewed for validation of the diagnosis. In another recently published study from Israel by Hirsch et al., based on data from a large health care database, the mean annual incidence of CS between 2005 and 2014 was 4.5 cases per million (16), also higher than previously reported. Of note is that in both the study by Broder and Hirsch, patients in the
databases without CS were used as the denominator for calculation of incidence. It is therefore likely that the incidence of CS was overestimated in both studies.
The prevalence of endogenous CS has, to our knowledge, only been reported once previously (8). A prevalence of 79 cases per million was found and is higher than the rate in the current study (57 cases per million). It is, however, probable that the true prevalence of endogenous CS in our region is underestimated. The reason is that some patients, who were treated before 2002, and are considered to be cured, are no longer followed at our hospital, but at smaller hospitals in the region, and were therefore not captured in the search in the DRG-registry that was restricted to the Sahlgrenska University Hospital.
Fourteen of 39 (36%) patients with CD in our cohort had macroadenoma. This is a somewhat higher proportion than that showed in most reports where 11-19% of patients with CD had macroadendoma (8, 17-20). There are, however, studies showing almost as high proportion (27-32%) of macroadenomas as in our cohort of (21-23). All patients in our cohort had clinically overt CS and the high proportion can therefore not be explained by the inclusion of patients with silent corticotropic adenoma; instead, a finding by chance would fit as the most reasonable explanation.
All patients with endogenous CS in the Västra Götaland County are referred to the
Sahlgrenska University Hospital for evaluation and treatment. Therefore, we feel confident that all patients diagnosed with benign forms of CS are included in the analysis. However, even though we found a high incidence of ectopic CS, we cannot rule out that some of these patients may have been missed. For example, it is possible that some patients with ectopic CS, due to disseminated and incurable cancer at diagnosis, and stormy disease course, were treated locally and never referred to the Sahlgrenska University Hospital. As a matter of fact,
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the true incidence of ectopic CS may be largely underestimated since ACTH and cortisol excess are not systematically measured in patients with malignancies. Similarly, of 22 patients with ACTH-independent CS, 17 (77%) had benign adrenal CS, and 5 (23%) had adrenocortical carcinoma. These results differ from the commonly reported proportions between adrenal adenoma and adrenocortical carcinoma of 60 and 40%, respectively (1, 12). Two patients with cortisol-producing adrenocortical cancer had not received a diagnostic code for CS. In future epidemiological studies on CS, the DRG-registries at all hospitals in the region of interest should be used for identification of patients, and the diagnostic code for adrenocortical cancer (C74.0) should as well be included in the search criteria.
All 39 patients with CD had received a correct diagnostic code for pituitary dependent CS (E24.0). However, the diagnostic code was apparently also used incorrectly for several patients without CD. Thus, in epidemiologic research, the diagnosis of CD cannot be based solely on diagnostic codes. Instead, review of medical records is necessary to confirm the diagnosis. On the contrary, the code for ectopic CS (E24.3) was almost only used for patients with the disease. However, one-third of patients with ectopic CS had not received the code and would not have been captured if the search criteria had only included this specific code. In the ICD-10 system, no specific code exists for patients with cortisol-producing adrenal tumours, reflected by the inconsequent use of diagnostic codes in this group of patients, i.e., approximately half of the patients received the code for unspecified CS (E24.9) and the other half received the code for other specified CS (E24.8). In the up-coming versions of the ICD system, a specific code for cortisol-producing adrenal tumours should be added to the system, preferably one for adrenal adenoma and one for adrenocortical carcinoma. In fact, it is peculiar that rarer CS-related conditions such as Nelson’s syndrome and alcohol induced CS have specific codes while adrenal CS does not.
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The major limitation of the study is the relatively small number of patients. However, the major strength of the study is the inclusion of all subgroups of patients diagnosed with endogenous CS in the modern era. In fact, the only two population-based studies that have included other aetiologies than CD are based on data from patients diagnosed between 1985- 1995 and 1960-2005, respectively (8, 9). Another strength is that almost all patients with ACTH-producing microadenoma performed an inferior petrosal sinus sampling preoperatively and that the diagnosis was confirmed by a histopathological examination in the majority of the cases. Finally, the Västra Götaland County has a large and well-defined population, making it possible to provide a reliable calculation of incidence rates of rare diseases such as CS.
In conclusion, approximately three new cases of endogenous CS, per one million inhabitants, were diagnosed annually in the Västra Götaland County in Sweden between 2002 and 2017. Half of the CS cases were caused by CD, one-fourth by an ectopic ACTH-producing tumour and one-fourth by adrenal disease. Compared to previous reports, proportionally more patients had ectopic CS. The reason for this is unclear although an increased awareness of hypercortisolism in patients with malignant tumours in the modern era is a possible explanation. Further research, preferably on larger populations in different geographical areas, is necessary to establish the true incidence and prevalence rates of endogenous CS.
Acknowledgements: We thank Peter Thorsson for identifying the patients in the DRG register.
Data Availability Statement: Raw data can be obtained upon request to the corresponding author.
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| All (n=82)ª | Cushing's disease (n=39) | Adrenal adenoma (n=14) | * | Ectopic CS (n=21) | P | P | |
|---|---|---|---|---|---|---|---|
| Age (yrs) | 50±18 | 48±17 | 46±15 | 0.8 | 59±18 | 0.03 | 0.03 |
| Female gender | 57 (70) | 27 (69) | 13 (93) | 0.08 | 13 (62) | 0.6 | 0.04 |
| Hypertension | 60 (73) | 28 (72) | 10 (71) | 1.0 | 17 (81) | 0.4 | 0.5 |
| Diabetes mellitus | 27 (33) | 10 (26) | 5 (36) | 0.5 | 11 (52) | 0.04 | 0.3 |
| S-cortisol following 1 mg ONDST (nmol/L) | 574 (330- 810; 61- 2520) | 430 (167- 644; 61- 1670) | 476 (338- 640; 140- 930) | 0.6 | 899 (720- 1060; 530-2520) | 0.001 | 0.001 |
| UFC (times the ULN | 4.0 (1.8- 9.5; 0.7- 316) | 2.9 (1.8- 6.6; 0.9- 67) | 1.5 (1.2- 3.1; 0.9- 7.2) | 0.02 | 20 (6.6- 49; 0.7- 316) | <0.001 | <0.001 |
| S-cortisol at midnight (nmol/L) | 590 (402- 900; 87- 4690) | 535 (380- 827; 87- 1840) | 420 (250- 550; 210- 870) | 0.3 | 1100 (800- 2330; 360-4690) | 0.001 | <0.001 |
| P-ACTH (pmol/L) | - | 18 (11-38; 3.1-91) | 1.2 (0.3- 2.0; 0.2- 2.7) | <0.001 | 82 (33- 163; 10- 400) | <0.001 | <0.001 |
Data is presented as mean ± standard deviation, median (interquartile range; range) or n (%). P Cushing’s disease versus benign adrenal CS, P ** Cushing’s disease versus ectopic CS, P *** benign adrenal CS versus ectopic CS. ªThe total number of patients includes also five patients with adrenocortical carcinoma, two patients with primary pigmented nodular adrenocortical disease, and one patient with macronodular adrenal hyperplasia.
Abbreviations: ACTH, adrenocorticotropic hormone at 0800 am (ref 2.0-11 pmol/L); CD, Cushing’s disease; CS, Cushing’s syndrome; ONDST: 1 mg overnight dexamethasone suppression test; UFC, 24-hr urinary free cortisol; ULN: upper limit of the normal range ACTH: adrenocorticotropic hormone at 0800 am (ref 2.0-11 pmol/L)
Accepted Article
ccepted Article
| Number of patients Incidence (cases per million per year) | ||||||||
|---|---|---|---|---|---|---|---|---|
| Author (year of publication) [reference] | Country | Period | All endogenous CS | CD | Ectopic CS | Adrenal adenoma | ACC | Comments |
| Lindholm et al. (2001) | Denmark, nationwide | 1985- 1995 | 166 2.8 | 73 (99ª) 1.2 (1.7) | 16b 0.3 | 37 0.6 | 11 0.2 | ª73 patients with confirmed CD, additionally 26 had probable CD. 6 patients with carcinoid and 10 with nonadrenal carcinoma |
| Bolland et al. (2011) | New Zealand, nationwide | 1960- 2005 | 253º 1.8 | 188 1.3 | 19€ 0.1 | 37 0.3 | _c | "Patients with malignant ectopic CS and ACC excluded from the analysis. Patients from 4 main centers in New Zealand were included (>90% of CS patients in the country) |
| Current study | Sweden, Västra Götaland County | 2002- 2017 | 82 3.2 | 39 1.5 | 21 0.8 | 14 0.5 | 5 0.2 | |
Abbreviations: ACC, adrenocortical carcinoma; CD, Cushing’s disease; CS, Cushing’s syndrome
Figure legends
Figure 1. Flow chart over patients who had received a diagnostic code for Cushing’s syndrome (CS) at the Sahlgrenska University Hospital between 2002 and 2017. (*Two patients with adrenocortical carcinoma had not received a diagnostic code for CS).
Figure 2. Number of patients diagnosed with endogenous Cushing’s syndrome (CS) in the Västra Götaland County between 2002 and 2017.
Accepted Article
Patients who had received a diagnostic code for CS N=236
Endogenous CS N=153
CS diagnosis before 2002 N=54
Iatrogenic CS N=24
Patients not living in the Västra Götaland County N=17
Mild autonomous hypercortisolism N=21
· Halland County N=6
. East Götaland County N=1
Diagnosis 2002-2017, Västra Götaland County N=82
Excluded for other reason N=38
· Iceland N=9
. Norway N=1
·Suspected CS, ruled out N=11
· Other endocrine diagnosis N=18
. Non-endocrine diagnosis N=7
. Unavailable medical chart N=2
Cushing’s disease CD N=39
Adrenal CS N=22
Ectopic CS N=21
· ACTH-secreting pituitary adenoma N=38
· Cortisol producing adrenal adenoma N=14
· Lung cancer N=8
· Lung NET N=1
· Aggressive ACTH-secreting pituitary tumor N=1
· PPNAD N=2
· Pancreas-NET N=4
· Macronodular hyperplasia N=1
· Thymus-NET N=1
· Cortisol producing adrenocortical carcinoma N=5*
. Small intestine NET N=1
· Prostate cancer N=1
. Occult ectopic CS N=5
Accepted Article
Accepted Article
Pituitary CS
Benign adrenal CS
Ectopic CS
Adrenal carcinoma
1
10
3
8
1
6
2
2
3
1
3
1
2
1
1
1
4
2
2
2
1
1
2
2
2
1
1
2
4
2
4
4
4
3
3
3
3
2
2
2
2
2
2
1
1
0
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
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2017