Summary
Ectopic Cushing’s syndrome (ECS) is a rare disease associated with significant comorbidity. Among the causes of Cushing's syndrome, adrenocorticotropic hormone-producing extrapituitary tumours are rarely reported. This low frequency makes it difficult for the physician to acquire experience in its management.
In this report, we aimed to describe the clinical presentation, diagnostic approach and treatment modalities of 12 patients with ECS treated in a single tertiarycentre over a 17-year period. Although they can appear in different locations through the neuroendocrine system, lung tumours are the most frequently reported, as it occurs in our series. They can show different levels of aggressiveness and mild to severe clinical course. Therefore, distinguishing Cushing's disease can be challenging and sometimes requires more specific techniques such as invasive tests or no conventional imaging. Treatment includes controlling both hypercortisolism and neoplastic disease, and multidisciplinary management is recommended.
Learning points
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Ectopic Cushing's syndrome (ECS) accounts for 15% of endogenous Cushing's syndromes. Its infrequency implies that both diagnosis and treatment can be a challenge for clinicians without experience in its management.
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The most common location is the lung. Although older series reported small cell lung carcinoma (SCLC) as the main ECS-producing tumour, currently most cases are attributed to lung carcinoids.
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Low-grade tumours (lung carcinoids) present themselves with a more subtle and gradual hypercortisolism, and clinically this can be difficult to differentiate from hypercortisolism due to CD. In contrast, high-grade tumours (SCLC) show severe hypercortisolism with rapid evolution.
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The diagnostic approach is complex especially when the tumour is not previously known and the clinical presentation is subtle. Functional tests are mandatory in these cases, and nuclear medicine imaging can help when conventional imaging tests fail to identify the tumour.
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ECS treatment includes a wide variety of modalities oriented to treat both the excess of cortisol and the tumour itself. The tumour prognosis depends fundamentally on the type of adrenocorticotropic hormone-secreting tumour.
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Expert and multidisciplinary team is essential for successfully treating these complex and ill patients.
Background
Cushing’s syndrome (CS) is caused by a number of underlying disturbances that must be differentiated to ensure successful treatment. The ectopic Cushing’s syndrome (ECS) compromises approximately 15% of cases of endogenous CS (1). The frequency of these adrenocorticotropic hormone (ACTH)-secreting non-pituitary tumours has varied in the different series over the years. Initially, there was a preponderance of aggressive tumours, specifically small cell lung carcinomas (SCLCs). However, more indolent tumours such as lung carcinoids are now recognized to cause most cases of ECS.
Lung carcinoids typically present in a more subtle clinical manner in contrast with SCLC. This gradual development of the clinical syndrome is associated with more subtle biochemistry and leads to considerable challenges in distinguishing this ECS form from pituitary tumours causing Cushing’s disease (CD) (2).
Additionally, no single imaging modality can itself identify and localize every tumour responsible for CS. There are three main reasons: up to 20–30% of secretory pituitary adenomas may not be visible on MRI, up to 10% may show a pituitary incidentaloma not responsible for excess ACTH secretion and up to 12–18% of ECS can be an occult ectopic ACTH-secreting tumour not identified after initial morphological imaging (3, 4).
Despite this complex scenario, localization of the source of ectopic ACTH secretion remains crucial in order to establish the appropriate treatment, which includes resection of the tumour when possible and medical treatment for progressive or advanced/metastatic disease. Medical therapy options are aimed to treat both the hypercortisolism and the tumour itself.
The aim of our study was to present several patients with ECS treated at our centre over a period of 17 years. We describe our experience in the diagnostic approach, treatment modalities and long-term prognosis, as well as a literature review.
Clinical presentation
We included a total of 12 patients diagnosed with ECS in our Endocrinology department between 2005 and 2022 (Table 1). There was a majority of male patients (8) and the mean age at diagnosis for the whole cohort was 57 years (range: 29–77 years). The median time from the onset of symptoms to hypercortisolism diagnosis was 2 months (range: 1–24 months). The most frequent comorbidities were hypertension in 11 patients (92%), diabetes mellitus, asthenia and oedema of limbs in 9 patients (75%). It was also common to observe ‘typical’ features of CS such as proximal weakness, capillary fragility, Cushingoid phenotype and weight gain, which were observed with 67, 58, 58 and 58% each.
Epidemiological and clinical data.
Case number | Gender | Age (years) | Symptoms and signs | Laboratory tests alterations | Time to diagnosis (months) |
---|---|---|---|---|---|
1 | M | 62 | Proximal myopathy, Cushingoid phenotype, weight gain, osteoporosis/fractures, asthenia, hyperpigmentation, oedema of limbs, unusual infections, constitutional syndrome | ↓ K; ↑ALP, GGT, ALT, AST; ↑leucocytes; DM |
2 |
2 | M | 29 | Facial plethora, proximal myopathy, striae, Cushingoid phenotype, weight gain, osteoporosis/fractures, asthenia, oedema of limbs, hypertension, nephrolithiasis, psychiatric disorders, gynecomastia | None | 24 |
3 | F | 40 | Capillary fragility, Cushingoid phenotype, weight gain, osteoporosis/fractures, asthenia, hypertension, menstrual disorders | ↓ K | 12 |
4 | M | 68 | Cushingoid phenotype, weight gain, oedema of limbs, hypertension, gynecomastia | ↓ K; DM; DL. | 2 |
5 | M | 31 | Proximal myopathy, striae, Cushingoid phenotype, weight gain, asthenia, hypertension | ↓ K; ↑ ALP, GGT, ALT, AST; DM | 12 |
6 | M | 50 | Facial plethora, proximal myopathy, capillary fragility, Cushingoid phenotype, weight gain, asthenia, oedema of limbs, hypertension, psychiatric disorders, gynecomastia | ↓ K; ↑ALP, GGT, ALT, AST; ↑leucocytes; DM; DL | 2 |
7 | F | 77 | Proximal myopathy, asthenia, oedema of limbs, hypertension, psychiatric disorders | ↓ K; ↑leucocytes; DM; DL | 2 |
8 | M | 61 | Facial plethora, proximal myopathy, capillary fragility, asthenia, oedema of limbs, hypertension | ↓ K; ↑leucocytes; DM; DL; ↑ALT, AST | 1 |
9 | M | 76 | Proximal myopathy, capillary fragility, osteoporosis/fractures, hyperpigmentation, oedema of limbs, hypertension, nephrolithiasis, unusual infections, deep vein thrombosis | ↓ K; ↑leucocytes; DM; DL | 4 |
10 | F | 61 | Proximal myopathy, capillary fragility, weight gain, asthenia, hypertension, unusual infections | ↓ K; ↑ALP, GGT, ALT, AST; ↑leucocytes; DM | 1 |
11 | F | 61 | Capillary fragility, Cushingoid phenotype, oedema of limbs, hypertension, virilisation | ↓ K; ↑leucocytes | 1 |
12 | M | 66 | Capillary fragility, asthenia, oedema of limbs, hypertension | ↓ K; ↑leucocytes; DM | 4 |
ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase; DL, dyslipidemia; DM, diabetes mellitus; F, female; GGT, gamma-glutamyl transferase; K, serum potassium; M, male.
Other presentation forms included hyperpigmentation, virilisation or menstrual disturbances in females, gynecomastia in males, psychiatric disorders, osteoporotic fractures, unusual infections or nephrolithiasis, although they were less frequently detected.
Regarding laboratory test disturbances, we highlight the hypokalemic metabolic alkalosis that was present in almost all patients (92%). Furthermore, in two cases (number 4 and 6) the hypokalaemia could not be controlled despite continuous intravenous potassium supplementation and was persistent until death. Leucocytosis and hypertransaminasemia were often detected too (67 and 42%, respectively).
Investigation
Biochemical diagnosis
Relating to CS diagnosis, the mean serum cortisol was 55.5 ± 24.7 µg/dL (≥2× ULN; normal range (NR): 5–25 µg/dL), mean urinary free cortisol (UFC) was 3558.5 ± 3582.6 µg/24 h (≥30× ULN; NR: 20–120 µg/24 h), mean late-night salivary cortisol was 0.81 ± 0.82 µg/dL (≥4× ULN; NR: 0.0–0.2 µg/dL) and mean ACTH was 186.3 ± 74.9 µg/dL (≥3× ULN; NR: 5–60ng/L). It is remarkable that all cases had a significant increase in UFC at least four times above normal value and none case had an ACTH in the normal range (Table 2).
Hormonal parameters.
Case number | PC (µg/dL) | ACTH (pg/mL) | LNSC (µg/dL) | UFC (µg/24 h) | 1-mg DST (µg/dL) | 8-mg DST ΔPCa % | CRH stimulation testb | BIPSS (ACTH C/P gradient)c | BIPSS (PRL C/P basal gradient) | Other hormones and biomarkers | |||||
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ΔACTH, % | ΔPC, % | Basal | After CRH | 17OH, µg/L | ADS, µg/dL | 5HIIA, mg/24h | CgA, ng/mL | ||||||||
Normal range | 5–25 | 5-60 | 0.0–0.2 | 20–120 | PC < 1.8 | 0.25–3.90 | 0.30–2.60 | 7–8.2 | 19–98 | ||||||
1 | 40.5 | 263 | - | 4470 | 37.2 | - | +43.91 | +14.04 | 1.78 | 0.97 | 29.5/12.8 = 2.30 | 8.26 | >10 | 82.7 | |
2 | 20 | 132.6 | 0.296 | 1229 | - | −1 | +45.02 | +8.83 | 1.39 | 1.73 | 11.8/10.8 = 1.09 | 5.86 | 9.6 | ||
3 | 49 | 75 | 1.21 | 838 | - | - | +19.41 | +11.5 | 1.39 | 1.56 | 5.5/8.1 = 0.67 | 5.26 | 293 | ||
4 | 27.8 | 139.5 | 0.063 | 2227 | 28.4 | +0.6 | +10 | +18.5 | 1.02 | 1.42 | - | >10 | |||
5 | 52.1 | 226 | - | 6246 | - | - | −20 | - | - | - | |||||
6 | 79.6 | 271.6 | - | 1500 | 86.1 | - | - | - | - | 3302 | |||||
7 | 98.1 | 248.2 | - | 1860 | 34.4 | −18.89 | - | - | - | >10 | ↑ | ||||
8 | 47.1 | 162.9 | - | 11,876 | 54.3 | - | - | - | - | 89 | |||||
9 | 42.4 | 274.8 | 1.12 | 1395 | 43.3 | −36.55 | - | - | - | 186 | |||||
10 | 62.8 | 120.1 | 0.05 | 2552 | 27.5 | - | - | - | - | - | |||||
11 | 49.9 | 84.6 | 2.12 | - | 45.7 | −8.61 | - | - | - | - | |||||
12 | 97.1 | 236.7 | - | 1920 | 79.4 | −13.18 | - | - | - | - |
aSuppression was considered if ΔPC < −50%; bStimulationwas positive for Cushing’s disease if ΔACTH > 50% and ΔPC >20%; cACTH C/P gradient basal >2 or after stimulation by CRH >3 was positive for Cushing’s disease.
1-mg DST, 1-mg (low-dose) dexamethasone suppression test; 5HIIA, 5 hydroxyindolacetic acid; 8-mg DST, 8-mg (high-dose) dexamethasone suppression test; 17OHP, 17 hydroxyprogesterone; ACTH, adrenocorticotropic hormone; BIPSS, bilateral inferior petrosal sinus sampling; C/P, central/peripheral; CgA, chromogranin A; CRH, corticotropin-releasing hormone; LNSC, late-night salivary cortisol; PC, plasma cortisol; PRL, prolactin; UFC, 24-h urinary free cortisol.
The ectopic origin was established in three cases (6, 8 and 10) without functional test. In cases 6 and 8, that were due to the inverse diagnosis process, the imaging was performed before confirming CS. These patients were studied for local symptoms of the tumour (respiratory clinic and superior vena cava syndrome) and the neoplasm was clearly evidenced in convectional radiological imaging. Regarding case 10, inferior petrosal sinus sampling (IPSS) and corticotropin-releasing hormone (CRH) for stimulation test were temporarily unavailable in the centre when this patient was treated, so we guided the diagnosis by performing pituitary MRI, CT and Octreoscan. In all the remaining cases, dynamic tests were performed to approach the diagnosis (8-mg dexamethasone suppression test, CRH stimulation test and/or IPSS (ACTH central/peripheral gradient basal and after CRH)) which were compatible with ECS in all patients.
Localization studies
In all cases, radiological images were performed (CT or MRI) and they could detect the neoplasm in 10 of the 12 cases (Table 3). In the two patients with CT and/or MRI negative (numbers 2 and 7), the localization of ACTH source was achieved using nuclear medicine imaging. In case number 2, it was localized by a 68Ga-DOTATE PET/CT whereas Octreoscan and FDG-PET/CT were negative. In case number 7, both Octreoscan and FDG-PET/CT showed a hypercaptant left lung area.
Localization studies.
Case number | CT | MRI | OctreoScan | FDG-PET/CT | 68Ga- PET/CT | Pituitary gland MRI | Final diagnosis |
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1 | 14.4 mm nodule in left lung. Liver metastases. Gastroenterohepatic lymphadenopathy | - | Positive. Hypercaptation in primary tumour | Positive. Hypermetabolism in primary tumour and loco-regional lymphadenopathy | - | No findings | Lung carcinoid |
2 | No findings | No findings | Negative | Negative | Positive. Right pulmonary nodule | No findings | Lung carcinoid |
3 | - | 7 mm lingular nodule | Positive. Hypercaptation in primary tumour | - | - | Pituitary microadenoma 7 mm size | Lung carcinoid |
4 | Nodule in LUL of lung | - | Negative | - | - | Pituitary microadenoma 5 mm size | SCLC |
5 | 8 mm nodule in RLL of the lung. | - | Negative | Negative | - | No findings | Lung carcinoid |
6 | 85 mm right parahilar mass. Mediastinal lymphadenopathy, pleural, liver and adrenal metastases | - | - | - | - | - | SCLC |
7 | Bilateral adrenal hyperplasia. Left adrenal nodule of 14 mm | - | Positive. Hypercaptant left lung area | Positive. Hypermetabolic lesion in the left lung | - | No findings | Unknown origin |
8 | 96 mm subcarinal mass infiltrating and compressing surrounding structures (superior vena cava, left atrium, oesophagus, main bronchi, right main pulmonary artery) | No findings at pancreatic-liver level | - | - | - | SCLC | |
9 | 17 mm nodule in LUL of the lung | - | Positive. Hypercaptation in primary tumour | - | - | Lung carcinoid | |
10 | 20 mm nodule in RUL of the lung | 14 mm cystic lesion in the pancreas compatible with a mucinous tumour | Positive. Hypercaptation in primary tumour | - | Right pituitary microadenoma 5 mm size | Lung carcinoid | |
11 | Multifocal and bilateral lung metastases. Liver metastases and peritoneal implants. | - | - | - | - | SCLC | |
12 | 44 mm mass in RUL of the lung. | - | - | - | - | - | SCLC |
CT, computed tomography; FDG-PET/CT, fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography; 68Ga- PET/CT,68Ga-DOTATATE positron emission tomography/computed tomography; LUL, left upper lobe; MRI, magnetic resonance imaging; OctreoScan, 111InDTPApentetreotide scintigraphy; RLL, right lower lobe; RUL, right upper lobe; SCLC, small cell lung carcinoma.
Pathological anatomy results.
Case number | Size (cm)a | Localization | Grade | Ki67 index (%) | Mitotic count (10 HPF) | TNM | Final diagnosis |
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1 | NAb | Lung | G2 | 1–5 | <2 | Stage IV | Atypical carcinoid |
2 | 1.7 | Lung | G1 | 3 | - | Stage IA2 (pT1b pN0 cM0)c | Typical carcinoid |
3 | 2 | Lung | G2 | 10 | - | Stage IIIA (pT1b pN2 cM0)c | Atypical carcinoid |
4 | 2 | Lung | - | - | - | Stage IV | SCLC |
5 | 1.3 | Lung | G1 | - | <2 | Stage IA (pT1b pN0 cM0)d | Typical carcinoid |
6 | NAb | Lung | - | - | - | Stage IV | SCLC |
7 | - | Lung | - | - | - | - | Unknown origin. No finding of tumour cells (necrotic tissue). |
8 | 9.6 | Lung | G3 | 90 | - | Stage IV | SCLC |
9 | 1.7 | Lung | G1 | 1 | - | Stage IA2 (pT1b pN0)c | Typical carcinoid |
10 | 2 | Lung | G1 | 2 | - | Stage IA2 (pT1b pN0)c | Typical carcinoid |
11 | NA | Lung | - | - | - | Stage IV | SCLC |
12 | 4.4 | Lung | G3 | 90 | - | Stage IV | SCLC |
aMaximum diameter; bCytology results (fine needle aspiration); cTNM-staging 8th edition; dTNM-staging 6th edition.
HPF, high-power field (2 mm2); NA, not available.
Additionally, nuclear medicine imaging was used on six more patients (numbers 1, 3, 4, 5, 9 and 10) to prove the neuroendocrine origin of the neoplasm observed in the anatomical studies. That was possible in cases 1, 3, 9 and 10, where CT/MRI findings were concordant with hypercaptation in Octreoscan. However, in cases 4 and 5, Octreoscan was negative and did not provide any additional information, neither FDG-PET/CT as well performed in case number 5.
Furthermore, an MRI of the pituitary gland was done in seven cases (numbers 1, 2, 3, 4, 5, 7 and 10) as part of the diagnosis approach. It showed a microadenoma in three cases with a mean size of 5.7 mm (range 5–7 mm) and no findings in rest of the cases. In those patients with microadenoma observed, CD was appropriately ruled out with dynamic test.
Pathological features
A pathological diagnosis was obtained in 11 patients. In patient 7, the tissue removed from the hypermetabolic lesion was entirely necrotic. No viable tumour tissue was identified in the specimen.
All the neoplasms detected were lung neuroendocrine tumours (six carcinoids and five SCLC). The size of the primary tumour varied between 1.3 and 9.6 cm, with a mean of 3.08 cm. As high as 50% presented with metastatic dissemination at diagnosis, they were all the SCLC cases and only one of the carcinoid patients (case number 1).
Treatment
Hypercortisolisim treatment
All patients received medical treatment for hypercortisolism before undergoing antitumour therapy (Table 5). Therapeutic management of CS included ketoconazole as the first line for hypercortisolism control in 75% of cases (9/12). In those cases where ketoconazole could not be used (numbers 1, 9 and 12), metyrapone was indicated instead. The main reason for not using ketoconazole was persistent hypertransaminasemia or a history of liver cirrhosis. Ketoconazole or metyrapone was indicated in monotherapy except for one case (number 1) in which metyrapone was combined with long-acting somatostatin (SST) analogue. With first-line therapy, complete control of hypercortisolism was achieved only in one case (number 2), 25% cases got partial control and half of the patients had persistence of hypercortisolism (6/12).
Hypercortisolism treatment.
Case number | 1st line treatment | 2nd line treatment | 3rd line treatment | Final state of CS | |||
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Drug | Response | Drug | Response | Drug | Response | ||
1 | Metyrapone (250 mg TID)+ long-acting SST analogue (pasireotide 0,6 mg BID SC) | P | - | - | - | - | Uncontrolled |
2 | Ketoconazole (200 mg TID) | CC | - | - | - | - | Cured |
3 | Ketoconazole (200 mg TID) | P until Qx | Ketoconazole (200 mg TID) + long acting SST (octreotide 20 mg/28d SC) | P until Qx | Ketoconazole (200 mg TID) + long acting SST (octreotide 20 mg/28d SC) + metyrapone (500 mg BID) | P until Qx | Cured |
4 | Ketoconazole (200 mg BID) | PC | - | - | - | Uncontrolled | |
5 | Ketoconazole (NA) | P until Qx | - | - | - | - | Cured |
6 | Ketoconazole (400 mg BID) | P | Ketoconazole (400 mg BID) + metyrapone (250 mg TID) | P | - | - | Uncontrolled |
7 | Ketoconazole (200 mg TID) | P | - | - | - | - | Uncontrolled |
8 | Ketoconazole (200 mg TID) | P | Metyrapone (250 mg TID) | PC | - | - | Uncontrolled |
9 | Metyrapone (500 mg BID) | PC until Qx | - | - | - | - | Cured |
10 | Ketoconazole (200 mg BID) | PC until Qx | - | - | - | - | Cured |
11 | Ketoconazole (200 mg TID) | P | - | - | - | - | Uncontrolled |
12 | Metyrapone (500 mg QID) | P | - | - | - | - | Uncontrolled |
SST, somatostatin; P, persistence; CC, complete control; PC, partial control; Qx, surgery; CS, Cushing’s syndrome.
Second-line therapy was only indicated in three cases, either due to persistent or recurrent hypercortisolism or due to drug toxicity. In case number 6, metyrapone was added to ketoconazole, but despite this, CS was not controlled. In case number 8, ketoconazole was changed to metyrapone due to the development of hypertransaminasemia with the first drug; however, the hypercortisolism also remained uncontrolled. Case number 3 required the addition of two other drugs (long-acting SST and metyrapone) to control CS. In spite of that, the disease persisted until primary tumour resection.
In the remaining patients, a second-line treatment was not administered. In the case of carcinoid tumours, hypercortisolism was resolved following primary tumour surgery, while in the cases of SCLC, second-line treatment was not pursuedd due to comorbidities, poor prognosis and disease progression.
Antitumour treatment
The treatment of the primary tumour included surgery in 50% of the patients (6/12) (Table 6). Between carcinoid patients, those with typical carcinoid (grade 1) achieved cure of the neoplastic disease in 100% of cases (numbers 2, 5, 9 and 10). The two cases with atypical carcinoids (grade 2) required systemic therapy in addition to surgery (somatostatin analogues for both cases combined with sunitinib in case number 1 and with chemotherapy in case number 3). Second-line treatment of patients with atypical carcinoids reached remission in one case but not in the other, who showed disease progression up to death.
Antitumour treatment.
Case number | 1st line treatment | 2nd line treatment | Final state of neoplastic disease | ||
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Therapy | Response time | Therapy | Response time | ||
1 | Sunitinib+ long-acting SST analogue (Octreotide LAR) | TP: 8 months | SST analogue (Pasireotide) | TP: 4 months | Dead (TP) |
2 | Qx | CR | - | - | Disease-free |
3 | Qx+ long-acting SST | - | Chemotherapy (carboplatin etoposide) | CR: 30 months | Remission |
4 | Chemotherapy (carboplatin-etoposide) | PR: 11 months | Chemotherapy (topotecan)a | TP: 10 monthsa | Dead (TP) |
5 | Qx | CR | - | - | Disease-free |
6 | Chemotherapy (carboplatin-etoposide) | TP | - | - | Dead (TP) |
7 | Qx | - | - | - | Dead (CCS) |
8 | Chemotherapy (carboplatin-etoposide) | TP: 1 month | Chemotherapy (camptothecin-11) | TP: 1 month | Dead (TP) |
9 | Qx | CR | - | - | Disease-free |
10 | Qx | CR | - | - | Disease-free |
11 | Chemotherapy (carboplatin-etoposide) | TP: 3 months | Radiotherapy | TP: 2 months | Dead (TP) |
12 | Chemotherapy (carboplatin-etoposide) | TP: 1 month | - | - | Dead (CCS) |
TP, tumor progression; CR, complete remission; PR, partial remission; CCS, Complications of Cushing’s syndrome.
aMultiple subsequent chemotherapy lines: Placlitaxel (TP: 6 months), Lurbinectedin (TP: 11 months), Temozolamide and Radiotherapy (TP: 4 months), Adriamycin plus Cyclophosphamide plus Radiotherapy (TP: 5 months), Gemcitabine-Oxaliplatin (GEMOX) (TP: 2 months)
Patients with SCLC were treated all with chemotherapy being the first-line carboplatin-etoposide. Second-line of chemotherapy was only indicated in two of five patients (case numbers 4 and 8). In one case, radiotherapy was added (case number 11). All SCLC patients showed tumour progression to chemotherapy.
There was one case without a final diagnosis that only could receive surgery of the suspicious lesion as antitumour treatment, and the patient was not eventually cured (case number 7).
Outcome and follow-up
At follow-up, 7 patients died due to tumour progression and/or complications derived from hypercortisolism (Table 6). Those cases corresponded to the SCLCs, the ECS of unknown origin and one of the atypical carcinoid grade 2 (case number 1). Of the five patients who remain alive, four were typical carcinoids and one an atypical carcinoid grade 2 (case number 3). All currently present cured CS without hypercortisolism or antitumour treatment.
Discussion
ECS is a rare disease, as we can realize looking at this series that could only collect 12 cases over a 17-year period at a third-level hospital treating a population area above 400,000 inhabitants.
The average age of manifestation and the gender distribution in our study did not differ from that presented in the literature (5, 6, 7). Several patients of our series showed a rapidly progressive CS with mineralocorticoid predominant signs and symptoms such as oedema or hypokalemia, which are quite suspicious of ectopic ACTH production. However, when ECS was due to a carcinoid tumour, time to diagnosis tended to be delayed (median 12 vs 2 months in our series). These carcinoid cases were also associated to a mild hypercortisolism that could be difficult to distinguish clinically from CD.
Regarding biochemical parameters, markedly high levels of ACTH and UFC were observed in ECS patients and this is consistent with other studies when comparing with CD. However, cut-off points have not been described to differentiate the ectopic or central origin of CS.
Tumour size was not related to ACTH and cortisol levels, which has already been reported in other studies (8). Neither the origin carcinoid nor SCLC seemed to have a relationship with these biochemical values.
Regarding functional tests, they are required to differentiate between a pituitary and ectopic source of ACTH, especially when the clinical presentation is slowly progressive and does not associate constitutional symptoms related to neoplastic disease. Additionally, when the imaging is negative and primary tumour detection is not the first manifestation of the disease, performing a functional test turns essential to determine the cause of CS. In our series, these tests were required in 75% (9/12) of cases. None of the dynamic tests to distinguish between CD and ECS have a high specificity and even results can be discordant. An 8-mg dexamethasone suppression test is highly specific for identifying CD subjects when plasma cortisol suppression is superior to 50%, but a lower percentage of suppression is poorly specific for ECS (9). Desmopressin (DDAVP) and CRH stimulation testing have higher accuracy. It is based on the vasopressin and CRH receptors overexpression in pituitary adenomas but not in ectopic tumours, so increased plasma ACTH and cortisol concentrations after CRH or DDAVP usually indicate CD. However, well-differentiated neuroendocrine tumours may express these receptors and lead to false-positive results. In our series, most cases showed an increase in ACTH after CRH administration, but none of them was 50% or more over baseline, which is commonly accepted as response criteria for CD diagnosis. DDAVP testing was not performed in our cohort. IPSS is considered the gold standard and it was performed in 41% (5/12) of the cases (10). The results of the ACTH C/P gradient at baseline and after CRH were compatible with an ectopic origin in all patients who underwent IPSS. On the other hand, the values of the prolactin (PRL) central/peripheral (C/P) gradient did not suggest an ectopic origin in two of the three cases with prolactin measurement during the IPSS. However, the role of PRL C/P ratio for tumour localization still remains unclear and needs further investigation (11).
In 10 cases (83%), the tumour or its metastases could be identified by conventional imaging tests. This localization rate is higher than that reported in other series, which ranges around 50% (12). Nuclear medicine imaging can be helpful in those cases with negative CT or MRI. In our study, there was one patient whose tumour was not seen on cross-sectional imaging, neither on Octreoscan, but the lesion could be localized with 68GaDOTATATE. In this regard, 68GaDOTATATE localizes about 65% of these tumours that are not definitively identified on CT and has a higher sensitivity for small lesions than 111InDTPA pentetreotide scintigraphy (4).
Ectopic ACTH-secreting tumours have a variety of locations and histological types. Their frequencies vary among previously published case series, but most of them show the lungs as the most frequent tumour site (50%) and bronchial carcinoid as the first pathological type revealed (25–40%) (4, 13). Our series results are in the same line as previous literature, lung carcinoid being responsible for 50% of ECS cases, followed by SCLC (42%). Eight percent (one case) remained with unknown origin compared with 18.6% reported in other series (occult ECS) (12). It should be noted that in our series no cases of ECS of non-lung origin were reported. Although less frequently, ECS is also associated with pancreatic neuroendocrine tumours (NETs), pheohcoromcytomas, thymic carcinoids/carcinomas or medullary thyroid carcinomas (2, 14).
Surgical excision or complete removal of the neoplastic disease is the ideal curative treatment for ECS (11). This is possible in most of the well-differentiated and excisable tumours. However, many patients are not candidates for surgical resection due to unresectable disease with local invasion and/or distant metastases. In poorly differentiated tumours, platinum-based chemotherapy is the treatment of choice, while therapies such as somatostatin analogues (octreotide, lanreotide, pasireotide), kinase inhibitors (sunitinib), mTOR inhibitors (everolimus) and peptide receptor radionuclide therapy are employed in well-differentiated tumours, with variable response rates (13, 15). Currently, there is no established initial therapy or preferred sequence for specific tumour interventions. As a result, it is recommended that the therapeutic strategy be personalized and discussed by a multidisciplinary team with relevant experience, taking into consideration the patient’s individual condition.
In addition to antitumour drug therapy, control of hypercortisolism with pharmacological treatment is mandatory before submitting the patient to surgery or chemotherapy, since it significantly reduces morbidity, mortality and toxicity related to these therapies. On the other hand, controlling excessive cortisol secretion is a key element when tumour remission is not possible. Steroidogenesis inhibitors are a first-line treatment option for hypercortisolism secondary to ECS due to their efficacy and rapidity of action (13). Ketoconazole and metyrapone, used alone or in combination or associated with somatostatin analogues, were employed in most of our patients with efficacy.
The prognosis of ECE depends on the type of tumour responsible for ACTH secretion and its extension as well as the severity of hypercortisolism and the rapidity and efficacy of its treatment. Several CS worsens the prognosis even in absence of tumour progression. In our series, only 40% of patients remained alive free of disease or in remission, and they were all bronchial carcinoids, but not the cases of SCLC.
In conclusion, ECS is associated with significant morbidity and mortality both due to the complications derived from excess cortisol production and the tumour itself and its dissemination. Mortality differs according to the underlying primary tumour, showing SCLC the poorest prognosis. This fact highlights the importance of both hypercortisolism control and antitumour treatment, which requires multidisciplinary management.
Declaration of interest
The 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 until now, until accepted for publication.
Patient consent
Written consent has been obtained from each patient or subject after full explanation of the purpose and nature of all procedures used
Author contribution statement
All authors were physicians of the patients at some point during their follow-up.
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