Medullary Thyroid Cancer with Ectopic Cushing's Syndrome: A Case Report and Systematic Review of Detailed Cases from the Literature

Abstract

Background:

Medullary thyroid cancer (MTC) is a neuroendocrine tumor arising from parafollicular C-cells of the thyroid gland that, in rare cases, can cause a paraneoplastic ectopic Cushing's syndrome (ECS). The development of Cushing's syndrome (CS) in MTC patients is generally associated with advanced disease and poor prognosis.

Summary:

We described a case of severe CS due to MTC in a young male. We performed a systematic review to identify cases of ECS due to MTC. We searched PubMed, Scopus, and Web of Science for publications between database inception and February 2022 and we collected the patient characteristics, disease presentation, employed treatment strategies, and disease outcomes. In addition to our patient, we identified 96 cases of ECS due to MTC reported in literature. Mean age at diagnosis was 44.4 years (range 10–84), and there was a male predominance (male:female [M:F] = 1.8:1). Most patients (51%) presented with metastatic disease at diagnosis and showed severe hypercortisolism. Seventeen patients developed distant metastasis and hypercortisolism during follow-up. Interestingly, in 48% of patients, the diagnosis of CS followed the diagnosis of MTC with a median time of 48 months but, among patients in whom the diagnosis was concomitant (38%), symptoms due to hypercortisolism were frequently the reason for seeking medical advice. Pathology results showed evidence of adrenocorticotropic hormone (ACTH) or corticotropin releasing hormone (CRH) positive cells in 76% of patients in whom they were tested. The management of hypercortisolism was challenging in most patients with 48% requiring, eventually, definitive treatment with bilateral adrenalectomy (BLA). Recently, some limited evidence has emerged regarding tyrosine kinase inhibitors (TKIs) treatment for hypercortisolism in patients with ECS due to MTC. Despite limited information on survival, prognosis was generally poor and the main causes of death were either complications of CS or disease progression.

Conclusions:

Despite its rarity, MTC should be considered in the differential diagnosis of ECS. Management of hypercortisolism is a key factor to improve the patient's symptoms but it is often challenging and BLA is frequently required. Further studies are needed for investigating the role of TKIs in patients with MTC with ECS.

Introduction

Medullary thyroid cancer (MTC) is a rare neuroendocrine tumor arising from the parafollicular C-cells of the thyroid. The term “medullary” was definitively adopted in 1959, after Hazard et al. presented the distinctive histological features of this tumor (1). Despite its incidence slightly increasing in the past decades, it only accounts for 1–2% of all thyroid cancers, which is also due to the more consistent incidence and increase of papillary thyroid cancer (PTC) (2,3).

The MTC is usually more aggressive than differentiated thyroid cancer (DTC: PTC and follicular thyroid cancer), with the main prognostic factors being age (worse for patients ≥45 years old) and disease stage at diagnosis (4,5). The prognosis of early stage disease is still very good, with an estimated 10-year overall survival of 100% and 93% for patients with stage I and stage II disease, respectively. Unfortunately, more than 70% of patients with palpable disease at diagnosis have cervical lymph node metastases and 10% have distant metastases with a 10-year survival of 71% and 21% for stage III and stage IV disease, respectively (5,6).

About 75% of MTC are sporadic and the rest of them are hereditary as a component of autosomal dominant disease such as multiple endocrine neoplasia (MEN) type 2A and 2B or familiar MTC (FMTC), generally considered a variant of MEN 2A. Almost all patients with inherited MTC have germline mutations in the protooncogene RET, while only half of the sporadic cases have somatic RET mutations. Germline mutations in inherited MTC show a genotype–phenotype correlation. Germline mutations in MEN 2A and FMTC syndromes have been described in exons 10, 11, 13, 14, and 15 of RET, while germline mutation in exon 16 (M918T) is responsible for more than 95% of unrelated MEN 2B cases (7). Some mutations in sporadic MTC (e.g., M918T) are associated with a more aggressive disease course and a worse prognosis (8,9).

Calcitonin and carcinoembryonic antigen (CEA) are the main tumor markers in MTC but C-cells can also secrete several bioactive hormones that rarely give rise to a paraneoplastic syndrome, the most common of which is Cushing's syndrome (CS) due to corticotropin releasing hormone (CRH) or adrenocorticotropic hormone (ACTH) secretion. In 1932, Harvey Cushing described a group of patients affected by a “polyglandular syndrome,” which he ascribed to the presence of a basophil adenoma of the pituitary gland.

This syndrome was, therefore, called “pituitary basophilism” but it soon became referred to as “Cushing's syndrome” (10). The evidence that certain “nonendocrine” tumors could give rise to CS through ACTH secretion was first presented in the works of Christy and of Liddle's groups in the early 1960s (11,12). It very soon became clear that nonpituitary endocrine tumors also could cause CS and the term “ectopic ACTH syndrome” was, therefore, coined (13).

In 1968, Donahower et al. reported for the first time two cases of MTC associated with CS in which ACTH assays of the tumors confirmed ectopic ACTH production (14). Until then, only 11 other cases of CS supposedly due to thyroid cancer had been reported, with 7 of them probably of medullary type, but without clear evidence of ACTH production by the MTC (15 –21).

Ectopic Cushing's Syndrome (ECS) is an uncommon cause of CS that accounts for 5–10% of cases of ACTH-dependent CS. The most frequent causes of ECS are small cell lung cancer and other neuroendocrine tumors of the lung, thymus, and pancreas. The MTC is a rare and less frequent source of ECS (22), and the development of CS in MTC patients is generally associated with advanced disease and poor prognosis. Together with primary cancer treatment, the control of hypercortisolism has a key role in the management of these patients as the complications of CS worsen quality of life and prognosis and may prevent adequate cancer management.

The main treatment strategies of hypercortisolism include tumor debulking, steroidogenesis inhibitors, and bilateral adrenalectomy (BLA). Recently, tyrosine kinase inhibitors (TKIs) have been proposed as a new treatment strategy to manage ECS in MTC.

In this article, we present a systematic review of ECS due to MTC, starting from a new case report. We also discuss the role of laparoscopic BLA and of TKIs in this setting.

Case Presentation

In September 2020, a 32-year-old male was referred to our Endocrinology department for suspected Cushing's disease with central hypothyroidism and a suspicious thyroid nodule. The patient reported marked fatigue, proximal muscle weakness, and weight loss in the past 3 months. Physical examination showed moon face, facial plethora, proximal muscle atrophy, and easy bruising. Buffalo hump and striae rubra were not present. Blood pressure and blood glucose levels were normal. Initial blood tests showed marked hypokalemia, inappropriately low thyrotropin associated with low free thyroxine, and free triiodothyronine and severe ACTH-dependent hypercortisolism.

Both 8 mg-dexamethasone suppression test and CRH stimulation test were performed, and the results were indicative of ECS. All the test results are available in Supplementary Table S1. Pituitary magnetic resonance imaging (MRI) was performed and showed a normal gland. The alteration in thyroid functions tests, mimicking central hypothyroidism, was considered secondary to the inhibitory effects of glucocorticoids on the Hypothalamus-Pituitary-Thyroid axis (23) and thyroxine replacement was not judged useful.

Thyroid ultrasound showed a thyroid nodule suspicious for thyroid cancer (American College of Radiology Thyroid Imaging, Reporting and Data System score: TR5) with bilateral cervical lymph nodes metastasis. The MTC diagnosis was confirmed by cytology and serum calcitonin levels of >20,000 pg/mL (normal value [n.v.] <10), and CEA of 3054.2 ng/mL (n.v. <5). Serum calcium and urinary catecholamines, metanephrines, and normetanephrine were normal. Genetic testing excluded both germinal and somatic RET mutations. ⁶⁸Ga-DOTATOC positron emission tomography (PET)/contrast-enhanced computed tomography revealed metastasis in every bone segment and in cervical and mediastinal lymph nodes with moderate tracer uptake and a miliary distribution of metastasis in the lungs and liver.

During hospitalization, the patient developed worsening hypokalemia, despite 120 mEq/day I.V. KCl replacement and I.V. canrenone 200 mg bid, and severe psychiatric symptoms non-responsive to medical therapy. Due to these complications and the rapid worsening in general conditions, the patient required urgent simultaneous BLA that was personalized by the surgeons based on the patient's clinical needs. Indeed, a modified anterior transabdominal laparoscopic approach was used to reduce the risk of patient's positioning related to multiple bone metastasis especially at the spine level.

Intraoperative liver biopsy showed localization of MTC with ACTH expression at immunohistochemistry. After surgery, the patient started hydrocortisone and fludrocortisone replacement therapy and had a rapid recovery with a significant improvement in the general conditions. The patient was discharged home 13 days after surgery with the plan to perform thyroidectomy soon and in the meantime lanreotide 120 mg/28 days was started. Five weeks later, he underwent total thyroidectomy with central and bilateral cervical lymph node dissection to control the disease locally. Histology confirmed the diagnosis of multifocal MTC with infiltration of the left laryngeal recurrent nerve (pT4aN1b).

Due to the high disease burden, systemic therapy with lanreotide 120 mg/28 days was continued and vandetanib 300 mg/day was initiated 2 weeks after the thyroid surgery. After 6 months, total-body computed tomography (CT) scan showed stable disease. The patient is now in good clinical conditions; he resumed work and light physical activity and is continuing treatment without severe side effects. Considering the diffuse bone metastasis with a high risk of skeletal-related events, zolendronic acid 4 mg/28 days was initiated in May 2021.

Systematic Review of the Literature

Methods

Search strategy and selection criteria

We performed a systematic review to identify cases of ECS due to MTC and synthesize the patient characteristics, disease presentation, employed treatment strategies, and disease outcomes.

We searched PubMed, Scopus, and Web of Science for publications between database inception and February 7, 2022 using the following as keywords and MeSH terms: (“medullary thyroid cancer” OR “medullary thyroid carcinoma” OR “medullary carcinoma” OR “medullary cancer” OR “thyroid cancer” OR “thyroid carcinoma”) AND (“cushing syndrome” OR “ACTH” OR “hypercortisolism” OR “paraneoplastic syndrome” OR “paraneoplastic” OR “ectopic cushing”). No language restrictions were used. In the attempt to identify any relevant manuscript not already found in this search, the references of the retrieved articles were also screened and relevant studies were included.

After duplicate articles were removed, two reviewers (A.C., V.R.) selected relevant articles independently first by title and abstract and then by reviewing the full text of the remaining articles. All articles reporting new cases of ECS due to MTC were considered relevant, and studies in which individual participant data were reported were included. Two reviewers (A.C., V.R.) evaluated independently the final selected studies using the Joanna Briggs Institute (JBI) critical appraisal checklist for case reports and case series (24); disagreement was solved by discussion. No study was excluded on the basis of quality since the available evidence was already limited.

This research was conducted in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (25).

Data extraction and analysis

For each included manuscript, available data regarding patient demographic characteristics, disease stage, clinical presentation, biochemical tests, CS treatment, MTC treatment, immunohistochemistry results, and disease outcome were extracted independently by two reviewers (A.C., V.R.). Data were then cross-checked, and any discrepancies were discussed and mediated by a third reviewer (P.L.). Both reviewers and abstractors worked independently.

The significant heterogeneity of the included studies, especially in terms of outcome measures, did not allow us to perform a meta-analysis. Therefore, we conducted a narrative synthesis without additional statistical analysis.

Results

Included articles

Database search yielded 1029 results, of which 130 were selected after titles and abstracts screening. Twelve articles were excluded, because the full text was not available. Sixteen articles were excluded because they were in a non-English language. The list of these potentially relevant articles that were excluded can be found in Supplementary Data.

The full text of 102 articles were screened, and 70 were included (Fig. 1). The 70 included articles contained data on 96 patients with ECS due to MTC. To this group we added the patient we described in the present report for a total of 97 patients. Of note, 11 out of 97 cases have been retrieved from a recent matched case series (26) and are not included in the results of this article as data regarding each single case were not reported. Nonetheless, the key findings of this matched case series are discussed in the “Discussion” section.

FIG. 1.

Flowchart of literature search and study selection. Adapted from PRISMA. *The full list of potentially relevant articles excluded due to lack of full-text availability and/or language (non-English) can be found in Supplementary Data. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; WoS, Web of Science.

Overall, despite a significant variation across quality domains, the quality of the included articles was acceptable. In particular, among the case reports, the domains with the highest quality were those regarding the description of the demographic characteristics and the diagnosis and treatment; the domains with the lowest quality were those regarding the outcome and the reporting of adverse effects. The results of the quality assessment according to the JBI checklist can be found in Supplementary Tables S2 and S3 and Supplementary Figures S1 and S2.

Patients' characteristics

The mean age at diagnosis was 44.4 years (range 10–84). There were 55 males (64%) and 31 females (36%). The MTC was sporadic in 34 patients (39%), hereditary in 11 patients (13%) and the disease form was not available in the remaining 41 patients (48%).

Among patients with hereditary MTC, four cases were MEN 2A, four were MEN 2B, and three were not better specified.

The most common clinical presentation at diagnosis was either a new onset neck mass and/or sign and symptoms suggestive for CS. At diagnosis, distant metastasis was already present in 44 patients (51%); 16 patients had only lymph node metastasis (19%), and 17 patients had local or locally advanced disease (20%). The disease stage at diagnosis was not available for nine patients (10%).

Among the 33 patients with non-metastatic disease at diagnosis, 17 (52%) developed distant metastasis between 2 months and 24 years. Overall, the most common site of metastasis was the liver followed by lung and bone (Table 1).

Table 1.

Clinical Characteristics of Patients and Disease Stage at Diagnosis

Patient ID number	Age	Gender	MTC form	Presentation	Disease stage at diagnosis	Site of metastasis	References
1	19	F	NA	Back pain	Metastatic	Lung, liver, ovary	Dyson (15)
2	31	F	NA	NA	Metastatic	Lung, liver	Hökfelt et al. (16)
3	13	F	NA	Neck mass	Locally advanced	NA	Roberts (18)
4	33	M	NA	Neck mass	Probably metastatic	Liver, cervical, and abdominal LN	O'Riordan et al. (19)
5	NA	M	NA	Confusion	Metastatic	Liver, bone	Goldberg and McNeil (21)
6	46	F	Probably hereditary	Weakness	Metastatic	Cervical LN, lung, pleura, pericardium	Williams et al. (27)
7	49	F	NA	Diarrhea	NA	NA	Williams et al. (27)
8	33	M	NA	Abdominal pain, diarrhea	Locally advanced, N+	Cervical LN	Donahower et al. (14)
9	27	F	NA	Neck mass	Local	14 Months later: lung	Donahower et al. (14)
10	39	M	NA	CS	Metastatic	Cervical LN, lung, pleura, liver	Szijj et al. (28)
11	53	F	NA	Neck mass	Local	No	Melvin et al. (29)
12	61	F	NA	Neck mass	NA	NA	Croughs et al. (30)
13	12	M	Sporadic	Neck mass	Metastatic	Cervical LN, liver	Bordi et al. (31); Bussolati et al. (32)
14	51	F	NA	Leg pain, diarrhea	Metastatic	Liver, uterus, and bones	Plymate and Fariss (33)
15	54	M	NA	Diarrhea	Local	18 Months later: liver	Hajjar et al. (34)
16	45	F	NA	CS	Metastatic	NA	Birkenhäger et al. (35)
17	54	M	Sporadic	NA	NA	NA	Kameya et al. (36)
18	48	F	Sporadic	NA	NA	NA	Kameya et al. (36)
19	40	M	Probably sporadic	Neck mass, diarrhea	Probably metastatic	Cervical LN, lung, and liver	Keusch et al. (37)
20	53	M	NA	NA	Metastatic	Liver	Takai et al. (38)
21	64	F	NA	Osteoporosis	Metastatic	LN, lung	Rosenberg et al. (39)
22	34	F	NA	Osteoporosis	Locally advanced	36 Months later: liver	Jolivet et al. (40)
23	48	M	NA	Neck mass	N+	LN	Chin et al. (41)
24	33	F	NA	NA	NA	NA	Charpin et al. (42)
25	57	M	NA	NA	Metastatic	LN, liver	Davies et al. (43)
26	54	M	NA	Neck mass	Metastatic	LN, liver	Kakudo et al. (44)
27	54	M	NA	Muscle weakness	Metastatic	LN, pleura	Shimatsu et al. (45)
28	57	M	NA	NA	NA	NA	Ratcliffe et al. (46)
29	64	F	NA	Muscle weakness	N+	LN	Belsky et al. (47)
30	59	F	NA	Dysphagia, diarrhea	N+	LN	Lind et al. (48)
31	62	M	NA	Neck mass, diarrhea	Local	No	Ahlman and Tisell (49)
32	58	M	NA	NA	NA	NA	Tourniaire et al. (50)
33	51	F	NA	Neck mass	N+	LN	Blunt et al. (51)
34	45	M	NA	Polyuria/polydipsia; visual impairment	Metastatic	Pituitary	Popovic et al. (52)
35	32	M	NA	CS	Metastatic	LN, liver	Hijazi et al. (53)
36	45	M	Hereditary	NA	Local	25 Months later: LN, liver	Mure et al. (54)
37	34	F	Sporadic	NA	Local	40 Months later: LN, bone, breast, and liver	Mure et al. (54)
38	39	F	Sporadic	NA	Local	20 Months later: LN, lung, and liver	Mure et al. (54)
39	36	F	Sporadic	NA	Local	2 Months later: Liver	Mure et al. (54)
40	84	M	NA	NA	Metastatic	Liver	Winquist et al. (55)
41	62	F	NA	Diarrhea, fatigue	Metastatic	Liver	Oates et al. (56)
42	47	M	MEN 2A	CS	Local	132 Months later: liver	von Mach et al. (57)
43	38	M	MEN 2A	CS	Local	24 Months later: LN	Smallridge et al. (58)
44	40	M	Sporadic	NA	Metastatic	LN, liver	Barbosa et al. (59)
45	52	M	Sporadic	NA	Metastatic	LN, lung, and pituitary	Barbosa et al. (59)
46	41	M	Sporadic	CS	Metastatic	LN, liver	Barbosa et al. (59)
47	68	M	Sporadic	NA	Metastatic	LN, liver	Barbosa et al. (59)
48	35	F	Sporadic	NA	Metastatic	LN, liver, lung, and brain	Barbosa et al. (59)
49	45	M	Hereditary	NA	Metastatic	LN, liver, lung, and bone	Barbosa et al. (59)
50	41	M	Sporadic	NA	Metastatic	LN, liver, lung, and bone	Barbosa et al. (59)
51	48	M	Sporadic	CS	Local	No	Barbosa et al. (59)
52	30	M	Sporadic	CS	Metastatic	LN, lung	Barbosa et al. (59)
53	75	M	Sporadic	NA	N+	LN; 21 months later: liver, pancreas, lung, and bone	Barbosa et al. (59)
54	51	M	Probably sporadic	Neck mass	Probably metastatic	LN, liver, and lung	Bourlet et al. (60)
55	42	M	Sporadic	CS	NA	Liver, bone, and lung	Sand et al. (61)
56	45	M	Sporadic	CS	N+	LN; 288 months later: liver	Chrisoulidou et al. (62)
57	51	F	MEN 2A	CS	Metastatic	Liver	Zaydfudim et al. (63)
58	13	M	MEN 2B	Growth retardation, Cushingoid habitus, proximal myopathy	N+	LN	Dhanwal et al. (64)
59	49	M	Sporadic	CS	Local	No	Wang et al. (65)
60	58	M	NA	CS	N+	Cervical and mediastinal LN	Baudry et al. (66)
61	31	F	MEN 2B	Hyperpigmentation	Local	96 Months later: brain, liver, and bone	Kurozumi et al. (67)
62	45	M	Sporadic	CS	Metastatic	Mediastinal and abdominal LN, lung, and liver	Barroso-Sousa et al. (68)
63	17	M	MEN 2B	Thyroid nodule, diarrhea	Metastatic	Lung, bone	Fox et al. (69); Nella et al. (70)
64	48	M	Sporadic	MTC	N+	LN; 144 months later: lung	Choi et al. (71)
65	13	M	MEN 2B	Growth deceleration, weight gain	Metastatic	LN, lung	Singer et al. (72)
66	30	M	Sporadic	Diabetes insipidus	N+	LN; 12 months later: lung; 48 months later: liver	Hammami et al. (73)
67	64	M	Sporadic	CS	N+	LN; 72 months later: lung	Marques et al. (74)
68	37	F	Sporadic	Fatigue, dyspnea	N+	LN; 192 months later: liver	Pitoia et al. (75)
69	51	M	NA	Hyperglycemia, hypokalemia	Probably metastatic	Bone, LN	Verburg et al. (76)
70	58	M	Sporadic	Diarrhea, muscle weakness, depression	Metastatic	Cervical and mediastinal LN, lung, liver, and bone	Paepegaey et al. (77)
71	42	F	NA	NA	Metastatic	NA	Sathyakumar et al. (78)
72	18	M	NA	NA	Metastatic	NA	Sathyakumar et al. (78)
73	35	M	Sporadic	Supraclavicular LN	N+	Supraclavicular and mediastinal LN	Wijewardene et al. (79)
74	53	M	NA	CS	Metastatic	LN, bone	Wijewardene et al. (79)
75	38	M	Sporadic	Palpable neck mass	Metastatic	Lung; 24 months later: liver	Wijewardene et al. (79)
76	54	M	NA	Facial plethora, neck mass	N+	LN; 6 months later: liver	Ferreira et al. (80)
77	74	F	Sporadic	Diarrhea, weight loss	Metastatic	LN, liver	Pivovarova et al. (81)
78	61	F	NA	NA	NA	NA	Shahidi et al. (82)
79	67	M	NA	Diarrhea, weakness	Metastatic	LN, liver	Matheny et al. (83)
80	41	M	Sporadic	Back pain	N+	LN	Forde et al. (84)
81	28	F	NA	NA	Probably metastatic	NA	Lopez-Montoya et al. (85)
82	22	F	Probably sporadic	Autopsy	Local	No	Cheong and Koo (86)
83	55	M	Sporadic	MTC	N+	Neck LN; during follow-up: mediastinal LN, lung, and bone	Bseiso et al. (87)
84	52	M	MEN 2A	Neck mass	Metastatic	LN, liver, and bone	Agosto et al. (88)
85	10	M	Probably sporadic	Growth retardation, Cushingoid habitus	Metastatic	LN, lung	Mahajan et al. (89)
86	32	M	Sporadic	Fatigue, muscle weakness and weight loss	Metastatic	LN, lung, liver, and bone	Current study

Patient ID number is a patient identifier number assigned consecutively for this study. Probably sporadic = no specific indication on disease form but history suggestive for sporadic. Probably hereditary = no specific indication on disease form but history suggestive for hereditary. Probably metastatic = no specific indication on disease stage at diagnosis but history suggestive for metastatic disease at diagnosis.

CS, Cushing's syndrome; F, female; LN, lymph nodes; M, male; MEN, multiple endocrine neoplasia; MTC, medullary thyroid cancer; N+, lymph nodes metastases; NA, not available.

CS in MTC

As expected, most patients with CS due to MTC showed severe hypercortisolism with a marked increase in serum cortisol and ACTH and in 24 hours urinary-free cortisol. Cortisol was not suppressed by high-dose dexamethasone in 36 out of 39 patients (92%), and there was no response to CRH in 6 out of 6 patients (100%). PET/CT using ⁶⁸Ga-labeled somatostatin receptor ligands was employed only in 4 patients and showed uptake in lymph nodes, lung, liver, and bone lesions (Supplementary Table S4).

Hypokalemia was present in most patients, and it was often severe and difficult to treat. As in other cases of ECS, the clinical presentation was variable, and the signs and symptoms typical of Cushing's disease were not always present. The full list of signs and symptoms of CS that characterized these patients is summarized in Table 2. The diagnosis of MTC preceded that of CS in 41 out of 86 patients (48%; median time = 42 months), was concomitant with CS in 33 out of 86 patients (38%), and followed CS only in 2 out of 86 patients (2%).

Table 2.

Signs and Symptoms of Cushing's Syndrome

	N (%)
Cushingoid appearance
Yes	48 (56)
No/NA	38 (44)
Obesity
Yes	26 (30)
No/NA	60 (70)
Buffalo hump
Yes	17 (20)
No/NA	69 (80)
Hyperpigmentation
Yes	17 (20)
No/NA	69 (80)
Moon face
Yes	32 (37)
No/NA	54 (63)
Diabetes or IGT
Yes	33 (38)
No/NA	53 (62)
Muscle atrophy
Yes	36 (41)
No/NA	50 (59)
Hypertension
Yes	37 (42)
No/NA	49 (58)
Mood alteration
Yes	10 (12)
No/NA	76 (88)
Bruising
Yes	18 (21)
No/NA	68 (79)
Hirsutism
Yes	11 (13)
No/NA	75 (87)
Striae
Yes	17 (20)
No/NA	69 (80)
Osteoporosis
Yes	16 (19)
No/NA	70 (81)
Diarrhea
Yes	23 (27)
No/NA	63 (73)

The presence of a sign or symptoms was derived from the description of the case reports and it was not possible, in most cases, to define the severity. Moreover, as in most studies it was not always specified when a symptom was not present, we preferred to include “No” and “NA” in the same field.

IGT, impaired glucose tolerance.

In 10 out of 86 patients (12%), the timing between MTC and CS diagnosis was not specified (Table 3). Of note, among patients in whom the diagnosis of MTC and CS was concomitant, the reason for seeking medical advice was frequently symptoms or signs associated with hypercortisolism.

Table 3.

Time Between Cushing's Syndrome and Medullary Thyroid Cancer Diagnosis, Treatment, and Follow-Up

Patient ID number	Time between CS and MTC diagnosis (months)	Treatment of MTC	Treatment of CS	Overall survival	Cause of death	References
1	Concomitant	None	Bilateral adrenalectomy	33 Days	Cryptococcal meningitis	(15)
2	Concomitant	TT	Bilateral adrenalectomy	NA	NA	(16)
3	45 Months (MTC before CS)	TT+LFN+RT	None	NA	NA	(18)
4	11 Months (MTC before CS)	Hemithyroidectomy	Metyrapone	24 Months	Cachexia	(19)
5	Concomitant	Hemithyroidectomy	Bilateral adrenalectomy	24 Months	MTC	(21)
6	Concomitant	None	None	NA	During surgery	(27)
7	12 Months (MTC before CS)	Hemithyroidectomy	None	18 Months	NA	(27)
8	7 Months (CS before MTC)	TT+LFN	Bilateral adrenalectomy	10 Months	Diverticulitis perforation	(14)
9	Concomitant	TT+LFN (in three times)	Bilateral adrenalectomy	NA	NA	(14)
10	Concomitant	None	None	20 Days	Pulmonary edema	(28)
11	Concomitant	TT+RT	TT	NA	NA	(29)
12	60 Months (MTC before CS)	RT	Bilateral adrenalectomy	72 Months	Bronchopneumonia	(30)
13	18 Months (MTC before CS)	TT+LFN (in two times)	NA	NA	NA	(31,32)
14	192 Months (MTC before CS)	NA	NA	Few days	Sepsis	(33)
15	18 Months (MTC before CS)	TT+RT	Bilateral adrenalectomy	NA	NA	(34)
16	Concomitant	TT+metastasectomy	TT+metastasectomy	NA	NA	(35)
17	NA	NA	NA	NA	NA	(36)
18	NA	NA	NA	NA	NA	(36)
19	36 Months (MTC before CS)	TT	None	72 Months	NA	(37)
20	NA	TT	Bilateral adrenalectomy	NA	NA	(38)
21	Concomitant	Subtotal thyroidectomy	Metyrapone	2 Months	Acute intestinal obstruction	(39)
22	Concomitant	TT	TT	NA	NA	(40)
23	Concomitant	NA	NA	NA	Duodenal ulcer perforation	(41)
24	NA	TT	Bilateral adrenalectomy	36 Months	NA	(42)
25	Concomitant	Subtotal thyroidectomy	Bilateral adrenalectomy	NA	NA	(43)
26	Concomitant	TT+LFN	Bilateral adrenalectomy	31 Months	NA	(44)
27	Concomitant	“Neck surgery”+CHT	Bilateral adrenalectomy	NA	NA	(45)
28	8 Months (MTC before CS)	NA	NA	3 Months	NA	(46)
29	Concomitant	TT	Bilateral adrenalectomy	3 Months	Diverticulitis perforation	(47)
30	37 Months (MTC before CS)	“Neck surgery”+CHT	Metyrapone	42 Months	Progressive metastatic disease	(48)
31	180 Months (MTC before CS)	TT+metastasectomy+SSA (for intractable diarrhea)	Bilateral adrenalectomy	NA	NA	(49)
32	24 Months (CS before MTC)	TT	TT	NA	NA	(50)
33	108 Months (MTC before CS)	TT+RT+CHT	Metyrapone+aminoglutethimide → bilateral adrenal venous ablation → bilateral arterial embolization → bilateral adrenalectomy	NA	NA	(51)
34	8 Months (MTC before CS)	RT of neck → craniotomy for pituitary mass reduction → RT of pituitary+CHT	NA	13 Months	NA	(52)
35	Concomitant	TT+LFN+metastasectomy	Ketoconazole+aminoglutethimide+metyrapone → bilateral adrenalectomy	NA	NA	(53)
36	29 Months (MTC before CS)	TT+LFN+RT+CHT	SSA → ketoconazole+mitotane → bilateral adrenalectomy	39 Months	NA	(54)
37	95 Months (MTC before CS)	TT+LFN+RT	NA	95 Months	Pulmonary disease	(54)
38	20 Months (MTC before CS)	TT+LFN+CHT	Ketoconazole → mitotane → bilateral adrenalectomy	42 Months	Disease progression	(54)
39	2 Months (MTC before CS)	TT+LFN+CHT	Ketoconazole → SSA → mitotane+aminoglutethimide → bilateral adrenalectomy	30 Months	Brain metastases	(54)
40	NA	NA	Ketoconazole	NA	NA	(55)
41	Concomitant	Octreotide → chemoembolization of liver metastases	No treatment	6 Months	NA	(56)
42	132 Months (MTC before CS)	TT	Bilateral adrenalectomy	NA	NA	(57)
43	48 Months (MTC before CS)	TT+LFN (in two times)	Bilateral adrenalectomy	NA	NA	(58)
44	50 Months (MTC before CS)	NA	NA	65 Months	Peritonitis	(59)
45	36 Months (MTC before CS)	NA	NA	49 Months	Peritonitis	(59)
46	Concomitant	NA	NA	20 Months	MTC	(59)
47	36 Months (MTC before CS)	NA	NA	38 Months	MTC	(59)
48	3 Months (MTC before CS)	NA	NA	33 Months	MTC	(59)
49	17 Months (MTC before CS)	NA	NA	29 Months	MTC	(59)
50	91 Months (MTC before CS)	NA	NA	95 Months	Peritonitis	(59)
51	Concomitant	“Neck surgery”	“Neck surgery”	108 Months	NA	(59)
52	Concomitant	NA	“Anticortisolic drugs”	36 Months	NA	(59)
53	36 Months (MTC before CS)	NA	NA	43 Months	MTC	(59)
54	45 Months (MTC before CS)	TT+LFN+CHT	CHT+mitotane+embolization of hepatic and adrenal metastases → mitotane	NA	NA	(60)
55	120 Months (MTC before CS)	TT+LFN	Ketoconazole → bilateral adrenalectomy	NA	Chest infection and respiratory failure	(61)
56	288 Months (MTC before CS)	NA	Metyrapone	291 Months	NA	(62)
57	Concomitant	CHT	Ketoconazole → bilateral adrenalectomy	NA	NA	(63)
58	Concomitant	TT+LFN	TT+LFN	NA	NA	(64)
59	Concomitant	TT+LFN	NA	NA	NA	(65)
60	Concomitant	Vandetanib	Metyrapone+mitotane+SSA+ketoconazole → vandetanib	NA	NA	(66)
61	240 Months (MTC before CS)	TT	Previous bilateral adrenalectomy for pheocromocitoma	NA	NA	(67)
62	Concomitant	Sorafenib	Sorafenib	NA	NA	(68)
63	Concomitant	TT+LFN+metastasectomy+RT → vandetanib → sunitinib → sorafenib → cabozantinib	Vandetanib → ketoconazole → bilateral adrenalectomy	72 Months	MTC	(69,70)
64	168 Months (MTC before CS)	TT+LFN+MIBG	Ketoconazole → bilateral adrenalectomy	NA	NA	(71)
65	33 Months (MTC before CS)	TT+LFN	Bilateral adrenalectomy	NA	NA	(72)
66	42 Months (MTC before CS)	TT+LFN+RT → sorafenib	Sorafenib+mifepristone	43 Months	Liver failure+sepsis	(73)
67	96 Months (MTC before CS)	TT+LFN+RT → sunitinib	Metyrapone → sunitinib	NA	NA	(74)
68	192 Months (MTC before CS)	TT+LFN (in five times) → vandetanib	Vandetanib	NA	NA	(75)
69	48 Months (MTC before CS)	NA	SSA → bilateral adrenalectomy	49 Months	Sepsis, bone marrow infiltration, respiratory failure	(76)
70	Concomitant	Vandetanib → metastasectomy+LFN	Metyrapone → mitotane → SSA → ketoconazole → vandetanib	NA	NA	(77)
71	NA	NA	NA	NA	Sepsis	(78)
72	NA	NA	NA	NA	Sepsis	(78)
73	6 Months (MTC before CS)	TT+LFN → vandetanib	Ketoconazone → ketoconazole+vandetanib → vandetanib+mitotane	18 Months	Pneumonia	(79)
74	Concomitant	TT+LFN+RT	RT+ketoconazole	NA	CS	(79)
75	24 Months (MTC before CS)	TT+LFN → vandetanib	Ketoconazole → ketoconazole+vandetanib → ketoconazole+metyrapone → metyrapone+mitotane	48 Months	CS	(79)
76	Concomitant	RT+CHT	Ketoconazole	6 Months	NA	(80)
77	30 Months (MTC before CS)	TT → vandetanib	Ketoconazole	36 Months	NA	(81)
78	NA	NA	NA	NA	NA	(82)
79	Concomitant	Vandetanib	Ketoconazole → mifepristone → etomidate+vandetanib → bilateral adrenalectomy	1 Month	Pneumonia	(83)
80	Concomitant	TT+LFN → vandetanib → cabozantinib → selpercatinib	Metyrapone+SSA → vandetanib → cabozantinib → selpercatinib	NA	NA	(84)
81	NA	TT+SSA	Bilateral adrenalectomy	3 Months	MTC	(85)
82	NA	NA	NA	NA	NA	(86)
83	240 Months (MTC before CS)	TT+LFN → SSA → vandetanib	Metyrapone → vandetanib	NA	NA	(87)
84	60 Months (MTC before CS)	TT+LFN → vandetanib → cabozantinib+RT on vertebral spine metastases	Metyrapone → selpercatinib	NA	NA	(88)
85	Concomitant	NA	“Inhibitors of adrenal steroidogenesis” → bilateral adrenalectomy	NA	NA	(89)
86	Concomitant	TT+LFN → SSA+vandetanib	Bilateral adrenalectomy	NA	NA	Current study

Patient ID number is a patient identifier number assigned consecutively for this study. Combination therapy is identified with a “+” sign between the different drugs employed. Sequential therapy is identified with a “→” sign between the different treatment employed.

CHT, chemotherapy; LFN, regional lymphadenectomy (distinction between central and laterocervical compartment lymphadenectomy was not available from most studies); MIBG, metaiodobenzylguanidine; RT, radiotherapy; SSA, somatostatin analogues; TT, total thyroidectomy.

Immunohistochemical results

Calcitonin-positive cells were detected in the vast majority of patients in whom it was tested, including in our case (Supplementary Table S5).

Different techniques have been employed to confirm that the MTC primary tumor or its distant metastasis was, indeed, the source of ACTH and/or CRH. Results of this investigation were available for 41 patients (Supplementary Table S5). Overall, including radioimmunoassays, immunofluorescence, immunohistochemistry, arteriovenous gradients, and messenger RNA (mRNA) in situ hybridization, ACTH in MTC lesions was detected in 24 patients (59%); evidence of CRH secretion was observed in 6 patients (15%), and proopiomelanocortin (POMC) mRNA expression was detected in 1 patient (2%). In the remaining 10 patients (24%), no evidence of ACTH was observed in tumor tissues.

Treatment and evolution

Regarding MTC treatment, 52 patients (60%) underwent thyroid surgery. In particular, 28 out of 52 patients (54%) underwent total thyroidectomy with regional lymphadenectomy, 16 out of 52 (31%) total thyroidectomy, 5 out of 52 (9%) hemithyroidectomy or subtotal thyroidectomy and 3 out of 52 (6%) neck surgery not better specified. After surgery, especially in the earlier reports, some patients underwent external neck radiotherapy and systemic chemotherapy. Differently, in the most recent reports, patients with significant disease burden after surgery were mainly treated with TKIs in line with current guidelines.

Information regarding CS treatment was available for 65 patients. Obtaining a good control of CS turned out to be challenging in most patients. Indeed, 31 out of 65 patients (48%) eventually required BLA. Interestingly, in 19 out of 31 patients, BLA was used as the first-line treatment for CS while for the remaining 12 patients it was a “rescue treatment” after failure of medical therapy with steroidogenesis inhibitors.

Among the 34 patients who did not undergo BLA, 6 (18%) were cured by total thyroidectomy, in 4 (12%) a good control of hypercortisolism was obtained with steroidogenesis inhibitors (2 patients on metyrapone, 1 on mitotane and 1 on “anticortisolic drugs” not better specified), in 8 (23%) a good control was obtained with TKIs (4 on Vandetanib, 1 on sorafenib, 1 on subitinib, and 2 on selpercatinib), 8 (26%) did not achieve a good control with steroidogenesis inhibitors, 6 (18%) did not receive any treatment, 1 (3%) had already undergone previous BLA for pheochromocytoma and 1 (3%) did not achieve a good control of hypercortisolism despite combination treatment with sorafenib and mifepristone (Table 3).

Although information on survival was limited due to the nature of the studies (case reports or case series with a relatively short-term follow-up), overall the prognosis was relatively poor with overall survival ranging between a few days and 24 years (291 months). The main causes of death were related either to complications of CS (including respiratory tract infections, peritonitis due to intestinal perforations, sepsis) or to MTC progression (Table 3).

Discussion

MTC is a rare thyroid tumor and one of the least frequent causes of ECS. It has been estimated that only 0.7% of patients with MTC develop ECS (59) and that, in turn, 2–8% of all ECS cases are caused by MTC (90).

After a systematic literature review, we collected the clinical characteristics of 86 cases of ECS due to MTC reported between 1959 and February 2022. We observed, in line with previous case series, a male predominance and the mean age at diagnosis was 44.4 years. Most patients were affected by sporadic MTC with only 11 cases of familial MTC reported although in about half of the reports, and especially in the earliest ones when genetic analysis was not routinely available, the disease form was not specified.

In most patients, MTC preceded ECS diagnosis by several months. However, the time between MTC diagnosis and ECS presentation was variable with some cases of ECS diagnosed even before MTC diagnosis and others more than 20 years later, suggesting that tumor cells may acquire the ability to produce ACTH or CRH at any time of the cancer natural history. Interestingly, in some patients, the diagnosis of hypercortisolism was concomitant with the development of metastatic disease. In line with this, the prevalence of distant metastasis at diagnosis in this cohort is relatively high (around 50%) when compared with that of MTC not associated with paraneoplastic syndrome (10–15%) (6).

A possible and tempting explanation is that the process leading to metastization and/or the tumor microenvironment at the metastatic site might play a role in the acquisition of the ability to produce ACTH or CRH by the tumor cells as a result of tumor dedifferentiation, as already hypothesized for other neuroendocrine tumors (91,92). Another possible explanation is that ACTH or CRH secretion is present since disease onset but it is the increase in tumoral burden associated with metastatic disease that leads to clinically significant hypercortisolism. A schematic representation of the hypothalamus-pituitary-adrenal axis in normal conditions and in patients with MTC secreting ACTH or CRH is shown in Figure 2.

FIG. 2.

Regulation of the hypothalamus-pituitary-adrenal axis in normal conditions and in patients affected with Cushing's syndrome due to MTC. (A) In healthy individuals, the hypothalamic release of CRH, regulated by CNS centers, promotes the release of ACTH from the anterior pituitary gland. In turn, ACTH stimulates adrenal secretion of the cortisol, which by a negative feedback mechanism inhibits the secretion of CRH and ACTH. (B) In ECS due to MTC secreting ACTH, the ACTH secretion is autonomous, leading to adrenal hyperplasia and hypercortisolism. Cortisol negative feedback inhibits CRH and ACTH secretion by the hypothalamus and pituitary gland, respectively, but this has no relevant impact on blood cortisol levels that are sustained by tumoral ACTH secretion. (C) In ECS due to MTC secreting CRH (less likely compared with panel B), the autonomous CRH secretion stimulates ACTH release by the anterior pituitary gland and may lead to pituitary hyperplasia. Excess ACTH stimulates the adrenal glands, leading to adrenal hyperplasia and hypercortisolism. Cortisol negative feedback inhibits CRH secretion by the hypothalamus while pituitary ACTH secretion is sustained by tumoral CRH. ACTH, adrenocorticotropic hormone; CNS, central nervous system; CRH, corticotropin releasing hormone; ECS, ectopic Cushing's syndrome; MTC, medullary thyroid cancer.

The clinical presentation of CS was variable and in most cases it was not helpful in distinguishing between Cushing's disease and ECS. The biochemical investigations, on the other hand, documented severe hypercortisolism in almost every patient, there was no suppression by high-dose dexamethasone in 36 out of 39 patients, and there was no response to CRH in 6 out of 6 patients, suggesting the ectopic source. Therefore, we believe that the application of the validated algorithm for the diagnosis of CS would correctly point to an ectopic source and MTC should be considered at that point among the differentials (93). On the other hand, when a patient with progressive MTC shows clinical and laboratory findings suggestive of hypercortisolism ECS due to MTC should be strongly considered.

ACTH- or CRH-positive cells were detected in the majority, but not all, of patients in whom they were tested. Negative ACTH and CRH immunostaining despite clear evidence for tumor causing CS has been reported by several authors. One of the most feasible proposed explanations is that the tumor has a high hormonal secretion rate with a consequently low storage concentration of ACTH or CRH that can be found in tumor tissue (59,94). Another possible explanation is that extrapituitary tumors tend to have an abnormal processing of POMC with increased production of ACTH precursors. In line with this, POMC mRNA in situ hybridization has been proposed as a useful tool to identify the source of ectopic ACTH production (58,95).

MTC treatment and CS management must be addressed at the same time. Indeed, the complications of hypercortisolism are often debilitating and have a significant impact on prognosis being one of the main causes of death in these patients. In the setting of locoregional or oligometastatic disease, curative surgery should be considered the first line of treatment.

However, this approach is feasible in a minority of patients and only 6 out of 86 (7%) patients were cured by surgery without the need for further treatment. Since most patients presented with or developed diffuse metastatic disease, the first treatment goal was to prevent the complications due to hypercortisolism and improve the patient general conditions to initiate as soon as possible systemic therapy for MTC. Steroidogenesis inhibitors are considered first line in ECS due to unresectable or metastatic tumors and they were often employed in patients with ECS due to MTC. However, the control of hypercortisolism was often not satisfactory and BLA was, indeed, employed as rescue treatment in a good proportion of patients.

BLA is the most effective treatment of hypercortisolism but in ECS it is generally considered a rescue treatment, when steroidogenesis inhibitors are ineffective or not tolerated, because of the mortality and morbidity risks especially in patients with severe CS. With the advent of laparoscopic BLA, which has reduced morbidity and hospital stay (96), the choice between medical therapy and BLA in the setting of severe hypercortisolism has become debated and a shift toward BLA can be considered, especially in patients who need to start immediate treatment with antineoplastic drugs.

Since this review of the literature includes cases that have been managed in a wide range of decades, we have tried to observe whether there were some temporal trends explaining differences in diagnosis, treatment, and outcome. Regarding MTC treatment, there is a clear change in the surgical approach with more conservative surgeries (i.e., hemithyroidectomy and subtotal thyroidectomy) performed almost exclusively in the earliest reports (until the 1980s). Also, the “adjuvant treatment” approach radically changed during time with radiotherapy and chemotherapy being the only option up until 2013 when Baudry et al. reported a case of reversal of CS in MTC by the recently approved TKI Vandetanib (66).

Similarly, a temporal trend can be observed in the management of CS. Indeed, in the earliest reports, BLA was often the only treatment employed while starting from the late 1980s, steroidogenesis inhibitors were usually the first line of treatment, and BLA was reserved as a “rescue treatment.”

Recently, a multicenter case series investigated the overall survival (OS) in 11 MTC patients with ECS compared with 22 matched MTC patients without ECS. The results showed, as expected, that the presence of the paraneoplastic syndrome worsened the outcome of MTC patients (OS in patients with ECS vs. without ECS = 87 months [confidence interval, CI: 64–111] vs. 190 months [CI: 95–285]). In line with our results, MTC usually preceded the diagnosis of ECS and ECS occurred mainly in patients with advanced disease (26).

Interestingly, also in this case series, hypercortisolism was severe and BLA was performed in half of the patients who received treatment and proved to be safe and effective.

In the last few years, some authors showed that TKIs may be a new treatment option in patients with ECS due to MTC. Since the first report by Baudry et al. (66), 13 cases have been reported describing the role of TKIs to manage hypercortisolism in patients with MTC (Table 3). The TKIs were initiated due to progressive MTC in 9 out of 13 patients and to control hypercortisolism after failure of steroidogenesis inhibitors in 4 out of 13 patients.

In most of these cases (9/13), treatment with TKIs (including vandetanib, sorafenib, sunitinib, cabozantinib, and selpercatinib) showed an amelioration of CS, with a reduction of cortisol levels since the first days of treatment. Interestingly, some authors reported that often the control of hypercortisolism did not correspond to a reduction in tumor burden and it sometimes persisted even in patients with disease progression, suggesting that TKIs might have a direct antisecretory effect on MTC cells that may be independent from their antineoplastic effect (70).

Therefore, if a significant antisecretory effect is confirmed, TKIs in patients with ECS due to MTC could theoretically represent the best treatment strategy, allowing us to address MTC and hypercortisolism simultaneously.

In patients with metastatic disease, thyroid surgery is often performed but is usually less extensive as the goal is palliative debulking while trying to minimize complications and maintaining the patient's functions of speech and swallowing.

The case we presented underlines the effectiveness of emergency BLA for prompt management of severe hypercortisolism with marked and rapid improvement in patient conditions that allowed the initiation of systemic therapy for MTC.

We present the reasoning behind the choice of treatment for our patient, as we believe it may be applicable to a good proportion of patients with ECS due to MTC.

All available treatment strategies were thoroughly discussed in a multidisciplinary meeting.

Among steroidogenesis inhibitors, mitotane was the first to be excluded due to the delay in the control of CS that is in the range of several months (97). On the opposite, etomidate, a short-acting intravenous anesthetic agent that suppresses steroidogenesis by inhibiting 11β-hydroxylase, was a possible treatment option since it allows a rapid control of hypercortisolism (within hours) (98) but it needs intensive care unit monitoring and it is not a useful strategy for the long-term control of hypercortisolism.

The use of ketoconazole and metyrapone either alone or in combination was proposed and deeply evaluated (99). Among the main side effects of metyrapone, there is the possible worsening of hypokalemia but this effect is attenuated when used in combination with ketoconazole. On the other hand, ketoconazole treatment necessitates close monitoring of liver function as it may lead to hepatic toxicity and this was a further concern for our patient considering the diffuse hepatic involvement.

The use of somatostatin analogues was not considered useful in this acute setting, as the effect on CS control is often suboptimal but it was employed later on as a cytostatic agent considering the ⁶⁸Ga-PET/CT results. Similarly, mifepristone was not considered an option as evidence in the treatment of ECS is limited (99).

TKIs are one of the newest proposed treatment strategies to manage CS in patients with MTC. Among the different TKIs, treatment with vandetanib was considered the preferred one since it is readily available in our center, it is approved for the treatment of metastatic MTC, and the results regarding its efficacy are consolidated. However, the patient's clinical conditions did not allow a safe initiation of this treatment.

BLA was finally taken in consideration. Although it carries a not negligible risk of morbidity and mortality in patients with severe CS, it is the most effective and immediate treatment for hypercortisolism (96,100). The decision came down to either combination therapy with ketoconazole and metyrapone or BLA, and these were also discussed with the patients' wife. BLA was preferred because our goal was immediate and definitive control of hypercortisolism to establish further MTC treatment as soon as possible.

Among the different advantages of BLA, the prevention of possible drug interactions, especially between steroidogenesis inhibitors and vandetanib, was judge significant. Although different approaches are available (posterior retroperitoneoscopic, lateral transabdominal, open) (101) in the present case a modification of the laparoscopic transperitoneal approach via an anterior route was adopted, to avoid the need of patient positioning, which cannot be feasible in patients with multiple bone metastasis and severely reduced bone density. Despite being more technically demanding, the absence of positioning time allows for a faster operation and lowers the risk of bone fractures.

To the best of our knowledge, this is the first systematic review collecting evidence regarding ECS due to MTC. However, there are several limitations to this review. First, all the included studies were case reports or cases series with a relatively low number of patients. Second, all the studies except for one excluded matched case series (26) do not include a control group so it is difficult to judge treatment outcomes and prognosis. Third, the wide time range of the included studies limits the consistency of the comparison of labs, treatment, and outcomes. Finally, this systematic review was not registered in Prospero.

Conclusions

The MTC is a rare cause of ECS, with 97 cases reported so far in the literature. Most of these patients present with advance disease and develop significant complications due to the CS. The control of CS is a priority to facilitate the initiation of antineoplastic treatment but these patients may poorly respond to conventional pharmacological treatments of hypercortisolism. Indeed, BLA is frequently required, and it is important not to delay this intervention as it may not improve management and survival if it is employed too late in the disease course.

Laparoscopic BLA is considered a safe procedure when performed by experienced surgeons in high-volume centers and the anterior approach might have some advantages, especially in patients with bone disease due to either the hypercortisolism and/or metastatic localizations. There are some promising recent reports on the use of TKIs in managing CS due to MTC, but more research is needed to inform the mechanism of action as well as potential treatment utility.

Footnotes

Authors' Contributions

A.C., V.R., P.L., R.M.P., M.R., and S.M.C. contributed to the study design, literature search, data collection and interpretation, writing, and approval of the article. G.P., E.D.R., A.P., and C.D.C. contributed to writing and approval of the article. F.T. contributed to reviewing and approval of the article.

Author Disclosure Statement

All authors have no conflict of interests to disclose.

Funding Information

No funding was received for this article.

Supplementary Material

Supplementary Data

Supplementary Figure S1

Supplementary Figure S2

Supplementary Table S1

Supplementary Table S2

Supplementary Table S3

Supplementary Table S4

Supplementary Table S5

References

Hazard

, Hawk

, Crile

Jr . 1959. Medullary (solid) carcinoma of the thyroid; a clinicopathologic entity. J Clin Endocrinol Metab, 19:152–161.

Lim

, Devesa

, Sosa

, Check

, Kitahara

. 2017. Trends in thyroid cancer incidence and mortality in the United States, 1974–2013. JAMA, 317:1338–1348.

SEER Cancer Statistics

Review

, 1975–2016. Cancer of the thyroid. Percent distribution and counts by histology among histologically confirmed cases, 2012–2016. Available at https://seer.cancer.gov/archive/csr/1975_2016/results_merged/sect_26_thyroid.pdf (accessed January 18, 2022 ).

Kebebew

, Ituarte

, Siperstein

, Duh

, Clark

. 2000. Medullary thyroid carcinoma: clinical characteristics, treatment, prognostic factors, and a comparison of staging systems. Cancer, 88:1139–1148.

Modigliani

, Cohen

, Campos

, Conte-Devolx

, Maes

, Boneu

, Schlumberger

, Bigorgne

, Dumontier

, Leclerc

, Corcuff

, Guilhem

. 1998. Prognostic factors for survival and for biochemical cure in medullary thyroid carcinoma: results in 899 patients. The GETC Study Group. Groupe d'étude des tumeurs à calcitonine. Clin Endocrinol (Oxf), 48:265–273.

Moley

. 2010. Medullary thyroid carcinoma: management of lymph node metastases. J Natl Compr Canc Netw, 8:549–556.

Torino

, Paragliola

, Barnabei

, Corsello

. 2010. Medullary thyroid cancer: a promising model for targeted therapy. Curr Mol Med, 10:608–625.

Elisei

, Cosci

, Romei

, Bottici

, Renzini

, Molinaro

, Agate

, Vivaldi

, Faviana

, Basolo

, Miccoli

, Berti

, Pacini

, Pinchera

. 2008. Prognostic significance of somatic RET oncogene mutations in sporadic medullary thyroid cancer: a 10-year follow-up study. J Clin Endocrinol Metab, 93:682–687.

Wells

Jr. , Asa

, Dralle

, Elisei

, Evans

, Gagel

, Lee

, Machens

, Moley

, Pacini

, Raue

, Frank-Raue

, Robinson

, Rosenthal

, Santoro

, Schlumberger

, Shah

, Waguespack

. 2015. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid, 25:567–610.

10.

Cushing

. 1994. The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism). 1932. Obes Res, 2:486–508.

11.

Christy

. 1961. Adrenocorticotrophic activity in the plasma of patients with Cushing's syndrome associated with pulmonary neoplasms. Lancet, 1:85–86.

12.

Meador

, Liddle

, Island

, Nicholson

, Lucas

, Nuckton

, Luetscher

. 1962. Cause of Cushing's syndrome in patients with tumors arising from “nonendocrine” tissue. J Clin Endocrinol Metab, 22:693–703.

13.

Liddle

, Island

, Ney

, Nicholson

, Shimizu

. 1963. Nonpituitary neoplasms and Cushing's syndrome: ectopic “adrenocorticotropin” produced by nonpituitary neoplasms as a cause of Cushing's syndrome. Arch Intern Med, 111:471–475.

14.

Donahower

, Schumacher

, Hazard

. 1968. Medullary carcinoma of the thyroid—a cause of Cushing's syndrome: report of two cases. J Clin Endocrinol Metab, 28:1199–1204.

15.

Dyson

. 1959. Cushing's disease; report of a case associated with carcinoma of the thyroid gland and cryptococcosis. N Engl J Med, 261:169–172.

16.

Hökfelt

, Sjögren

, Falkheden

. 1959. Steroid hormone production in a case of Cushing's syndrome with electrolyte changes simulating primary aldosteronism. Acta Endocrinol (Copenh), 31:175–184.

17.

Riggs

Jr. , Sprague

. 1961. Association of Cushing's syndrome and neoplastic disease: observations in 232 cases of Cushing's syndrome and review of literature. Arch Intern Med, 108:841–849.

18.

Roberts

PAL

. 1962. Carcinoma of the thyroid, hypoparathyroidism and Cushing's syndrome. Proc R Soc Med, 55:805–806.

19.

O'Riordan

JLH

, Blanshard

, Moxham

, Nabarro

JDN

. 1966. Corticotirophin-secreting carcinomas. QJM, 35:137–147.

20.

Anderson

, Glenn

. 1966. Cushing's syndrome associated with anaplastic carcinoma of the thyroid gland. J Urol, 95:1–4.

21.

Goldberg

, McNeil

. 1967. Cushing's syndrome due to an ACTH-producing carcinoma of the thyroid. Can Med Assoc J, 96:1577–1579.

22.

Lacroix

, Feelders

, Stratakis

, Nieman

. 2015. Cushing's syndrome. Lancet, 386:913–927.

23.

Paragliola

, Corsello

, Papi

, Pontecorvi

, Corsello

. 2021. Cushing's syndrome effects on the thyroid. Int J Mol Sci, 22:3131.

24.

Moola

, Munn

, Tufanaru

, Aromataris

, Sears

, Sfetcu

, Currie

, Qureshi

, Mattis

, Lisy

, Mu P-F 2020 Chapter 7: systematic reviews of etiology and risk. In: Aromataris E, Munn Z (eds) JBI Manual for Evidence Synthesis. JBI, Appendix 7.3 and 7.4. Available at https://synthesismanual.jbi.global (accessed May 01, 2022 ).

25.

Page

, McKenzie

, Bossuyt

, Boutron

, Hoffmann

, Mulrow

, Shamseer

, Tetzlaff

, Akl

, Brennan

, Chou

, Glanville

, Grimshaw

, Hróbjartsson

, Lalu

, Li

, Loder

, Mayo-Wilson

, McDonald

, McGuinness

, Stewart

, Thomas

, Tricco

, Welch

, Whiting

, Moher

. 2021. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Syst Rev, 10:89.

26.

Koehler

, Fuss

, Berr

, Frank-Raue

, Raue

, Hoster

, Hepprich

, Christ

, Pusl

, Reincke

, Spitzweg

, Kroiss

. 2022. Medullary thyroid cancer with ectopic Cushing's syndrome: a multicentre case series. Clin Endocrinol (Oxf), 96:847–856.

27.

Williams

, Morales

, Horn

. 1968. Thyroid carcinoma and Cushing's syndrome. A report of two cases with a review of the common features of the “non-endocrine” tumours associated with Cushing's syndrome. J Clin Pathol, 21:129–135.

28.

Szijj

, Csapó

, László

, Kovács

. 1969. Medullary cancer of the thyroid gland associated with hypercorticism. Cancer, 24:167–173.

29.

Melvin

, Tashjian

Jr ., Cassidy

, Givens

. 1970. Cushing's syndrome caused by ACTH- and calcitonin-secreting medullary carcinoma of the thyroid. Metabolism, 19:831–838.

30.

Croughs

, Eastham

, Hackeng

, Schopman

, Feltkamp-Vroom

, Dolman

, Hennemann

. 1972. ACTH and calcitonin secreting medullary carcinoma of the thyroid. Clin Endocrinol (Oxf), 1:157–171.

31.

Bordi

, Anversa

, Vitali-Mazza

. 1972. Ultrastructural study of a calcitonin-secreting tumor. Typhology of the tumor cells and origin of amyloid. Virchows Arch A Pathol Pathol Anat, 357:145–161.

32.

Bussolati

, van Noorden

, Bordi

. 1973. Calcitonin- and ACTH-producing cells in a case of medullary carcinoma of the thyroid. Immunofluorescence investigations. Virchows Arch A Pathol Pathol Anat, 360:123–127.

33.

Plymate

, Fariss

. 1974. Ectopic ACTH production in medullary carcinoma of the thyroid gland. Mil Med, 139:619–621.

34.

Hajjar

, Hill

Jr ., Samaan

. 1975. Adrenal mediation of the effect of excess ACTH on testosterone levels in male: a study of a patient with probable ACTH secreting medullary thyroid carcinoma. Acta Endocrinol (Copenh), 80:339–343.

35.

Birkenhäger

, Upton

, Seldenrath

, Krieger

, Tashjian

Jr . 1976. Medullary thyroid carcinoma: ectopic production of peptides with ACTH-like, corticotrophin releasing factor-like and prolactin production-stimulating activities. Acta Endocrinol (Copenh), 83:280–292.

36.

Kameya

, Shimosato

, Adachi

, Abe

, Kasai

, Kimura

, Baba

. 1977. Immunohistochemical and ultrastructural analysis of medullary carcinoma of the thyroid in relation to hormone production. Am J Pathol, 89:555–574.

37.

Keusch

, Binswanger

, Dambacher

, Fischer

. 1977. Ectopic ACTH syndrome and medullary thyroid carcinoma. Acta Endocrinol (Copenh), 86:306–316.

38.

Takai

, Ogihara

, Miyauchi

, Higashi

, Nishimura

. 1977. [A case of medullary thyroid carcinoma with ectopic ACTH syndrome (author's transl)]. Nihon Naibunpi Gakkai Zasshi, 53:1279–1291.

39.

Rosenberg

, Hahn

, Orth

, Deftos

, Tanaka

. 1978. ACTH-secreting medullary carcinoma of the thyroid presenting a severe idiopathic osteoporosis and senile purpura: report of a case and review of the literature. J Clin Endocrinol Metab, 47:255–262.

40.

Jolivet

, Beauregard

, Somma

, Band

. 1980. ACTH-secreting medullary carcinoma of the thyroid: monitoring of clinical course with calcitonin and cortisol assays and immunohistochemical studies. Cancer, 46:2667–2670.

41.

Chin

, Goodman

, Jacobs

, Wolfe

, Daniels

, Habener

. 1981. Medullary thyroid carcinoma identified by cell-free translation of tumor messenger ribonucleic acid in a patient with a neck mass and the syndrome of ectopic adrenocorticotropin. J Clin Endocrinol Metab, 52:572–575.

42.

Charpin

, Andrac

, Monier-Faugere

, Hassoun

, Cannoni

, Vagneur

, Toga

. 1982. Calcitonin, somatostatin and ACTH immunoreactive cells in a case of familial bilateral thyroid medullary carcinoma. Cancer, 50:1806–1814.

43.

Davies

, Joplin

, Welbourn

. 1982. Surgical management of the ectopic ACTH syndrome. Ann Surg, 196:246–258.

44.

Kakudo

, Miyauchi

, Ogihara

, Takai

, Kitamura

, Kumahara

, Kawaoi

. 1982. Medullary carcinoma of the thyroid with ectopic ACTH syndrome. Acta Pathol Jpn, 32:793–800.

45.

Shimatsu

, Kato

, Tanaka

, Nakai

, Fukunaga

, Imura

. 1983. Plasma calcitonin and ACTH responses to lysine vasopressin, calcium and pentagastrin in a patient with medullary thyroid carcinoma associated with Cushing's syndrome. Clin Endocrinol (Oxf), 18:119–125.

46.

Ratcliffe

, Knight

, Besser

, Landon

, Stansfeld

. 1972. Tumor and plasma ACTH concentrations in patients with and without the ectopic ACTH syndrome. Clin Endocrinol (Oxf), 1:27–44.

47.

Belsky

, Cuello

, Swanson

, Simmons

, Jarrett

, Braza

. 1985. Cushing's syndrome due to ectopic production of corticotropin-releasing factor. J Clin Endocrinol Metab, 60:496–500.

48.

Lind

, Weitzman

. 1985. The insidious development of symptomatic secondary hormone syndromes in patients with malignant endocrine tumors. Am J Med Sci, 290:107–110.

49.

Ahlman

, Tisell

. 1987. The use of a long-acting somatostatin analogue in the treatment of advanced endocrine malignancies with gastrointestinal symptoms. Scand J Gastroenterol, 22:938–942.

50.

Tourniaire

, Rebattu

, Conte-Devolx

, Trouillas

, Grino

, Berger-Dutrieux

, Peix

, Pugeat

. 1988. [Cushing's syndrome caused by ectopic production of CRF by a medullary carcinoma of the thyroid body]. Ann Endocrinol (Paris), 49:61–67.

51.

Blunt

, Pirmohamed

, Chatterjee

, Burrin

, Allison

, Joplin

. 1989. Use of adrenal arterial embolization in severe ACTH-dependent Cushing's syndrome. Postgrad Med J, 65:575–579.

52.

Popovic

, Milosevic

, Doniach

, Micic

, Nesovic

, Odavic

, Petakov

, Kendereski

, Sumarac

, Manojlovic

, Micic

, Besser

. 1991. Elevated adrenocorticotropic hormone and cortisol levels in a patient with medullary carcinoma of the thyroid containing ectopic immunoreactive corticotropin-releasing hormone and bombesin. Endocr Pathol, 2:56–60.

53.

Hijazi

, Nieman

, Medeiros

. 1992. Medullary carcinoma of the thyroid as a cause of Cushing's syndrome: a case with ectopic adrenocorticotropin secretion characterized by double enzyme immunostaining. Hum Pathol, 23:592–596.

54.

Mure

, Gicquel

, Abdelmoumene

, Tenenbaum

, Francese

, Travagli

, Gardet

, Schlumberger

. 1995. Cushing's syndrome in medullary thyroid carcinoma. J Endocrinol Invest, 18:180–185.

55.

Winquist

, Laskey

, Crump

, Khamsi

, Shepherd

. 1995. Ketoconazole in the management of paraneoplastic Cushing's syndrome secondary to ectopic adrenocorticotropin production. J Clin Oncol, 13:157–164.

56.

Oates

, Roth

, Molitch

. 2000. Corticotropin-releasing hormone-producing medullary thyroid carcinoma causing Cushing's syndrome: clinical and pathological findings. Endocr Pathol, 11:277–285.

57.

von Mach

, Kann

, Piepkorn

, Bruder

, Beyer

. 2002. [Cushing's syndrome caused by paraneoplastic ACTH secretion 11 years after occurence of a medullary thyroid carcinoma]. Dtsch Med Wochenschr, 127:850–852.

58.

Smallridge

, Bourne

, Pearson

, Van Heerden

, Carpenter

, Young

. 2003. Cushing's syndrome due to medullary thyroid carcinoma: diagnosis by proopiomelanocortin messenger ribonucleic acid in situ hybridization. J Clin Endocrinol Metab, 88:4565–4568.

59.

Barbosa

, Rodien

, Leboulleux

, Niccoli-Sire

, Kraimps

, Caron

, Archambeaud-Mouveroux

, Conte-Devolx

, Rohmer

. 2005. Ectopic adrenocorticotropic hormone-syndrome in medullary carcinoma of the thyroid: a retrospective analysis and review of the literature. Thyroid, 15:618–623.

60.

Bourlet

, Dumousset

, Nasser

, Chabrot

, Pezet

, Thieblot

, Garcier

, Boyer

. 2007. Embolization of hepatic and adrenal metastasis to treat Cushing's syndrome associated with medullary thyroid carcinoma: a case report. Cardiovasc Intervent Radiol, 30:1052–1055.

61.

Sand

, Uecker

, Bechara

, Gelos

, Sand

, Wiese

, Mann

. 2007. Simultaneous ectopic adrenocorticotropic hormone syndrome and adrenal metastasis of a medullary thyroid carcinoma causing paraneoplastic Cushing's syndrome. Int Semin Surg Oncol, 4:15.

62.

Chrisoulidou

, Pazaitou-Panayiotou

, Georgiou

, Boudina

, Kontogeorgos

, Iakovou

, Efstratiou

, Patakiouta

, Vainas

. 2008. Ectopic Cushing's syndrome due to CRH secreting liver metastasis in a patient with medullary thyroid carcinoma. Hormones (Athens), 7:259–262.

63.

Zaydfudim

, Stover

, Caro

, Phay

. 2008. Presentation of a medullary endocrine neoplasia 2A kindred with Cushing's syndrome. Am Surg, 74:659–661.

64.

Dhanwal

, Tandon

, Chumber

, Ammini

. 2010. Multiple endocrine neoplasia (MEN) syndrome-2B with ectopic Cushing syndrome. Endocrinologist, 20:13–14.

65.

Wang

, Mu

, Dou

, Zhong

, Lü

, Lu

, Pan

. 2011. Medullar thyroid carcinoma in mediastinum initially presenting as ectopic ACTH syndrome. A case report. Neuro Endocrinol Lett, 32:421–424.

66.

Baudry

, Paepegaey

, Groussin

. 2013. Reversal of Cushing's syndrome by vandetanib in medullary thyroid carcinoma. N Engl J Med, 369:584–586.

67.

Kurozumi

, Okada

, Arao

, Nakamoto

, Togashi

, Tanaka

. 2013. Case of multiple endocrine neoplasia 2B with probable ectopic adrenocorticotropic hormone-secreting liver metastasis from medullary thyroid carcinoma. J UOEH, 35:193–199.

68.

Barroso-Sousa

, Lerario

, Evangelista

, Papadia

, Lourenço

Jr ., Lin

, Kulcsar

, Fragoso

, Hoff

. 2014. Complete resolution of hypercortisolism with sorafenib in a patient with advanced medullary thyroid carcinoma and ectopic ACTH (adrenocorticotropic hormone) syndrome. Thyroid, 24:1062–1066.

69.

Fox

, Widemann

, Chuk

, Marcus

, Aikin

, Whitcomb

, Merino

, Lodish

, Dombi

, Steinberg

, Wells

, Balis

. 2013. Vandetanib in children and adolescents with multiple endocrine neoplasia type 2B associated medullary thyroid carcinoma. Clin Cancer Res, 19:4239–4248.

70.

Nella

, Lodish

, Fox

, Balis

, Quezado

, Whitcomb

, Derdak

, Kebebew

, Widemann

, Stratakis

. 2014. Vandetanib successfully controls medullary thyroid cancer-related Cushing syndrome in an adolescent patient. J Clin Endocrinol Metab, 99:3055–3059.

71.

Choi

, Kim

, Moon

, Yoon

, Ku

, Kang

, Na

, Lee

, Park

, Kim

, Ku

. 2014. Medullary thyroid carcinoma with ectopic adrenocorticotropic hormone syndrome. Endocrinol Metab (Seoul), 29:96–100.

72.

Singer

, Heiniger

, Thomas

, Worden

, Menon

, Chen

. 2014. Ectopic Cushing syndrome secondary to metastatic medullary thyroid cancer in a child with multiple endocrine neoplasia syndrome type 2B: clues to early diagnosis of the paraneoplastic syndromes. J Pediatr Endocrinol Metab, 27:993–996.

73.

Hammami

, Duaiji

, Mutairi

, Aklabi

, Qattan

, Abouzied Mel

, Sous

. 2015. Case report of severe Cushing's syndrome in medullary thyroid cancer complicated by functional diabetes insipidus, aortic dissection, jejunal intussusception, and paraneoplastic dysautonomia: remission with sorafenib without reduction in cortisol concentration. BMC Cancer, 15:624.

74.

Marques

, Vieira Mda

, Bugalho

. 2015. Ectopic Cushing in a patient with medullary thyroid carcinoma: hypercortisolism control and tumor reduction with Sunitinib. Endocrine, 49:290–292.

75.

Pitoia

, Bueno

, Schmidt

, Lucas

, Cross

. 2015. Rapid response of hypercortisolism to vandetanib treatment in a patient with advanced medullary thyroid cancer and ectopic Cushing syndrome. Arch Endocrinol Metab, 59:343–346.

76.

Verburg

, Anlauf

, Mottaghy

, Karges

. 2015. Somatostatin receptor imaging-guided pasireotide therapy in medullary thyroid cancer with ectopic adrenocorticotropin production. Clin Nucl Med, 40:e83–e84.

77.

Paepegaey

, Cochand-Priollet

, Louiset

, Sarfati

, Alifano

, Burnichon

, Bienvenu-Perrard

, Lahlou

, Bricaire

, Groussin

. 2017. Long-term control of hypercortisolism by vandetanib in a case of medullary thyroid carcinoma with a somatic RET mutation. Thyroid, 27:587–590.

78.

Sathyakumar

, Paul

, Asha

, Gnanamuthu

, Paul

, Abraham

, Rajaratnam

, Thomas

. 2017. Ectopic Cushing syndrome: a 10-year experience from a tertiary care center in Southern India. Endocr Pract, 23:907–914.

79.

Wijewardene

, Glastras

, Learoyd

, Robinson

, Tsang VHM 2017 ACTH-secreting medullary thyroid cancer: a case series. Endocrinol Diabetes Metab Case Rep, 2017, eCollection 2017.

80.

Ferreira

, Leal

CTS

, Ferreira

, Ezequiel

DGA

, Costa

. 2019. Atypical presentation of a medullary thyroid carcinoma producing Acth and serotonin. Case Rep Oncol, 12:742–748.

81.

Pivovarova

, Patrick

, Reddy

. 2019. Sporadic medullary thyroid carcinoma with paraneoplastic Cushing syndrome. Case Rep Endocrinol, 2019:6414921.

82.

Shahidi

, Phillips

, Chik

. 2019. Intestinal perforation in ACTH-dependent Cushing's syndrome. Biomed Res Int, 2019:9721781.

83.

Matheny

, Wilson

, Baum HBA 2016 Ectopic ACTH production leading to diagnosis of underlying medullary thyroid carcinoma. J Invest Med High Impact Case Rep 4, eCollection Apr–Jun 2016.

84.

Forde

, Mehigan-Farrelly

, Ryan

, Moran

, Greally

, Duffy

, Byrne

. 2021. Metastatic medullary thyroid carcinoma presenting as ectopic Cushing's syndrome. Endocrinol Diabetes Metab Case Rep, 2021:20-0207.

85.

Lopez-Montoya

, Gutierrez-Restrepo

, Grajales

JLT

, Aristizabal

, Pantoja

, Roman-Gonzalez

, Jimenez

. 2021. Ectopic Cushing syndrome in Colombia. Arch Endocrinol Metab, 64:687–694.

86.

Cheong

, Koo

. 2021. Medullary thyroid carcinoma with diabetic ketoacidosis: an autopsy case report and literature review. Forensic Sci Med Pathol, 17:711–714.

87.

Bseiso

, Lev-Cohain

, Gross

, Grozinsky-Glasberg

. 2016. Vandetanib induces a marked anti-tumor effect and amelioration of ectopic Cushing's syndrome in a medullary thyroid carcinoma patient. Endocrinol Diabetes Metab Case Rep 2016, Epub 2016 Oct 24.

88.

Agosto

, Subbiah

, Zhu

. 2019. Successful resolution of Cushing syndrome due to ectopic ACTH syndrome in metastatic medullary thyroid carcinoma during treatment with selpercatinib (LOXO-292), a novel highly selective RET inhibitor. Thyroid, 29:A107.

89.

Mahajan

, Agarwala

, Jain

, Dhua

, Khadgawat

, Tandon

, Jana

, Kandasamy

, Prasad

, Kumar

, Lodha

. 2021. Metastatic medullary thyroid carcinoma (MTC) as a source of ectopic adrenocorticotropic hormone (ACTH) leading to Cushing's syndrome in a 10-year-old child. Pediatr Blood Cancer, 68:S315.

90.

Alexandraki

, Grossman

. 2010. The ectopic ACTH syndrome. Rev Endocr Metab Disord, 11:117–126.

91.

Crona

, Norlén

, Antonodimitrakis

, Welin

, Stålberg

, Eriksson

. 2016. Multiple and secondary hormone secretion in patients with metastatic pancreatic neuroendocrine tumours. J Clin Endocrinol Metab, 101:445–452.

92.

de Mestier

, Hentic

, Cros

, Walter

, Roquin

, Brixi

, Lombard-Bohas

, Hammel

, Diebold

, Couvelard

, Ruszniewski

, Cadiot

. 2015. Metachronous hormonal syndromes in patients with pancreatic neuroendocrine tumors: a case-series study. Ann Intern Med, 162:682–689.

93.

Fleseriu

, Auchus

, Bancos

, Ben-Shlomo

, Bertherat

, Biermasz

, Boguszewski

, Bronstein

, Buchfelder

, Carmichael

, Casanueva

, Castinetti

, Chanson

, Findling

, Gadelha

, Geer

, Giustina

, Grossman

, Gurnell

, Ho

, Ioachimescu

, Kaiser

, Karavitaki

, Katznelson

, Kelly

, Lacroix

, McCormack

, Melmed

, Molitch

, Mortini

, Newell-Price

, Nieman

, Pereira

, Petersenn

, Pivonello

, Raff

, Reincke

, Salvatori

, Scaroni

, Shimon

, Stratakis

, Swearingen

, Tabarin

, Takahashi

, Theodoropoulou

, Tsagarakis

, Valassi

, Varlamov

, Vila

, Wass

, Webb

, Zatelli

, Biller

BMK

. 2021. Consensus on diagnosis and management of Cushing's disease: a guideline update. Lancet Diabetes Endocrinol, 9:847–875.

94.

Coates

, Doniach

, Howlett

, Rees

, Besser

. 1986. Immunocytochemical study of 18 tumours causing ectopic Cushing's syndrome. J Clin Pathol, 39:955–960.

95.

Sheikh-Ali

, Krishna

, Lloyd

, Smallridge

. 2007. Predicting the development of Cushing's syndrome in medullary thyroid cancer: utility of proopiomelanocortin messenger ribonucleic acid in situ hybridization. Thyroid, 17:631–634.

96.

Ritzel

, Beuschlein

, Mickisch

, Osswald

, Schneider

, Schopohl

, Reincke

. 2013. Clinical review: outcome of bilateral adrenalectomy in Cushing's syndrome: a systematic review. J Clin Endocrinol Metab, 98:3939–3948.

97.

Baudry

, Coste

, Bou Khalil

, Silvera

, Guignat

, Guibourdenche

, Abbas

, Legmann

, Bertagna

, Bertherat

. 2012. Efficiency and tolerance of mitotane in Cushing's disease in 76 patients from a single center. Eur J Endocrinol, 167:473–481.

98.

Preda

, Sen

, Karavitaki

, Grossman

. 2012. Therapy in endocrine disease: etomidate in the management of hypercortisolaemia in Cushing's syndrome: a review. Eur J Endocrinol, 167:137–143.

99.

Young

, Haissaguerre

, Viera-Pinto

, Chabre

, Baudin

, Tabarin

. 2020. Management of endocrine disease: Cushing's syndrome due to ectopic ACTH secretion: an expert operational opinion. Eur J Endocrinol, 182:R29–R58.

100.

Reincke

, Ritzel

, Oßwald

, Berr

, Stalla

, Hallfeldt

, Reisch

, Schopohl

, Beuschlein

. 2015. A critical reappraisal of bilateral adrenalectomy for ACTH-dependent Cushing's syndrome. Eur J Endocrinol, 173:M23–M32.

101.

Raffaelli

, Brunaud

, De Crea

, Hoche

, Oragano

, Bresler

, Bellantone

, Lombardi

. 2014. Synchronous bilateral adrenalectomy for Cushing's syndrome: laparoscopic versus posterior retroperitoneoscopic versus robotic approach. World J Surg, 38:709–715.