Three Cases of Ectopic, Cyclic Cushing Syndrome: A New Square Wave Variant

Posted on November 3, 2025 by MaryO

Abstract

Cyclic Cushing syndrome (CCS) is characterized by unpredictable, intermittent phases of excess cortisol, alternating with periods of normal or subnormal adrenocorticotropic hormone (ACTH) and cortisol levels. The mechanism is unclear. Due to its rarity and diverse clinical presentation, unpredictable phases, and various etiologies, CCS poses significant diagnostic and management challenges for endocrinologists. The authors describe 3 cases in which each patient’s initial presentation was a life-threatening hypercortisolemic phase that lasted from 4 days to 3 months, followed by spontaneous resolution to prolonged eucortisolemic phases lasting from 10 to 26 months. Further testing indicated an ectopic ACTH-secreting source; however, the locations of the offending tumors were indeterminate. The authors propose the term square wave CCS variant to characterize the unique, prolonged intercyclic phases of hypercortisolemia and eucortisolemia with this subtype that are distinct from conventional CCS characterized by shorter phases of transient hypercortisolemia shifting to periods of eucortisolemia or hypocortisolemia. This uncharacteristic pattern of cyclicity poses diagnostic and therapeutic challenges, thus underscoring the importance of careful diagnostic workup and treatment of these patients.

Keywords: ectopic, cyclic, Cushing syndrome, eucortisolemia, hypercortisolemia

Introduction

Cyclic Cushing syndrome (CCS) is a rare variant of Cushing syndrome (CS) characterized by intermittent episodes of cortisol peaks alternating with variable periods of normal or subnormal adrenocorticotropic hormone (ACTH) and cortisol levels (troughs) []. These cycles can occur at regular or irregular intervals [], with unpredictable intercyclic phases typically lasting from days to months [, ]. The prevalence of CCS in patients with CS is low, ranging from 8% to 19% []. Several alternative terms (eg, intermittent, variable, periodic, and episodic hypercortisolism) have been proposed to characterize the variable cyclicity of ACTH and cortisol secretion in patients with CCS [].

We describe 3 cases of suspected ectopic ACTH-dependent CS with an indeterminate ACTH source that presented with life-threatening hypercortisolemia lasting from 4 days to 3 months, followed by spontaneous eucortisolemic phases lasting from 10 to 26 months. The term square wave is proposed to describe this unique cyclic pattern to highlight the unpredictability of severe hypercortisolemia followed by spontaneous prolonged eucortisolemic phases, which is distinct from previously described transient regular or irregular cycles with shorter intercyclic phases of CCS that require medical intervention.

Case Presentation

Case 1

A 75-year-old man with atrial fibrillation, bilateral leg edema, 6-month weight loss of 7 pounds (3.2 kg), and generalized muscle weakness was referred for cardiac ablation therapy. However, just before he underwent the procedure, he was found to be profoundly hypokalemic with potassium of 2.9 mEq/L (SI: 2.9 mmol/L) (reference range, 3.6-5.3 mEq/L [SI: 3.6-5.3 mmol/L]) and hyperglycemic, with blood glucose of 498 mg/dL (SI: 27.8 mmol/L) (reference range, 70-99 mg/dL [SI: 3.9-5.5 mmol/L]) and glycated hemoglobin (HbA1c) of 7.4%. He was emergently treated with potassium supplementation and insulin therapy.

Case 2

A 61-year-old woman presented to the emergency department with palpitations, uncontrolled hypertension, weight loss of 20 pounds (9.1 kg) over 2 weeks, new signs of hyperandrogenism (eg, hirsutism, acne, muscle atrophy), lower back pains, easy bruising, and proximal muscle weakness.

Case 3

A 57-year-old woman presented to the emergency department in August 2021 with a 2-month history of facial swelling and generalized muscle weakness. She had reported a similar episode in April 2019 with hypokalemia (potassium, 2.5 mEq/L [SI: 2.5 mmol/L]) that was treated with potassium repletion therapy.

Diagnostic Assessment

Case 1

Further laboratory tests revealed elevated morning (Am) cortisol of 76.8 µg/dL (SI: 2119 nmol/L) (reference range, 5-25 µg/dL [SI: 138-690 nmol/L]), Am ACTH of 368 pg/mL (SI: 81 pmol/L) (reference range, 6-50 pg/mL [SI: 1.3-11.0 pmol/L]), and 24-hour urine free cortisol (UFC) of 4223 µg/24 hours (SI: 11 656 nmol/24 hours) (reference range, 1.5-18.1 µg/24 hours [SI: 4-50 nmol/24 hours]) (Table 1). Magnetic resonance imaging (MRI) of the pituitary (Fig. 1) and 68Ga-DOTATATE positron emission tomography (PET) (Table 2) of the chest, pelvis, and abdomen failed to identify the source of ACTH secretion. Inferior petrosal sinus sampling (IPSS) showed no significant ACTH gradient, supporting the likelihood of an ectopic ACTH-secreting source (Table 3).

Table 1.

Summary of biochemical testing data for the 3 patients with a square wave pattern of cyclic Cushing syndrome

Test, reference range Patient 1 (male, 75 years) Patient 2 (female, 61 years) Patient 3 (female, 57 years)
IP EP IP EP IP EP
AM cortisol 5-23 µg/dL (138-690 nmol/L) 76.8 µg/dL (2119 nmol/L) 14.2 µg/dL (392 nmol/L) 38.4 µg/dL (1060 nmol/L) 17.9 µg/dL (494 nmol/L) 56.8 µg/dL (1568 nmol/L) 14.4 µg/dL (397 nmol/L)
AM ACTH 6-50 pg/mL (1.3-11.0 pmol/L) 368 pg/mL (81 pmol/L) 38.1 pg/mL (8.4 pmol/L) 118 pg/mL (26 pmol/L] 16.5 pg/mL (3.6 pmol/L) 159 pg/mL (35 pmol/L] 39 pg/mL (8.6 pmol/L)
PM cortisol 2.9-17.3 µg/dL (80-477 nmol/L) 57.8 µg/dL (1594 nmol/L) — — — — <0.05 µg/dL (<1.4 nmol/L)
24-h UFC 1.5-18.1 µg/24 hours (4-50 nmol/24 hours) 4223 µg/24 hours (11 656 nmol/24 hours) 10.5 µg/24 hours (29 nmol/24 hours) 52.9 µg/24 hours (146 nmol/24 hours) 13 µg/24 hours (36 nmol/24 hours) 670.5 µg/24 hours (1851 nmol/24 hours) 23 µg/24 hours (63 nmol/24 hours)
Post 1-mg DST cortisol <1.8 ng/dL (<50 nmol/L) 74.6 ng/dL (2059 nmol/L) — 26.9 ng/dL (743 nmol/L) 1.4 ng/dL (<50 nmol/L) 16.7 ng/dL (461 nmol/L) —
Salivary cortisol < 0.09 µg/dL (<2.5 nmol/L) — 0.08 µg/dL (2.2 nmol/L) — 0.04 µg/dL (1.1 nmol/L) — —
S-DHEA 7-162 µg/dL (0.19-4.37 µmol/L) — 63 µg/dL — — — —
Chromogranin A <311 ng/mL* (<311 µg/L) 725 ng/mL (30.6 nmol/L) — — — — —
Lipase 8-78 U/L 40.0 U/L (40.0 U/L) — — — — —
Hemoglobin A1c <5.7% 8.9% 5.9% 9.2% 5.9% — —

International System of Units are included within parentheses.

Dash (–) indicates that no data are available.

* Method dependent.

Abbreviations: ACTH, adrenocorticotropic hormone; AM, morning; DST, dexamethasone suppression test; EP, eucortisolemic phase; IP, initial presentation; PM, afternoon; S-DHEA, serum dehydroepiandrosterone; UFC, urine free cortisol.

Figure 1.

Figure 1.

Case 1. (A) Sagittal and (B) coronal magnetic resonance images demonstrating normal appearance of the pituitary gland. From Barrow Neurological Institute, Phoenix, Arizona.

Table 2.

Imaging workup summary

Case Imaging modalities Interpretation
Case 1 Pituitary MRI, CT chest/abdomen/pelvis, pelvic USG, 68Ga-DOTATATE PET/CT No ectopic ACTH-secreting source identified
Case 2 Pituitary MRI, CT chest/abdomen/pelvis, 68Ga-DOTATATE PET/CT No ectopic ACTH-secreting source identified
Case 3 Pituitary MRI, CT chest/abdomen/pelvis, pelvic USG, 68Ga-DOTATATE PET/CT No ectopic ACTH-secreting source identified

Abbreviations: ACTH, adrenocorticotropic hormone; CT, computed tomography; MRI, magnetic resonance imaging; PET, positron emission tomography; USG, ultrasound.

Table 3.

ACTH levels from inferior petrosal sinus sampling

Variable −5 Minutes 0 Minutes +2 Minutes +5 Minutes +10 Minutes
CASE 1
Right IPS 239 pg/mL (52.6 pmol/L) 221 pg/mL (48.6 pmol/L) 218 pg/mL (48.0 pmol/L) 239 pg/mL (52.6 pmol/L) 217 pg/mL (47.8 pmol/L)
Left IPS 226 pg/mL (49.8 pmol/L) 221 pg/mL (48.6 pmol/L) 216 pg/mL (47.6 pmol/L) 251 pg/mL (55.3 pmol/L) 213 pg/mL (46.9 pmol/L)
Peripheral 225 pg/mL (49.5 pmol/L) 219 pg/mL (48.2 pmol/L) 210 pg/mL (46.2 pmol/L) 217 pg/mL (47.8 pmol/L) 237 pg/mL (52.2 pmol/L)
Right IPS: peripheral ratio 1.06 1.00 1.03 1.10 .92
Left IPS: peripheral ratio 1.00 1.00 1.02 1.15 .89
CASE 2
Right IPS 59 pg/mL (13.0 pmol/L) 79 pg/mL (17.4 pmol/L) 203 pg/mL (44.7 pmol/L) 296 pg/mL (65.2 pmol/L) 374 pg/mL (82.3 pmol/L)
Left IPS 61 pg/mL (13.4 pmol/L) 77 pg/mL (17.0 pmol/L) 196 pg/mL (43.2 pmol/L) 313 pg/mL (68.9 pmol/L) 341 pg/mL (75.1 pmol/L)
Peripheral 62 pg/mL (13.7 pmol/L) 64 pg/mL (14.1 pmol/L) 146 pg/mL (32.2 pmol/L) 235 pg/mL (51.8 pmol/L) 368 pg/mL (81.0 pmol/L)
Right IPS: peripheral ratio .95 1.23 1.39 1.26 1.02
Left IPS: peripheral ratio .98 1.20 1.34 1.33 .93
CASE 3
Right IPS 119 pg/mL (26.1 pmol/L) 121 pg/mL (26.6 pmol/L) 380 pg/mL (83.8 pmol/L) 581 pg/mL (128.0 pmol/L) 232 pg/mL (51.2 pmol/L)
Left IPS 124 pg/mL (27.4 pmol/L) 133 pg/mL (29.3 pmol/L) 358 pg/mL (78.9 pmol/L) 568 pg/mL (125.0 pmol/L) 262 pg/mL (57.7 pmol/L)
Peripheral 113 pg/mL (24.9 pmol/L) 111 pg/mL (24.4 pmol/L) 322 pg/mL (70.9 pmol/L) 527 pg/mL (116.0 pmol/L) 178 pg/mL (39.1 pmol/L)
Right IPS: peripheral ratio 1.04 1.09 1.18 1.10 1.31
Left IPS: peripheral ratio 1.10 1.20 1.13 1.08 1.48

International System of Units are included within parentheses.

Baseline IPS: P > 2.0; Suggests pituitary (Cushing’s disease).

Post-stim IPS: P > 3.0; Confirms pituitary ACTH source.

Abbreviations: ACTH, adrenocorticotropic hormone; IPS, inferior petrosal sinus.

Case 2

Laboratory tests revealed elevated Am cortisol of 38.4 µg/dL (SI: 1060 nmol/L) and Am ACTH of 118 pg/mL (SI: 26 pmol/L), hypokalemia (potassium, 2.9 mEq/L [SI: 2.9 mmol/L]) and new-onset type 2 diabetes mellitus with a random blood glucose of 489 mg/dL (SI: 27.2 mmol/L) and HbA1c of 9.2% (reference range, < 5.7%) (Table 1). Lumbar spine radiography and spine MRI demonstrated compression fractures of L1 to L4 vertebrae, and pituitary MRI showed a 2-mm hypo-enhancing foci within the midline and to the right of the pituitary gland (Fig. 2).

Figure 2.

Figure 2.

Case 2. (A) Sagittal and (B) coronal magnetic resonance images of the pituitary gland show 2-mm hypo-enhancing foci (arrows) within the midline and to the right side of the pituitary gland. From Barrow Neurological Institute, Phoenix, Arizona.

Case 3

During the present hospital admission, the patient was hypokalemic (potassium, 2.7 mEq/L [SI: 2.7 mmol/L]) and hypercortisolemic with Am cortisol and Am ACTH levels of 56.8 µg/dL (SI: 1568 nmol/L) and 159 pg/mL (SI: 35 pmol/L), respectively. After 4 days of hospitalization, the patient spontaneously became eucortisolemic with an Am cortisol of 16.8 µg/dL (SI: 464 nmol/L), 24-hour UFC of 670.5 µg/24 hours (SI: 1851 nmol), and late-night salivary cortisol of 0.03 µg/dL (SI: 0.828 nmol/L) with symptom improvement (Table 1). Pituitary MRI revealed a flattened, normal-appearing pituitary gland (Fig. 3).

Figure 3.

Figure 3.

Case 3. (A) Sagittal and (B) coronal magnetic resonance images of the pituitary gland showing a flattened pituitary gland. No discrete, sizable, differentially enhancing mass is detected within the sella. From Barrow Neurological Institute, Phoenix, Arizona.

Treatment

Case 1

Because of the patient’s worsening clinical condition and severe hypercortisolemia with no identifiable ACTH source, ketoconazole was considered to induce eucortisolemia. While electrocardiography and liver function tests were being measured before starting ketoconazole, the patient’s Am cortisol levels spontaneously normalized to 14.2 µg/dL (SI: 392 nmol/L) with symptomatic improvement.

Case 2

The patient began insulin, spironolactone, and levothyroxine therapy. After 2 days in the hospital, her Am cortisol decreased to 17.9 µg/dL (SI: 494 nmol/L) and remained within the range of 9.4 to 17.9 µg/dL (SI: 259-494 nmol/L). An IPSS performed 3 weeks later showed no significant ACTH gradient, supporting the likelihood of an ectopic ACTH-secreting source. By month 3, her Am cortisol levels consistently remained below 15 µg/dL (SI: 414 nmol/L). Blood pressure was controlled with one antihypertensive agent, and insulin was discontinued due to frequent hypoglycemic episodes.

Case 3

The patient was readmitted 18 months later with worsening muscle weakness, uncontrolled hypertension, hypokalemia (potassium, 2.4 mEq/L [SI: 2.4 mmol/L]), and hypercortisolemia with elevated Am cortisol and Am ACTH levels. 68Ga-DOTATATE PET did not reveal an ectopic ACTH source (Table 2), and IPSS did not reveal any significant ACTH gradient (Table 3). However, computed tomography (CT) of the chest, abdomen, and pelvis revealed a 0.7-cm lung nodule. During this hospitalization, the patient received supportive treatment, including antihypertensive therapy and electrolyte replacement. No pharmacologic intervention was required to control her cortisol levels.

Outcome and Follow-Up

Case 1

Late-night salivary cortisol levels measured were within the normal range (0.08 µg/dL, 0.06 µg/dL, and 0.08 µg/dL [SI: 2.2 nmol/L, 1.7 nmol/L, and 2.2 nmol/L]; reference range, < 0.09 µg/dL [SI: < 2.5 nmol/L]). Because of these biochemical and symptomatic improvements, ketoconazole therapy was deferred. At the most recent outpatient clinic follow-up 26 months after his cortisol levels normalized, the patient remained in remission without recurrence of hypercortisolemic symptoms.

Case 2

The patient remained in biochemical and clinical remission for 15 months until she began experiencing abdominal distention, bilateral leg edema, and facial swelling again. Blood pressure increased at this time, requiring 3 antihypertensive medications. Her Am cortisol levels rose to 29.1 µg/dL (SI: 803 nmol/L), but repeat IPSS showed no ACTH gradient, and 68Ga-DOTATATE PET/CT of the chest, abdomen, and pelvis was unremarkable (Tables 2 and 3). Block-and-replace therapy of osilodrostat and hydrocortisone was initiated to preemptively prevent hypercortisolemic episodes; after 3 months of therapy, she underwent successful bilateral adrenalectomy (BLA).

Case 3

On day 5 of hospitalization, her Am cortisol level decreased to 14.4 µg/dL (SI: 397 nmol/L) (reference range, 5-25 µg/dL [SI: 138-690 nmol/L]). Her symptoms improved, and she remained well for 11 months before recurrence of muscle weakness, hypokalemia, and hypercortisolemia with an Am cortisol of 58.7 µg/dL (SI: 1620 nmol/L) and Am ACTH of 194 pg/mL (SI: 43 pmol/L). The patient became eucortisolemic without any medical intervention and declined further treatment. She continues with regular outpatient follow-up.

Discussion

Diagnosing CCS poses considerable challenges because of its heterogeneous clinical manifestations, erratic intercyclic duration, frequency of phases, and various etiologies. Patients may experience transient or continuous symptoms with variable degrees of severity []. Our patients presented with severe hypercortisolemia lasting from days to months, followed by an extended period of spontaneous eucortisolemia, lasting from months to years. This unique presentation of cortisol kinetics differs from the classic presentation of CCS, which typically features shorter intercyclic phases [].

We coined the term square wave variant of CCS to characterize this unique feature of prolonged cyclicity of hypercortisolemia shifting spontaneously to eucortisolemia without medical intervention. The term square wave was chosen because the cortisol secretion pattern in these cases resembles a square waveform, with abrupt transitions between prolonged periods of high and low cortisol levels rather than the gradual fluctuations or short irregular peaks seen in typical CCS. This visual and kinetic analogy helps distinguish the pattern observed in our patients from the more classically described forms of CCS.

The absence of a standardized definition of CCS complicates the classification of cases such as ours, which diverge from conventional descriptions in the medical literature [, , ]. Most cases of CCS are associated with pituitary tumors (67%), whereas ectopic ACTH-secreting tumors (17%) and adrenal tumors (11%) are less common [, ]. Our patients had evidence of ectopic CS, of which the ACTH-secreting source was unidentifiable despite extensive imaging. The variability of symptom duration, severity, and timing in our patients implies distinct mechanisms for suppressing or desensitizing adrenal cortisol synthesis during the extended symptom-free periods. Other mechanisms include enhanced effects of specific neurotransmitters, hypothalamic dysregulation, spontaneous tumor hemorrhage, cyclic growth and apoptosis of ACTH-secreting tumor cells, and positive and negative feedback mechanisms []. Another explanation for the prolonged eucortisolemic phase may be due to altered POMC gene expression and defective ACTH secretion from the ectopic tumor []. Over time, the tumor may dedifferentiate or develop a transcriptional or posttranscriptional defect, leading to the secretion of ACTH with a decreased ability to stimulate adrenal cortisol secretion [, ]. Conversely, CCS might also be an exaggerated physiological cyclical variation of ACTH and cortisol secretion [, ]. However, the prolonged eucortisolemic phase observed in our patients argues against this exaggeration theory.

Recent studies have suggested that the anomalous cyclicity of cortisol and ACTH may be influenced by dysregulation of the peripheral clock system in endocrine tumors []. Certain tumors may exhibit aberrant expression of circadian regulators such as CLOCK, PER1, PER2, PER3, and TIMELESS, which can disrupt the physiological rhythmicity of cortisol and ACTH secretion [, ]. For instance, cortisol-secreting adrenal adenomas demonstrate downregulation of PER1, CRY1, and Rev-ERB, whereas adrenocortical carcinomas upregulate CRY1 and PER1 and downregulate BMAL1 and RORα. In patients with CS, clock gene expression in peripheral blood mononuclear cells has been shown to be significantly flattened, contributing to the loss of circadian variation in cortisol levels [].

Surgery is the preferred treatment option for CCS patients, provided the tumor is localizable []. Medical therapy is used when the tumor is undetectable, unresectable, or recurs. Medical therapy can overtreat and induce iatrogenic adrenal insufficiency during the eucortisolemic phases. This risk can be mitigated by the block-and-replace strategy of high-dose steroidogenesis inhibitors to suppress adrenal cortisol production and supplemented with exogenous glucocorticoids []. In patients for whom the ectopic tumor is unidentifiable, the initial tumor resection is ineffective, or if medical management does not adequately control hypercortisolemia, BLA may be considered [].

Although treatment of CCS resembles that of CS, the heterogeneity in the severity and duration of symptoms prohibits the implementation of some conventional treatment strategies. Consequently, long-term medical therapy may not align with the patient’s preferences, especially those whose course of illness is characterized by prolonged eucortisolemia and milder symptoms. Such patients should be educated to monitor symptoms closely during the eucortisolemic phase to recognize the signs and symptoms of hypercortisolism using objective parameters such as self-assessment of weight, blood pressure, and capillary blood glucose. Periodic biochemical monitoring may also be helpful, including standby kits for self-testing of late-night salivary cortisol and 24-hour UFC. If the source of ectopic ACTH secretion continues to elude detection, BLA during the eucortisolemic phase may be considered to prevent future life-threatening hypercortisolemic episodes.

Learning Points

  • Unlike typical CCS, there may be a subset of patients with a distinct square wave variant of CCS marked by severe hypercortisolemia followed by prolonged periods of eucortisolemia.
  • Ectopic ACTH-secreting sources in CCS may be linked to unusually long symptom-free intervals of eucortisolemia and hypocortisolemia between episodes of hypercortisolemia.
  • If possible, CCS management should be individualized to address its cause, with vigilant monitoring during the eucortisolemic phase to detect potential recurrence early.
  • If the source of the ectopic ACTH-secreting tumor is not identifiable, BLA may be considered during the eucortisolemic phase to prevent future life-threatening hypercortisolemic episodes.

Acknowledgments

We thank the staff of Neuroscience Publications at Barrow Neurological Institute for assistance with manuscript preparation.

Abbreviations

ACTH
adrenocorticotropic hormone
BLA
bilateral adrenalectomy
CCS
cyclic Cushing syndrome
CS
Cushing syndrome
CT
computed tomography
HbA1c
glycated hemoglobin
IPSS
inferior petrosal sinus sampling
MRI
magnetic resonance imaging
PET
positron emission tomography
UFC
urine free cortisol

Contributor Information

Mercedes Martinez-Gil, Department of Internal Medicine, Creighton University School of Medicine, Phoenix, AZ 85012, USA.

Tshibambe N Tshimbombu, Department of Neurology, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ 85013, USA.

Yvette Li Yi Ang, Division of Endocrinology, Department of Medicine, National University Hospital, Singapore 119228, Singapore.

Monica C Rodriguez, Barrow Pituitary Center, Barrow Neurological Institute, University of Arizona College of Medicine and Creighton University School of Medicine, Phoenix, AZ 85012, USA.

Kevin C J Yuen, Barrow Pituitary Center, Barrow Neurological Institute, University of Arizona College of Medicine and Creighton University School of Medicine, Phoenix, AZ 85012, USA.

Contributors

All authors contributed substantially to the manuscript. K.C.J.Y. supervised the project, provided content review, and edited the text. M.M.-G. and T.N.T. contributed equally to the preparation, writing, and submission of the manuscript. M.C.R. was responsible for the clinical management of one of the cases. Y.L.Y.A. contributed to the diagnosis, management, and writing of one of the cases. All authors reviewed and approved the final version of the manuscript.

Funding

All authors declare that they have no known competing financial interests or personal relationships that could appear to influence the work reported in this manuscript.

Disclosures

The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this manuscript.

Informed Patient Consent for Publication

Signed informed consents were obtained directly from the patients.

Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

References

  • 1. Swiatkowska-Stodulska  R, Berlinska  A, Stefanska  K, Klosowski  P, Sworczak  K. Cyclic Cushing’s syndrome—a diagnostic challenge. Front Endocrinol (Lausanne). 2021;12:658429. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2. Shapiro  MS, Shenkman  L. Variable hormonogenesis in Cushing’s syndrome. Q J Med. 1991;79(288):351‐363. [PubMed] [Google Scholar]
  • 3. Alexandraki  KI, Kaltsas  GA, Isidori  AM, et al.  The prevalence and characteristic features of cyclicity and variability in Cushing’s disease. Eur J Endocrinol. 2009;160(6):1011‐1018. [DOI] [PubMed] [Google Scholar]
  • 4. Meinardi  JR, Wolffenbuttel  BH, Dullaart  RP. Cyclic Cushing’s syndrome: a clinical challenge. Eur J Endocrinol. 2007;157(3):245‐254. [DOI] [PubMed] [Google Scholar]
  • 5. McCance  DR, Gordon  DS, Fannin  TF, et al.  Assessment of endocrine function after transsphenoidal surgery for Cushing’s disease. Clin Endocrinol (Oxf). 1993;38(1):79‐86. [DOI] [PubMed] [Google Scholar]
  • 6. Jahandideh  D, Swearingen  B, Nachtigall  LB, Klibanski  A, Biller  BMK, Tritos  NA. Characterization of cyclic Cushing’s disease using late night salivary cortisol testing. Clin Endocrinol (Oxf). 2018;89(3):336‐345. [DOI] [PubMed] [Google Scholar]
  • 7. Nowak  E, Vogel  F, Albani  A, et al.  Diagnostic challenges in cyclic Cushing’s syndrome: a systematic review. Lancet Diabetes Endocrinol. 2023;11(8):593‐606. [DOI] [PubMed] [Google Scholar]
  • 8. Brown  RD, Van Loon  GR, Orth  DN, Liddle  GW. Cushing’s disease with periodic hormonogenesis: one explanation for paradoxical response to dexamethasone. J Clin Endocrinol Metab. 1973;36(3):445‐451. [DOI] [PubMed] [Google Scholar]
  • 9. Sederberg-Olsen  P, Binder  C, Kehlet  H, Neville  AM, Nielsen  LM. Episodic variation in plasma corticosteroids in subjects with Cushing’s syndrome of differing etiology. J Clin Endocrinol Metab. 1973;36(5):906‐910. [DOI] [PubMed] [Google Scholar]
  • 10. Cai  Y, Ren  L, Tan  S, et al.  Mechanism, diagnosis, and treatment of cyclic Cushing’s syndrome: a review. Biomed Pharmacother. 2022;153:113301. [DOI] [PubMed] [Google Scholar]
  • 11. Coates  PJ, Doniach  I, Howlett  TA, Rees  LH, Besser  GM. Immunocytochemical study of 18 tumours causing ectopic Cushing’s syndrome. J Clin Pathol. 1986;39(9):955‐960. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. de Keyzer  Y, Bertagna  X, Lenne  F, Girard  F, Luton  JP, Kahn  A. Altered proopiomelanocortin gene expression in adrenocorticotropin-producing nonpituitary tumors. Comparative studies with corticotropic adenomas and normal pituitaries. J Clin Invest. 1985;76(5):1892‐1898. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13. Oliver  RL, Davis  JR, White  A. Characterisation of ACTH related peptides in ectopic Cushing’s syndrome. Pituitary. 2003;6(3):119‐126. [DOI] [PubMed] [Google Scholar]
  • 14. Atkinson  AB, Chestnutt  A, Crothers  E, et al.  Cyclical Cushing’s disease: two distinct rhythms in a patient with a basophil adenoma. J Clin Endocrinol Metab. 1985;60(2):328‐332. [DOI] [PubMed] [Google Scholar]
  • 15. Atkinson  AB, Kennedy  AL, Carson  DJ, Hadden  DR, Weaver  JA, Sheridan  B. Five cases of cyclical Cushing’s syndrome. Br Med J (Clin Res Ed). 1985;291(6507):1453‐1457. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. Angelousi  A, Nasiri-Ansari  N, Karapanagioti  A, et al.  Expression of clock-related genes in benign and malignant adrenal tumors. Endocrine. 2020;68(3):650‐659. [DOI] [PubMed] [Google Scholar]
  • 17. Hasenmajer  V, Sbardella  E, Sciarra  F, et al.  Circadian clock disruption impairs immune oscillation in chronic endogenous hypercortisolism: a multi-level analysis from a multicentre clinical trial. EBioMedicine. 2024;110:105462. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. Nieman  LK, Biller  BM, Findling  JW, et al.  Treatment of Cushing’s syndrome: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2015;100(8):2807‐2831. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. Bertherat  J. Cushing’s disease: role of bilateral adrenalectomy. Pituitary. 2022;25(5):743‐745. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

https://pmc.ncbi.nlm.nih.gov/articles/PMC12559019/

Filed under: Cushing's, Rare Diseases, symptoms | Tagged: , , , , | Leave a comment »

Survival Probabilities in Patients with Ectopic Cushing’s Syndrome

Posted on June 9, 2025 by MaryO

Abstract

Objective

We aimed to estimate 1- and 5-year survival probabilities in patients with different forms of ectopic Cushing’s syndrome (ECS) and identify factors influencing survival.

Methods

In this systematic review and meta-analysis, we searched the online databases PubMed, Scopus and Web of Science up to October 18th, 2023, for studies reporting survival in patients with ECS. Data extraction and risk of bias assessment were performed by three independent investigators. Primary outcome was survival in patients with ECS and secondary outcome was factors influencing survival.

Results

We included 40 studies with a total of 1148 patients. The pooled mean 1-year survival probability for ECS of mixed etiologies was 78% while the mean pooled 5-year survival probability was 47%. The 5-year survival probabilities for patients with pulmonary neuroendocrine neoplasm (NEN) was 81%, occult ECS 66%, thymic NEN 50% and pancreatic NEN 40%. Only eight studies reported factors influencing survival, where total resection of the primary tumor was associated with better overall survival, and unresectable tumors, metastatic disease at diagnosis, severe hypercortisolism, hypokalemia, and new onset diabetes mellitus were associated with worse prognosis.

Conclusion

Survival in ECS varies considerably, mainly due to the underlying origin of the tumor, tumor stage and severity of the hypercortisolism. Further studies analyzing the importance of factors affecting survival are needed.

Accepted manuscripts
Accepted manuscripts are PDF versions of the author’s final manuscript, as accepted for publication by the journal but prior to copyediting or typesetting. They can be cited using the author(s), article title, journal title, year of online publication, and DOI. They will be replaced by the final typeset articles, which may therefore contain changes. The DOI will remain the same throughout.

This content is only available as a PDF.

Filed under: Cushing's | Tagged: , , , | Leave a comment »

Thymic Neuroendocrine Tumor With Metastasis to the Breast Causing Ectopic Cushing’s Syndrome

Posted on April 9, 2025 by MaryO

Ectopic adrenocorticotropic hormone secretion (EAS) is responsible for approximately 10%–18% of Cushing’s syndrome cases. Thymic neuroendocrine tumors (NETs) comprise 5%–16% of EAS; therefore, they are very rare and the data about this particular tumors is scarce.

We present a case of a 34-year-old woman with a rapid onset of severe hypercortisolism in April 2016. After initial treatment with a steroid inhibitor (ketoconazole) and diagnostics including 68Ga DOTA-TATE PET/CT, it was shown to be caused by a small thymic NET.

After a successful surgery and the resolution of all symptoms, there was a recurrence after 5 years of observation caused by a metastasis to the breast, shown in the 68Ga DOTA-TATE PET/CT result and confirmed with a breast biopsy.

Treatment with a steroid inhibitor (metyrapone) and tumor resection were again curative. The last disease relapse appeared 7 years after the initial treatment, with severe hypercortisolism treated with osilodrostat. There was a local recurrence in the mediastinum, and a thoracoscopic surgery was performed with good clinical and biochemical effect.

The patient remains under careful follow-up. Our case stays in accordance with recent literature data, showing that patients with thymic NETs are younger than previously considered and that the severity of hypercortisolism does not correlate with the tumor size. The symptoms of EAS associated with thymic NET may develop rapidly and may be severe as in our case. Nuclear medicine improves the effectiveness of the tumor search, which is crucial in successful EAS therapy. Our case also underlines the need for lifelong monitoring of patients with thymic NETs and EAS.

1 Introduction

Ectopic adrenocorticotropic hormone secretion (EAS) represents between 9% and 18% of adrenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome (CS) cases (1–3). The tumors secreting ACTH may occur in many locations and present with different histopathological differentiation, resulting in various clinical outcomes. In the past, most of the EAS cases were associated with small cell lung cancer, characterized by rapid tumor progression and unfavorable prognosis. Recently, well-differentiated neuroendocrine tumors (NETs) from the foregut prevail in the clinical series of EAS, with most common locations in the lungs, thymus, and pancreas (1).

EAS is often associated with severe hypercortisolism. Typical Cushing’s appearance may not be present due to the rapid onset of the disease. Patients with this type of hypercortisolism need urgent treatment because they have the highest mortality of all forms of CS (4). A retrospective review of 43 patients with EAS reported deaths in 27 patients (62.8%) and a median overall survival of 32.2 months. The leading causes of mortality were the progression of primary malignancies and systemic infections; two patients died from pulmonary embolism (5).

Prompt surgical removal of the tumor secreting ACTH is the mainstay of the therapy. However, finding the tumor causing EAS can be challenging due to its small size and variety of locations. Most authors recommend a combination of computed tomography (CT) scanning of the chest, abdomen, and pelvis, with additional magnetic resonance imaging (MRI) of the pituitary, as the first-line examinations (1, 6, 7). However, the sensitivity of standard imaging modalities is suboptimal (8). In the analysis of 231 patients with EAS, cross-sectional imaging revealed the source of ACTH in 52.4% of them at initial evaluation, and another 29% was found during follow-up or due to nuclear medicine functional imaging, while 18.6% remained occult (9). Nuclear medicine improves the sensitivity of conventional radiology in the case of EAS, with the use of 18-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/CT (18F-FDG PET/CT) expected to be useful in identifying EAS tumors with high proliferative activity and 68gallium-labeled somatostatin analogues (68Ga DOTA-TATE) PET/CT with the potential to detect NETs. In the head-to-head comparison, the detection rate of the source of EAS was 75% for 68Ga DOTA-TATE and 60% for 18F-FDG PET/CT, while the highest sensitivity (90%) was achieved when both methods were combined (10).

Thymic NETs comprise 2%–5% of all thymic neoplasms and may cause some paraneoplastic syndromes, with the most frequent being myasthenia gravis, syndrome of inappropriate antidiuretic hormone secretion, and hypercortisolism (11). EAS associated with thymic NETs are rare, representing between 5% and 16% of EAS in published case series (1). Because of the rarity and heterogeneity of the disease, no evidence-based guidelines are available.

We present a case of a patient with thymic NET causing EAS, with metastasis to the breast after 5 years of post-surgical remission and another local recurrence 7 years after the first operation.

Our case is unique because thymic NETs causing EAS are known as an aggressive disease with a median recurrence time of 24 months after thymectomy (12). There are only a few cases described of metastases to the breast from thymic NETs causing EAS (13–16). Moreover, 68Ga-SSTR PET/CT was very helpful in detecting both primary and metastatic ectopic ACTH-secreting tumor, which underlines its role in the diagnostic workout of EAS.

2 Case description

A 32-year-old woman with no relevant medical history was admitted to the endocrinology department in April 2016 due to the rapid onset of symptoms: weight gain, hypertension, skin changes, and oligomenorrhoea.

The measurements at initial physical examination were as follows: body mass index (BMI)—29 kg/m2, blood pressure—180/90 mmHg, and heart rate—88/min. She had plethora, acne, moon face, buffalo hump, central obesity, many red striae in the abdominal area, and mild hirsutism. The baseline laboratory findings are presented in Table 1, with hypokalemia, diabetes, leukocytosis, high levels of serum cortisol, ACTH, and chromogranin A, and increased urine-free cortisol (UFC) secretion. There was no suppression of serum cortisol or UFC after a high-dose dexamethasone test. ACTH-dependent CS was diagnosed, and EAS was suspected. The patient’s family history was negative for endocrine diseases or genetic disorders.

Table 1

www.frontiersin.org

Table 1. Laboratory results at diagnosis (April 2016).

The first-line cross-sectional imaging studies (chest, abdomen, and pelvis CT and MRI of the pituitary gland) did not reveal the source of ACTH. Only a symmetrical enlargement of adrenals was observed. 68Ga DOTA-TATE PET/CT revealed an oval lesion in the anterior mediastinum (1.9 × 1.3 cm) with a subtle overexpression of somatostatin receptors (SUV max. 2.8, Figures 1A, B). The chest MRI confirmed a mass 1.5 × 2.0 × 2.5 cm, with high T2-weighted signal and high contrast enhancement, suggestive of NET. The patient was given ketoconazole (600 mg daily), spironolactone, potassium supplementation, antihypertensive drugs, and thromboembolic prophylaxis. In June 2016, thoracoscopic removal of the mediastinal tumor was performed. In the histopathological examination, the tumor was encapsulated, without evidence of invasion, and no lymph node metastases were described. The immunophenotype of the tumor was as follows: CgA (+), Syn (+), CKAE1+E3 (+) “dot-like”, S100 (-), calcitonin (-), EMA (+/-), Ki67 3% to 4% in hot spots, no necrosis, mitotic index 0/10HPF with conclusion: thymic NET—typical carcinoid (low-grade). The presence of paraganglioma was also taken into consideration, as such cases were described (17). However, the significant reaction with cytokeratin and lack of S100 protein expression made this diagnosis less probable.

Figure 1

www.frontiersin.org

Figure 1. 68Ga-DOTATATE PET/CT scans. (A, B) Before the first surgery (April 2016). (C, D) Before the second surgery (May 2021). (E, F) Before the third surgery (January 2023).

The postoperative morning serum cortisol concentration was below 5 µg/dL, indicating biochemical remission. The patient received hydrocortisone substitution for a month. The clinical signs of CS disappeared, and there was a normalization of UFC.

During 5 years of follow-up, the patient got pregnant and delivered a healthy child. Genetic counseling was performed, and no germline mutation of MEN1 gene was identified. Other clinical manifestations of MEN1 (like primary hyperparathyroidism and pituitary secreting tumors) were excluded.

In May 2021, the patient experienced a sudden recurrence of CS symptoms. The laboratory findings confirmed severe hypercortisolism (Table 2); therefore, treatment with steroid inhibitor metyrapone was administered. The patient tolerated only 750 mg daily; there were side effects (skin rash and tachycardia) with higher doses. The chest MRI revealed no recurrence in the location of the primary tumor, only a lesion in the right breast (1.2 × 1.0 × 1.1 cm) with atypical contrast enhancement. The 68Ga-DOTA-TATE PET/CT result showed a subtle overexpression of the tracer (SUV max 1.9) in the right breast (Figures 1C, D). Breast ultrasonography confirmed a hypoechogenic, hypervascular mass in the right breast, BIRADS 3/4, diagnosed as NET in the breast biopsy. The tumor was removed in July 2021 without complications. The histopathological samples were compared with the primary lesion, confirming the metastasis from thymic NET to the breast—tumor size 0.7 × 1.5 cm, clear surgical margins (8 mm) with Ki67 3% (NET G2), and no lymph node metastases. After the breast surgery, the cortisol levels normalized in blood and urine and the CS symptoms disappeared. 18F-FDG PET/CT and 68Ga-DOTA-TATE PET/CT were performed, showing no pathological increase of radiotracer uptake in post-operative locations or mediastinal lymph nodes. The patient consulted with the oncology team, and no adjuvant therapy was recommended.

Table 2

www.frontiersin.org

Table 2. Laboratory results during 7 years of observation.

The next recurrence of the disease occurred in February 2023, with the symptoms developing suddenly during a very short period (1 to 2 weeks), additionally with significant mental deterioration (concentration disorders, anxiety, severe mood swing). The laboratory findings confirmed excessive hypercortisolism (Table 2). The patient was given osilodrostat (the initial dose was 20 mg daily but later reduced to 10 mg daily for 2 weeks until surgery) and symptomatic treatment with good clinical and biochemical effect. The 68Ga-DOTA-TATE PET/CT result showed a slightly increased uptake of the tracer in the left mediastinum, between cervical vessels, 0.9 × 1.2 cm (Figures 1E, F)—probably a local recurrence. Thoracotomy was performed in February 2023, with subsequent clinical and biochemical improvement (Table 2). In the histopathological examination, mediastinal NET G1 was diagnosed, without necrosis, mitotic activity 0/2 mm2, immunophenotype CgA (+), CD56 (+), Ki 67 1%, CK AE1/AE3 (+), CD117 (+), p40 (-), TdT (-), PAX8 (-), and the presence of tumor cell embolism in the vessels. One metastatic lesion was found in the pericardium (the maximal dimension of the tissue was 13 mm, resected radically). Two metastatic lesions in the fat tissue were found (one tissue fragment from the mediastinum, max. 16 mm diameter, and the second tissue fragment was surrounding the jugular vein, max. diameter up to 40 mm, both resected radically). Two of the 10 resected lymph nodes had metastatic lesions: one from the area of the jugular vein, diameter 11 mm, with capsular invasion, and the second lymph node N2R with capsular invasion, both resected radically. The symptoms of hypercortisolism disappeared, and the cortisol values were normalized after the operation. The patient is currently under careful monitoring, without signs of clinical or biochemical recurrence. 68Ga-DOTA-TATE PET/CT is performed every 6 months.

3 Discussion

Our case is representative for thymic NETs causing EAS presented in literature, but it also shows some distinct features, giving new insight into this rare condition.

In recent series, ACTH-secreting thymic NETs occurred often in young adults, like our patient. The typical age of presentation is 21–35 years in the largest case series, and 7.4% were children under 15 years (12, 13). In contrast, the former series of thymic NETs showed a peak incidence in the sixth decade of life (11).

ACTH-secreting thymic NETs show a slight male preponderance (58.6%); however, the patient’s gender does not seem to relate with the disease outcome (12). There was only an association between male sex and larger tumor size preoperatively as found in one case series (13).

Thymic NETs causing EAS are very rarely associated with MEN1; we have also excluded it in our patient. On the contrary, 30% of thymic NETs not associated with CS are found in patients with MEN1, mostly male smokers (18). It is not clear why thymic NETs with EAS are less likely caused by MEN1 gene mutation, but the possibility of this genetic predisposition should always be taken into consideration.

Thymic NETs associated with EAS are generally considered aggressive, presenting significant cellular atypia in the histopathological examination (19). However, the biology of the tumors is variable. In the histopathological examination of 92 thymic NETs secreting ACTH, the most common subtype was atypical NET (46.7%), while 30.4% of the cases were typical NETs and 21.7% were carcinomas, with the median Ki-67 10%, ranging from 1% to 40%. The median tumor size among 112 patients was 4.7 cm, ranging from 1 to 20 cm, and 55.7% of patients had metastases at presentation (12). It proves the significant heterogeneity of the disease.

Our patient had typical NET with small dimensions and localized disease at the time of diagnosis. Despite this, we observed aggressive Cushing’s syndrome with a short duration of symptoms and life-threatening hypokalemia. It has been observed that there is no correlation between tumor size and hormone levels (12). Thymic NETs associated with EAS are often large, which simplifies the diagnosis and localization. However, in the case of incidental sellar mass or small thymic tumor, the differential diagnosis might be difficult. The highest sensitivity in distinguishing thymic EAS from Cushing’s disease was documented in inferior petrosal sinus sampling and corticotropin-releasing hormone (CRH) stimulation test (12, 20).

In severe cases, when small ACTH-secreting NET needs to be found urgently, PET/CT is a very helpful diagnostic tool. In a prospective study comprising 20 patients with histologically proven EAS, the 68Ga-DOTATATE PET/CT result correctly identified the tumor in 75%, with SUV max. ranging from 1.4 to 20.7, while the 18F-FDG PET/CT findings had a slightly worse result (identified 60% tumors), with SUV max. ranging from 1.8 to 10.0. Those methods are believed to be complementary in case of localization and discrimination of EAS. The 68Ga-DOTATATE PET/CT result revealed tumor in six cases with a negative 18F-FDG PET/CT result, while the 18F-FDG PET/CT procedure was diagnostic in three cases with a negative 68Ga-DOTATATE uptake; the combined sensitivity of both methods was 90% (10). The typical first-line diagnostic modalities’ (CT and MRI) sensitivities range from 52% to 66% (9). Our case remains in accordance with those results, showing difficulties in localizing the ACTH source in first-line radiological methods and with 68Ga-DOTATATE PET/CT being the most useful diagnostic tool. It should also be noted that the 68Ga-DOTATATE uptake was only mildly elevated both in primary tumor and its recurrences despite excessive hormonal activity. We did not perform 18F-FDG PET/CT until second operation, as it was believed to be rather helpful in poorly differentiated tumors and 68Ga-DOTATATE PET/CT was diagnostic. Later, we performed it in search for other metastatic tumors, but the examination showed no tumor spread.

The recommended treatment of thymic NETs regarded radically resectable is thymectomy by median sternotomy or thoracotomy and lymph node dissection (11, 21, 22). According to the last version of the ESMO Guidelines, available literature suggests no benefit from adjuvant therapy in ThCs. The majority of the authors of the Guidelines panel suggest individually discussing eventual postoperative therapies, including RT and/or systemic therapies, balancing the pros and cons only in selected patients with advanced stage R0 or R1-2 resection (22). Data on systemic therapies in thymic NETs are scarce; therefore, they should be discussed in a multidisciplinary expert team in case of morphologically progressive tumors, high tumor burden, or refractory hormonal syndromes. Somatostatin analogs are recommended as the first-line systemic therapy in typical carcinoids (22). We considered the adjuvant therapy with somatostatin analogs; however, due to the low uptake in PET examination and complete resolution of symptoms as well as the radical type of surgical removal, we did not decide to initiate such therapy. Other systemic treatment options include everolimus (second line in typical carcinoids or first line in atypical carcinoids), chemotherapy, peptide receptor radionuclide therapy (PRRT), and interferon-α (22, 23). There is also data on the benefits of combining long-acting lanreotide with temozolomide in progressive thymic NETs (24).

Due to the variable availability of steroid inhibitors during the course of the disease, our patient received three different preparations at each disease relapse. Both ketoconazole and osilodrostat were well tolerated and reduced the hypercortisolism within a few days, but metyrapone caused significant side effects (see below—”Patient’s perspective”), and it was not possible to normalize the cortisol values with this steroid inhibitor. It is worth noting that when using the most recent steroid inhibitor—osilodrostat—we initiated the therapy with a high dose without a previous dose titration. This strategy might be used in the case of severe hypercortisolism and proved effective and safe in our patient (25).

Most commonly, metastases from thymic NET producing ACTH are localized in lymph nodes, bone, lung, pleura, and, less commonly, liver and parotid gland (13). There are very few cases of EAS-related thymic NETs with breast metastases described in the literature, with some histopathological variability (one case related to atypical carcinoid, another to combined large-cell neuroendocrine carcinoma and atypical carcinoid, and third case of neuroendocrine carcinoma). All of them were female patients between 24 and 36 years of age, with mediastinal lymph nodes metastases at the time of presentation; one also had distant metastases to the bones (13–15). Contrary to the reported cases, our patient had typical carcinoid (confirmed by three independent pathologists from different centers) but similarly presented with severe hypercortisolism. It suggests that there is no connection between tumor differentiation and the severity of hypercortisolism. Interestingly, in a review of 661 patients with metastatic NETs from Sweden, there were 20 patients with NETs and breast metastases, and among them only one case of thymic NET (Ki 67 12%), but without EAS. A total of 11 patients with breast metastases had a primary tumor in the small intestine and eight in the lung (16).

Our case underlines the necessity of long-term follow-up in EAS, as the recurrences occurred 5 and 7 years after the initial successful treatment. According to guidelines, follow-up after treatment of thymic NETs should be life-long (22).

The strength of our report is the presentation of a thymic NET with metastasis to the breast, diagnosed and treated with many currently available tools and with a long period of follow-up. The limitation is the low number of other similar cases to compare, which is a consequence of the rarity of this disease.

In conclusion, our case proves that thymic NETs with EAS might present in young patients with well-differentiated character in histopathological examination and severe, life-threatening hypercortisolism despite the small size of the primary lesion. 68Ga-DOTATATE PET/CT is a very helpful tool to localize the tumor. Finally, life-long follow-up should be performed despite complete remission after surgery.

4 Patient’s perspective

The first symptoms that I observed were face edema and mood changes. I rapidly lost muscle mass (approximately 6 kg in 2 weeks), and I was not able to climb stairs, especially with my child’s pram. The most difficult to accept were changes in my appearances—hirsutism, losing hair, changes of my facial features. My sense of pain (for example, during medical procedures) was diminished. Other disruptive symptoms were intensive sweating, increased appetite, thirst, brain fog, and digestive problems. At every relapse, the disease manifestations were fluctuating, all of them intensifying at the same time, which was very difficult for me. Also stress evoked disease symptoms. I experienced a strange feeling of warm during cortisol outbursts.

As for the treatment, I did not tolerate metyrapone well. I had skin rash, anxiety attacks with heart palpitations, and a metallic taste in my mouth. Other drugs (ketoconazole, osilodrostat) were better for me.

After operations of the relapses, the symptoms diminished very quickly, especially the most difficult ones. My blood pressure and glycemia normalized within a few days. Other manifestations, like loss of hair or skin changes, persisted up to 3 months.

Data availability statement

The datasets presented in this article are not readily available because the data are potentially identifiable. Requests to access the datasets should be directed to Aleksandra Zdrojowy-Wełna, aleksandra.zdrojowy-welna@umw.edu.pl.

Ethics statement

This study was exempt from ethical approval procedures being a case report of a single patient who has voluntarily provided oral and written consent to participate in the study and to have her case published for the sake of helping us better understand the clinical picture and the course of thymic neuroendocrine tumors with EAS and share it with the medical community for awareness about it. Written informed consent was obtained from the participant/patient(s) for the publication of this case report.

Author contributions

AZ-W: Conceptualization, Data curation, Investigation, Methodology, Software, Writing – original draft. MB: Conceptualization, Supervision, Writing – review & editing. JS: Data curation, Investigation, Methodology, Writing – review & editing. AJ-P: Data curation, Investigation, Writing – review & editing. JK-P: Conceptualization, Data curation, Investigation, Methodology, Supervision, Writing – original draft.

Funding

The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.

Acknowledgments

We would like to thank Prof. Barbara Górnicka and Prof. Michał Jeleń for their collaboration throughout the patient’s treatment.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The handling editor AJ declared a past co-authorship with the author MB.

The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

 

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2025.1492187/full#supplementary-material

References

1. Young J, Haissaguerre M, Viera-Pinto O, Chabre O, Baudin E, Tabarin A. Management of endocrine disease: Cushing’s syndrome due to ectopic ACTH secretion: an expert operational opinion. Eur J Endocrinol. (2020) 182:29–58. doi: 10.1530/EJE-19-0877

PubMed Abstract | Crossref Full Text | Google Scholar

2. Feelders R, Sharma S, Nieman L. Cushing`s syndrome: epidemiology and developments in disease management. Clin Epidemiol. (2015) 7:281–93. doi: 10.2147/CLEP.S44336

PubMed Abstract | Crossref Full Text | Google Scholar

3. Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushing’s syndrome. Lancet Lond Engl. (2015) 386:913–27. doi: 10.1016/S0140-6736(14)61375-1

PubMed Abstract | Crossref Full Text | Google Scholar

4. Javanmard P, Duan D, Geer EB. Mortality in patients with endogenous cushing’s syndrome. Endocrinol Metab Clin North Am. (2018) 47:313–33. doi: 10.1016/j.ecl.2018.02.005

PubMed Abstract | Crossref Full Text | Google Scholar

5. Ejaz S, Vassilopoulou-Sellin R, Busaidy NL, Hu MI, Waguespack SG, Jimenez C, et al. Cushing syndrome secondary to ectopic adrenocorticotropic hormone secretion: the University of Texas MD Anderson Cancer Center Experience. Cancer. (2011) 117:4381–9. doi: 10.1002/cncr.v117.19

PubMed Abstract | Crossref Full Text | Google Scholar

6. Sookur PA, Sahdev A, Rockall AG, Isidori AM, Monson JP, Grossman AB, et al. Imaging in covert ectopic ACTH secretion: a CT pictorial review. Eur Radiol. (2009) 19:1069–78. doi: 10.1007/s00330-008-1274-5

PubMed Abstract | Crossref Full Text | Google Scholar

7. Yogi-Morren D, Habra MA, Faiman C, Bena J, Hatipoglu B, Kennedy L, et al. Pituitary MRI findings in patients with pituitary and ectopic ACTH-dependent cushing syndrome: does A 6- mm pituitary tumor size cut-off value exclude ectopic acth syndrome? Endocr Pract. (2015) 21:1098–103. doi: 10.4158/EP15662.OR

PubMed Abstract | Crossref Full Text | Google Scholar

8. Ilias I, Torpy DJ, Pacak K, Mullen N, Wesley RA, Nieman LK. Cushing’s syndrome due to ectopic corticotropin secretion: twenty years’ Experience at the national institutes of health. J Clin Endocrinol Metab. (2005) 90:4955–62. doi: 10.1210/jc.2004-2527

PubMed Abstract | Crossref Full Text | Google Scholar

9. Isidori AM, Sbardella E, Zatelli MC, Boschetti M, Vitale G, Colao A, et al. Conventional and nuclear medicine imaging in ectopic cushing’s syndrome: A systematic review. J Clin Endocrinol Metab. (2015) 100:3231–44. doi: 10.1210/JC.2015-1589

PubMed Abstract | Crossref Full Text | Google Scholar

10. Liu Q, Zang J, Yang Y, Ling Q, Wu H, Wang P, et al. Head-to-head comparison of 68Ga- DOTATATE PET/CT and 18F-FDG PET/CT in localizing tumors with ectopic adrenocorticotropic hormone secretion: a prospective study. Eur J Nucl Med Mol Imaging. (2021) 48:4386–95. doi: 10.1007/s00259-021-05370-8

PubMed Abstract | Crossref Full Text | Google Scholar

11. Gaur P, Leary C, Yao JC. Thymic neuroendocrine tumors: a SEER database analysis of 160 patients. Ann Surg. (2010) 251:1117–21. doi: 10.1097/SLA.0b013e3181dd4ec4

PubMed Abstract | Crossref Full Text | Google Scholar

12. Guerrero-Pérez F, Peiró I, Marengo AP, Teulé A, Ruffinelli JC, Llatjos R, et al. Ectopic Cushing’s syndrome due to thymic neuroendocrine tumours: a systematic review. Rev Endocr Metab Disord. (2021) 22:1041–56. doi: 10.1007/s11154-021-09660-2

PubMed Abstract | Crossref Full Text | Google Scholar

13. Neary NM, Lopez-Chavez A, Abel BS, Boyce AM, Schaub N, Kwong K, et al. Neuroendocrine ACTH-producing tumor of the thymus—Experience with 12 patients over 25 years. J Clin Endocrinol Metab. (2012) 97:2223–30. doi: 10.1210/jc.2011-3355

PubMed Abstract | Crossref Full Text | Google Scholar

14. Dzialach L, Wojciechowska-Luzniak A, Maksymowicz M, Witek P. Case report: A challenging case of severe Cushing’s syndrome in the course of metastatic thymic neuroendocrine carcinoma with a synchronous adrenal tumor. Front Endocrinol. (2024). doi: 10.3389/fendo.2024.1399930/full

PubMed Abstract | Crossref Full Text | Google Scholar

15. Gaur S, Ayyappan AP, Nahleh Z. Breast metastases from an adrenocorticotropic hormone secreting thymic neuro-endocrine tumor. Breast Dis. (2013) 34:81–6. doi: 10.3233/BD-130354

PubMed Abstract | Crossref Full Text | Google Scholar

16. Crona J, Granberg D, Norlén O, Wärnberg F, Stålberg P, Hellman P, et al. Metastases from neuroendocrine tumors to the breast are more common than previously thought. A diagnostic pitfall? World J Surg. (2013) 37:1701–6. doi: 10.1007/s00268-013-2037-2

PubMed Abstract | Crossref Full Text | Google Scholar

17. Li B, Yan Z, Huang H. Case report: an unusual case of ectopic ACTH syndrome caused by mediastinal paraganglioma. Front Endocrinol. (2021) 12:790975. doi: 10.3389/fendo.2021.790975

PubMed Abstract | Crossref Full Text | Google Scholar

18. Ferolla P, Falchetti A, Filosso P, Tomassetti P, Tamburrano G, Avenia N, et al. Thymic neuroendocrine carcinoma (carcinoid) in multiple endocrine neoplasia type 1 syndrome: the Italian series. J Clin Endocrinol Metab. (2005) 90:2603–9. doi: 10.1210/jc.2004-1155

PubMed Abstract | Crossref Full Text | Google Scholar

19. Moran CA, Suster S. Neuroendocrine carcinomas (Carcinoid tumor) of the thymus. Am J Clin Pathol. (2000) 114:100–10. doi: 10.1309/3PDN-PMT5-EQTM-H0CD

PubMed Abstract | Crossref Full Text | Google Scholar

20. Kakade HR, Kasaliwal R, Jagtap VS, Bukan A, Budyal SR, Khare S, et al. Ectopic acth- secreting syndrome: A single-center experience. Endocr Pract. (2013) 19:1007–14. doi: 10.4158/EP13171.OR

PubMed Abstract | Crossref Full Text | Google Scholar

21. Girard N. Neuroendocrine tumors of the thymus: the oncologist point of view. J Thorac Dis. (2017) 9:1491–500. doi: 10.21037/jtd.2017.08.18

PubMed Abstract | Crossref Full Text | Google Scholar

22. Baudin E, Caplin M, Garcia-Carbonero R, Fazio N, Ferolla P, Filosso PL, et al. Lung and thymic carcinoids: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol Off J Eur Soc Med Oncol. (2021) 32:439–51. doi: 10.1016/j.annonc.2021.01.003

PubMed Abstract | Crossref Full Text | Google Scholar

23. Ferolla P, Brizzi MP, Meyer T, Mansoor W, Mazieres J, Do Cao C, et al. Efficacy and safety of long-acting pasireotide or everolimus alone or in combination in patients with advanced carcinoids of the lung and thymus (LUNA): an open-label, multicentre, randomised, phase 2 trial. Lancet Oncol. (2017) 18:1652–64. doi: 10.1016/S1470-2045(17)30681-2

PubMed Abstract | Crossref Full Text | Google Scholar

24. Ferolla P, Berruti A, Spada F, Brizzi MP, Ibrahim T, Marconcini R, et al. Efficacy and safety of lanreotide autogel and temozolomide combination therapy in progressive thoracic neuroendocrine tumors (Carcinoid): results from the phase 2 ATLANT study. Neuroendocrinology. (2023) 113:332–42. doi: 10.1159/000526811

PubMed Abstract | Crossref Full Text | Google Scholar

25. Fleseriu M, Biller BMK. Treatment of Cushing’s syndrome with osilodrostat: practical applications of recent studies with case examples. Pituitary. (2022) 25:795–809. doi: 10.1007/s11102-022-01268-2

PubMed Abstract | Crossref Full Text | Google Scholar

Keywords: ectopic Cushing`s syndrome, thymic neuroendocrine tumor, thymic NET, ectopic ACTH secretion, case report

Citation: Zdrojowy-Wełna A, Bolanowski M, Syrycka J, Jawiarczyk-Przybyłowska A and Kuliczkowska-Płaksej J (2025) Case Report: Thymic neuroendocrine tumor with metastasis to the breast causing ectopic Cushing’s syndrome. Front. Oncol. 15:1492187. doi: 10.3389/fonc.2025.1492187

Received: 11 September 2024; Accepted: 31 January 2025;
Published: 25 February 2025.

Edited by:

Aleksandra Gilis-Januszewska, Jagiellonian University Medical College, Poland

Reviewed by:

Piero Ferolla, Umbria Regional Cancer Network, Italy
Lukasz Dzialach, Warsaw Medical University, Poland

Copyright © 2025 Zdrojowy-Wełna, Bolanowski, Syrycka, Jawiarczyk-Przybyłowska and Kuliczkowska-Płaksej. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Aleksandra Zdrojowy-Wełna, aleksandra.zdrojowy-welna@umw.edu.pl

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

95% of researchers rate our articles as excellent or good

Learn more about the work of our research integrity team to safeguard the quality of each article we publish.

Find out more

People also looked at

Supplementary Material
  • Data Sheet 1.pdf

Filed under: Cushing | Tagged: , , , , , , , , , , | Leave a comment »

Delayed Diagnosis of Ectopic Cushing Syndrome

Posted on April 3, 2024 by MaryO

Abstract

Here, we present the case of a 40-year-old man in whom the diagnosis of ectopic adrenocorticotropin (ACTH) syndrome went unrecognized despite evaluation by multiple providers until it was ultimately suspected by a nephrologist evaluating the patient for edema and weight gain. On urgent referral to endocrinology, screening for hypercortisolism was positive by both low-dose overnight dexamethasone suppression testing and 24-hour urinary free cortisol measurement. Plasma ACTH values confirmed ACTH-dependent Cushing syndrome. High-dose dexamethasone suppression testing was suggestive of ectopic ACTH syndrome. Inferior petrosal sinus sampling demonstrated no central-to-peripheral gradient, and 68Ga-DOTATATE scanning revealed an avid 1.2-cm left lung lesion. The suspected source of ectopic ACTH was resected and confirmed by histopathology, resulting in surgical cure. While many patients with Cushing syndrome have a delayed diagnosis, this case highlights the critical need to increase awareness of the signs and symptoms of hypercortisolism and to improve the understanding of appropriate screening tests among nonendocrine providers.

Introduction

Even in the face of overt clinical signs and symptoms of hypercortisolism, diagnosing Cushing syndrome requires a high index of suspicion, and people with hypercortisolism experience a long road to diagnosis. In a recent meta-analysis including more than 5000 patients with Cushing syndrome, the mean time to diagnosis in all Cushing syndrome, including Cushing disease and ectopic adrenocorticotropin (ACTH) syndrome, was 34 months (1). Reasons for delayed diagnosis are multifactorial, including the nonspecific nature of subjective symptoms and objective clinical signs, as well as notorious challenges in the interpretation of diagnostic testing. Furthermore, the health care system’s increasingly organ-specific referral patterns obfuscate multisystem disorders. Improving the recognition of and decreasing time to diagnosis in Cushing syndrome are critical factors in reducing morbidity and mortality.

Here, we present the case of a patient who, despite classic signs of Cushing syndrome as well as progressive physical and mental decline, remained undiagnosed for more than 3 years while undergoing repeated evaluation by primary care and subspecialty providers. The case (1) highlights the lack of awareness of Cushing syndrome as a potential unifying diagnosis for multiorgan system problems; (2) underscores the necessity of continued education on the signs and symptoms of hypercortisolism, appropriate screening for hypercortisolism, and early referral to endocrinology; and (3) provides an opportunity for systemic change in clinical laboratory practice that could help improve recognition of pathologic hypercortisolism.

Case Presentation

In August 2018, a previously healthy 40-year-old man with ongoing tobacco use established care with a primary care provider complaining that he had been ill since the birth of his son 13 months prior. He described insomnia, headaches, submandibular swelling, soreness in his axillary and inguinal regions, and right-sided chest discomfort (Fig. 1). Previously, he had been diagnosed with sinusitis, tonsillitis, and allergies, which had been treated with a combination of antibiotics, antihistamines, and intranasal glucocorticoids. He was referred to otolaryngology where, in the absence of cervical lymphadenopathy, he was diagnosed with sternocleidomastoid pain with recommendations to manage conservatively with stretching and massage. A chest x-ray demonstrated a left apical lung nodule. Symptoms continued unabated throughout 2019, now with a cough. Repeat chest x-ray demonstrated opacities lateral to the left hilum that were attributed to vascular structures.

 

Figure 1.

Timeline of development of subjective symptoms and objective clinical findings preceding diagnosis and surgical cure of ectopic Cushing syndrome.

In May 2020, increasingly frustrated with escalating symptoms, the patient transitioned care to a second primary care provider and was diagnosed with hypertension. He complained of chronic daily headaches that prompted brain imaging with magnetic resonance imaging (MRI), which noted findings consistent with left maxillary silent sinus syndrome. He was sent back to otolaryngology, which elected to proceed with sinus surgery. During this time, he suffered a fibular fracture for which he was evaluated by orthopedic surgery. In the second half of 2020, he was seen by neurology to evaluate his chronic headaches and paresthesias with electromyography demonstrating a left ulnar mononeuropathy consistent with cubital tunnel syndrome. His primary care provider diagnosed him with fibromyalgia for which he started physical therapy, and he was referred to a pain clinic for cognitive behavioral therapy. Unfortunately his wife, dealing with her husband’s increasing cognitive and personality changes including irritability and aggression, filed for divorce.

At the end of 2020, the patient developed bilateral lower extremity edema and was prescribed hydrochlorothiazide, subsequently developing hypokalemia attributed to diuretic use. With worsening bilateral lower extremity edema and new dyspnea on exertion, he was evaluated for heart failure with an echocardiogram, which was unremarkable. Over the next several months, he gained approximately 35 pounds (∼16 kg). It was in the setting of weight gain that he was first evaluated for hypercortisolism with random serum cortisol of 22.8 mcg/dL (629 nmol/L) and 45.6 mcg/dL (1258 nmol/L) in the late morning and mid-day, respectively. No reference range was provided for the times of day at which these laboratory values were drawn. Although these serum cortisol values were above provided reference ranges for other times of day, they were not flagged as abnormal by in-house laboratory convention, and they were overlooked. The search for other etiologies of his symptoms continued.

In early 2021, diuretic therapy and potassium supplementation were escalated for anasarca. He developed lower extremity cellulitis and received multiple courses of antibiotics. Skin biopsy performed by dermatology demonstrated disseminated Mycobacterium and later Serratia (2), prompting referral to infectious disease for management. Additional subspecialty referrals included rheumatology (polyarthralgia) and gastroenterology (mildly elevated alanine transaminase with planned liver biopsy). In July 2021, he was evaluated for edema by nephrology, where the constellation of subjective symptoms and objective data including hypertension, central weight gain, abdominal striae, fracture, edema, easy bruising, medication-induced hypokalemia, atypical infections, and high afternoon serum cortisol were noted, and the diagnosis of Cushing syndrome was strongly suspected. Emergent referral to endocrinology was placed.

Diagnostic Assessment

At his first clinic visit with endocrinology in June 2021, the patient’s blood pressure was well-controlled on benazepril. Following weight gain of 61 pounds (∼28 kg) in the preceding 2 years, body mass index was 33. Physical examination demonstrated an ill-appearing gentleman with dramatic changes when compared to prior pictures (Fig. 2), including moon facies, dorsocervical fat pad, violaceous abdominal striae, weeping lower extremity skin infections, an inability to stand without assistance from upper extremities, and depressed mood with tangential thought processes.

 

Figure 2.

Photographic representation of physical changes during the years leading up to diagnosis of ectopic Cushing syndrome in June 2021 and after surgical resection of culprit lesion.

Diagnostic workup for hypercortisolism included a morning cortisol of 33.4 mcg/dL (922 nmol/L) (normal reference range, 4.5-22.7 mcg/dL) and ACTH of 156 pg/mL (34 pmol/L) (normal reference range, 7.2-63 pg/mL) following bedtime administration of 1-mg dexamethasone, and 24-hour urine free cortisol of 267 mcg/24 hours (737 nmol/24 hours) (normal reference range, 3.5-45 mcg/24 hours). Morning serum cortisol and plasma ACTH following bedtime administration of 8-mg dexamethasone were 27.9 mcg/dL (770 nmol/L) and 98 pg/mL (22 pmol/L), respectively. Given concern for potential decompensation, he was hospitalized for expedited work-up. Brain MRI did not demonstrate a pituitary lesion (Fig. 3), and inferior petrosal sinus sampling under desmopressin stimulation showed no central-to-peripheral gradient (Table 1). He underwent a positron emission tomography–computed tomography 68Ga-DOTATATE scan that demonstrated a 1.2-cm left pulmonary nodule with radiotracer uptake (Fig. 4).

 

Figure 3.

A, Precontrast and B, postcontrast T1-weighted sagittal magnetic resonance imaging of the sella. Images were affected by significant motion degradation, precluding clear visualization of the pituitary gland on coronal imaging.

 

Figure 4.

68Ga-DOTATATE imaging. A, Coronal and B, axial views of the chest after administration of radiopharmaceutical. Arrow in both panels indicates DOTATATE-avid 1.2-cm left lung lesion.

 
Table 1.

Bilateral petrosal sinus and peripheral adrenocorticotropin levels preintravenous and postintravenous injection of desmopressin acetate 10 mcg

Time post DDAVP, min Left petrosal ACTH Left petrosal:peripheral ACTH Right petrosal ACTH Right petrosal:peripheral ACTH Peripheral ACTH Left:right petrosal ACTH
0 172 pg/mL
(37.9 pmol/L)		 1.1 173 pg/mL
(38.1 pmol/L)		 1.2 150 pg/mL
(33.0 pmol/L)		 1.0
3 288 pg/mL
(63.4 pmol/L)		 1.8 292 pg/mL
(64.3 pmol/L)		 1.8 162 pg/mL
(35.7 pmol/L)		 1.0
5 348 pg/mL
(76.6 pmol/L)		 1.8 341 pg/mL
(75.1 pmol/L)		 1.8 191 pg/mL
(42.1 pmol/L)		 1.0
10 367 pg/mL
(80.8 pmol/L)		 1.3 375 pg/mL
(82.6 pmol/L)		 1.3 278 pg/mL
(61.2 pmol/L)		 1.0

Abbreviations: ACTH, adrenocorticotropin; DDAVP, desmopressin acetate.

Treatment

The patient was started on ketoconazole 200 mg daily for medical management of ectopic ACTH-induced hypercortisolism while awaiting definitive surgical treatment. Within a month of initial endocrinology evaluation, he underwent thoracoscopic left upper lobe wedge resection with intraoperative frozen histopathology section consistent with a well-differentiated neuroendocrine tumor and final pathology consistent with a well-differentiated neuroendocrine tumor. Staining for ACTH was positive (Fig. 5). Postoperative day 1 morning cortisol was 1.4 mcg/dL (39 nmol/L) (normal reference range, 4.5-22.7 mcg/dL). He was started on glucocorticoid replacement with hydrocortisone and was discharged from his surgical admission on hydrocortisone 40 mg in the morning and 20 mg in the afternoon.

 

Figure 5.

Lung tumor histopathology. A, The tumor was epicentered around a large airway (asterisk) and showed usual architecture for carcinoid tumor. B, The tumor cells had monomorphic nuclei with a neuroendocrine chromatin pattern, variably granulated cytoplasm, and a delicate background vascular network. By immunohistochemistry, the tumor cells were strongly positive for C, synaptophysin; D, CAM5.2; and E, adrenocorticotropin. F, Ki-67 proliferative index was extremely low (<1%).

Outcome and Follow-up

Approximately 12 days after discharge, the patient was briefly readmitted from the skilled nursing facility where he was receiving rehabilitation due to a syncopal event attributed to hypovolemia. This was felt to be secondary to poor oral intake in the setting of both antihypertensive and diuretic medications as well as an episode of emesis earlier in the morning precluding absorption of his morning hydrocortisone dose. Shortly after this overnight admission, he was discharged from his skilled nursing facility to home. In the first month after surgery, he lost approximately 30 pounds (∼14 kg) and had improvements in sleep and mood.

Eight months after surgery, hydrocortisone was weaned to 10 mg daily. Cosyntropin stimulation testing holding the morning dose showed 1 hour cortisol 21.5 mcg/dL (593 nmol/L). Hydrocortisone was subsequently discontinued. In June 2022, 1 year following surgery, 3 sequential midnight salivary cortisol tests were undetectable. At his last visit with endocrinology in June 2023, he felt well apart from ongoing neuropathic pain in his feet and continued but improved mood disturbance. Though his health has improved dramatically, he continues to attribute his divorce and substantial life disruption to his undiagnosed hypercortisolism.

Discussion

Endogenous neoplastic hypercortisolism encompasses a clinical spectrum from subclinical disease, as is common in benign adrenal cortical adenomas, to overt Cushing syndrome of adrenal, pituitary, and ectopic origin presenting with dramatic clinical manifestations (3) and long-term implications for morbidity and mortality (4). Even in severe cases, a substantial delay in diagnosis is common. In this case, despite marked hypercortisolism secondary to ectopic ACTH syndrome, the patient’s time from first symptoms to diagnosis was more than 3 years, far in excess of the typical time to diagnosis in this subtype, noted to be 14 months in 1 study (1).

He initially described a constellation of somatic symptoms including subjective neck swelling, axillary and inguinal soreness, chest discomfort, and paresthesias, and during the year preceding diagnosis, he developed hypertension, fibular fracture, mood changes, weight gain, peripheral edema, hypokalemia, unusual infections, and abdominal striae. Each of these symptoms in isolation is a common presentation in the primary care setting, therefore the challenge arises in distinguishing common, singular causes from rare, unifying etiologies, especially given the present epidemics of diabetes, obesity, and associated cardiometabolic abnormalities. By Endocrine Society guidelines, the best discriminatory features of Cushing syndrome in the adult population are facial plethora, proximal muscle weakness, abdominal striae, and easy bruising (5). Furthermore, Endocrine Society guidelines suggest evaluating for Cushing disease when consistent clinical features are present at a younger-than-expected age or when these features accumulate and progress, as was the case with our patient (5).

However, even when the diagnosis is considered, the complexities of the hypothalamic-pituitary-adrenal axis make selection and interpretation of screening tests challenging outside the endocrinology clinic. We suspect that in most such situations, a random serum cortisol measurement is far more likely to be ordered than a validated screening test, such as dexamethasone suppression testing, urine free cortisol, and late-night salivary cortisol per Endocrine Society guidelines (5). Although random serum cortisol values are not considered a screening test for Cushing syndrome, elevated values can provide a clue to the diagnosis in the right clinical setting. In this case, 2 mid-day serum cortisols were, by in-house laboratory convention, not flagged as abnormal despite the fact that they were above the upper limit of provided reference ranges. We suspect that the lack of electronic medical record flagging of serum cortisol values contributed to these values being incorrectly interpreted as ruling out the diagnosis.

Cushing syndrome remains among the most evasive and difficult diagnoses in medicine due to the doubly difficult task of considering the disorder in the face of often protean signs and symptoms and subsequently conducting and interpreting screening tests. The challenges this presents for the nonendocrinologist have recently been recognized by a group in the United Kingdom after a similarly overlooked case (6). We believe that our case serves as a vivid illustration of the diagnostic hurdles the clinician faces and as a cautionary tale with regard to the potential downstream effects of a delay in diagnosis. Standardization of clinical laboratory practices in flagging abnormal cortisol values is one such intervention that may aid the busy clinician in more efficiently recognizing laboratory results suggestive of this diagnosis. While false-positive case detection is a significant downside to this approach, given the potential harm in delayed or missed diagnosis, the potential benefits may outweigh the risks.

Learning Points

  • People with Cushing syndrome frequently experience a prolonged time to diagnosis, in part due to lack of recognition in the primary care and nonendocrine subspecialty settings of the constellation of clinical findings consistent with hypercortisolism.
  • Endocrine Society guidelines recommend against random serum cortisol as initial testing for Cushing syndrome in favor of dexamethasone suppression testing, urine free cortisol, and late-night salivary cortisol.
  • Increased awareness of Cushing syndrome by primary care providers and specialists in other fields could be an important and impactful mechanism to shorten the duration of symptom duration in the absence of diagnosis and hasten cure where cure is achievable.
  • We suggest clinical laboratories consider standardizing flagging abnormal cortisol values to draw attention to ordering providers and perhaps lower the threshold for endocrinology referral if there is any uncertainty in interpretation, especially in the context of patients with persistent symptoms and elusive diagnoses.

Acknowledgments

We are grateful to the patient for allowing us to present his difficult case to the community with the hopes of improving time to diagnosis for patients with hypercortisolism.

Contributors

All authors made individual contributions to authorship. J.M.E., E.M.Z., and K.R.K. were involved in the diagnosis and management of this patient. B.C.M., J.M.E., E.M.Z., and K.R.K. were involved in manuscript submission. S.M.J. performed and analyzed histopathology and prepared the figure for submission. All authors reviewed and approved the final draft.

Funding

No public or commercial funding.

Disclosures

J.M.E. was on the editorial board of JCEM Case Reports at the time of initial submission.

Informed Patient Consent for Publication

Signed informed consent obtained directly from the patient.

Data Availability Statement

Data sharing is not applicable to this article as no data sets were generated or analyzed during the current study.

References

1

Rubinstein
G

,

Osswald
A

,

Hoster
E

, et al.

Time to diagnosis in Cushing’s syndrome: a meta-analysis based on 5367 patients

.

J Clin Endocrinol Metab

.

2020

;

105

(

3

):

dgz136

.

2

Park
MA

,

Gaghan
LJ

,

Googe
PB

,

Klein
KR

,

Mervak
JE

.

Disseminated cutaneous Mycobacterium chelonae infection as a presenting sign of ectopic adrenocorticotropic hormone syndrome

.

JAAD Case Rep

.

2021

;

18

:

79

‐

81

.

3

Reincke
M

,

Fleseriu
M

.

Cushing syndrome: a review

.

JAMA

.

2023

;

330

(

2

):

170

‐

181

.

4

Puglisi
S

,

Perini
AME

,

Botto
C

,

Oliva
F

,

Terzolo
M

.

Long-term consequences of Cushing’s syndrome: a systematic literature review

.

J Clin Endocrinol Metab

. 2024;

109

(

3

):

e901

‐

e909

.

5

Nieman
LK

,

Biller
BMK

,

Findling
JW

, et al.

The diagnosis of Cushing’s syndrome: an Endocrine Society clinical practice guideline

.

J Clin Endocrinol Metab

.

2008

;

93

(

5

):

1526

‐

1540

.

6

Scoffings
K

,

Morris
D

,

Pullen
A

,

Temple
S

,

Trigell
A

,

Gurnell
M

.

Recognising and diagnosing Cushing’s syndrome in primary care: challenging but not impossible

.

Br J Gen Pract

.

2022

;

72

(

721

):

399

‐

401

.

Abbreviations

 

  • ACTH

    adrenocorticotropin

  • MRI

    magnetic resonance imaging

© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

Filed under: Cushing's, Diagnostic Testing, Rare Diseases | Tagged: , , , , | Leave a comment »

Complete and Sustained Remission of Hypercortisolism With Pasireotide Treatment of an Adrenocorticotropic Hormone (Acth)-Secreting Thoracic Neuroendocrine Tumour: an N-Of-1 Trial

Posted on February 7, 2023 by MaryO
Abstract

N-of-1 trials can serve as useful tools in managing rare disease. We describe a patient presenting with a typical clinical picture of Cushing’s Syndrome (CS).

Further testing was diagnostic of ectopic Adrenocorticotropic Hormone (ACTH) secretion, but its origin remained occult. The patient was offered treatment with daily pasireotide at very low doses (300 mg bid), which resulted in clinical and biochemical control for a period of 5 years, when a pulmonary typical carcinoid was diagnosed and dissected. During the pharmacological treatment period, pasireotide was tentatively discontinued twice, with immediate flare of symptoms and biochemical markers, followed by remission after drug reinitiation.

This is the first report of clinical and biochemical remission of an ectopic CS (ECS) with pasireotide used as first line treatment, in a low-grade lung carcinoid, for a prolonged period of 5 years. In conclusion, the burden of high morbidity caused by hypercortisolism can be effectively mitigated with appropriate pharmacological treatment, in patients with occult tumors. Pasireotide may lead to complete and sustained remission of hypercortisolism, until surgical therapy is feasible. The expression of SSTR2 from typical carcinoids may be critical in allowing the use of very low drug doses for achieving disease control, while minimizing the risk of adverse events.

 

Filed under: adrenal, Cancer, Clinical trials, Cushing's, Rare Diseases, Treatments | Tagged: , , , , , , , | Leave a comment »