Longterm-Outcomes In Patients With Cushing’s Disease vs. Non-Functioning Pituitary Adenoma After Pituitary Surgery: An Active-Comparator Cohort Study

Posted on July 22, 2024 by MaryO

Abstract

Objective

There is increasing evidence that multisystem morbidity in patients with Cushing’s disease (CD) is only partially reversible following treatment. We investigated complications from multiple organs in hospitalized patients with CD compared to patients with non-functioning pituitary adenoma (NFPA) after pituitary surgery.

Design

Population-based retrospective cohort study using data from the Swiss Federal Statistical Office between January 2012 and December 2021.

Methods

Through 1:5 propensity score matching, we compared hospitalized patients undergoing pituitary surgery for CD or NFPA, addressing demographic differences. The primary composite endpoint included all-cause mortality, major adverse cardiac events (i.e., myocardial infarction, unstable angina, heart failure, cardiac arrest, ischemic stroke), hospitalization for psychiatric disorders, sepsis, severe thromboembolic events, and fractures in need of hospitalization. Secondary endpoints comprised individual components of the primary endpoint and surgical reintervention due to disease persistence or recurrence.

Results

After matching, 116 patients with CD (mean age 45.4 years [SD, 14.4], 75.0% female) and 396 with NFPA (47.3 years [14.3], 69.7% female) were included and followed for a median time of 50.0 months (IQR 23.5, 82.0) after pituitary surgery. CD presence was associated with a higher incidence rate of the primary endpoint (40.6 vs. 15.7 events per 1,000 person-years, HR 2.75; 95% CI, 1.54 to 4.90). CD patients also showed increased hospitalization rates for psychiatric disorders (HR 3.27; 95% CI, 1.59 to 6.71) and a trend for sepsis (HR 3.15; 95% CI, 0.95 to 10.40).

Conclusions

Even after pituitary surgery, CD patients faced a higher hazard of complications, especially psychiatric hospitalizations and sepsis.

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Spontaneous Cushing’s Disease Remission Induced by Pituitary Apoplexy

Posted on July 17, 2024 by MaryO

Abstract

Spontaneous remission of Cushing’s disease (CD) is uncommon and often attributed to pituitary tumor apoplexy. We present a case involving a 14-year-old female who exhibited clinical features of Cushing’s syndrome. Initial diagnostic tests indicated CD: elevated 24h urinary cortisol (235 µg/24h, n < 90 µg/24h), abnormal 1 mg dexamethasone overnight test (cortisol after 1 mg dex 3.4 µg/dL, n < 1.8 µg/dL), and elevated adrenocorticotropic hormone concentrations (83.5 pg/mL, n 10-60 pg/mL). A pituitary adenoma was suspected, so a nuclear MRI was performed, with findings suggestive of a pituitary microadenoma. The patient was referred for a transsphenoidal resection of the microadenoma. While waiting for surgery, the patient presented to the emergency department with a headache and clinical signs of meningism. A computed axial tomography of the central nervous system was performed, and no structural alterations were found. The symptoms subsided with analgesia. One month later, she presented again to the emergency department with clinical findings of acute adrenal insufficiency (cortisol level of 4.06 µg/dL), and she was noted to have spontaneous biochemical remission associated with the resolution of her symptoms of hypercortisolism. For that reason, spontaneous CD remission induced by pituitary apoplexy (PA) was diagnosed. The patient has been managed conservatively since the diagnosis and remains in clinical and biochemical remission until the present time, after 10 months of follow-up. There are three unique aspects of our case: the early age of onset of symptoms, the spontaneous remission of CD due to PA, which has been rarely reported in the medical literature, and the fact that the patient presented a microadenoma because there are fewer than 10 clinical case reports of PA associated with microadenoma.

Introduction

Cushing’s disease (CD) is characterized by excessive production of adrenocorticotropic hormone by a pituitary adenoma and represents the most common cause of endogenous Cushing’s syndrome (CS) [1]. CD was first reported in 1912 by Harvey Williams Cushing, and he described 12 cases at the Peter Bent Brigham Hospital in Baltimore [2]. This disease has a global incidence of approximately 2.2 cases per 1,000,000 people and occurs more frequently in women from 20 to 50 years of age [3]. Pituitary apoplexy (PA) is a rare condition that occurs in 2-12% of cases, and it has a high morbidity and mortality rate [4]. We report an interesting case of a woman diagnosed with CD who achieved spontaneous remission of her disease after a PA.

Case Presentation

A 14-year-old female presented with a two-year history of weight gain (32 kg), depression, elevated blood pressure, type 2 diabetes mellitus, and growth failure (height less than the third percentile). Her height was 140 cm, and her BMI was 28.1 (97th percentile). At presentation, she had not yet reached menarche. Physical examination revealed Tanner 2 breast development, acne, hirsutism, moon facies, dorsocervical fat pad, central obesity, and stretch marks. Initial laboratory tests showed hemoglobin A1C of 13%, low-density lipoprotein of 167 mg/dL, triglycerides of 344 mg/dL, high-density lipoprotein of 26 mg/dL, creatinine of 0.4 mg/dL, and elevated liver enzymes. Abdominal ultrasound indicated moderate hepatic steatosis changes.

Given the high suspicion of CS, a hormonal profile was conducted (Table 1), confirming CS and subsequently diagnosing CD. A nuclear MRI revealed a 2.6 × 1.8 mm pituitary lesion (Figure 1), prompting referral for transsphenoidal resection of the pituitary microadenoma.

Laboratories Reference range Initial One month Three months Six months
TSH (mUI/L) 0.35-4.94 – 2.17 – 2.01
AM cortisol (µg/dL) 6.02-18.4 17.3 4.06 <0.5 4.7
1 mg DST (µg/dL) <1.8 3.4 – – –
8 mg DST (µg/dL) <50% suppression 1.9 (78% suppression) – – –
Urine-free cortisol (µg/24h) <90 235 – – –
ACTH (pg/mL) 10-60 83.5 – 19.2 9.7
IGF-1 (ng/mL) 36-300 – – – 293
Table 1: Pertinent laboratory investigation at baseline and follow-up with our patient

ACTH, adrenocorticotropic hormone; DST, dexamethasone suppression test; IGF-1, insulin growth factor-1; TSH, thyroid-stimulating hormone

Axial-view-of-a-T1-MRI-with-contrast-showing-a-sellar-lesion
Figure 1: Axial view of a T1 MRI with contrast showing a sellar lesion

The red arrow shows a microadenoma in relation to the normal pituitary gland.

Approximately one month after the suppression tests and while awaiting surgery, the patient presented to the emergency department with a sudden, severe, holocranial headache accompanied by projectile vomiting and diplopia, suggestive of meningism. A computed axial tomography of the central nervous system was conducted, revealing no structural abnormalities. Symptoms resolved with intravenous analgesia within approximately four to six hours. Subsequently, the patient experienced a significant decrease in insulin requirements, ultimately leading to the suspension of insulin therapy due to persistent hypoglycemia.

Weeks after the headache episode, the patient was reevaluated in the emergency department with a three-day history of diffuse abdominal pain, vomiting, asthenia, myalgia, hypotension, tachycardia, orthostatism, and recurrent hypoglycemia despite insulin suspension. Acute adrenal insufficiency was suspected and confirmed by a cortisol level of 4.06 µg/dL. Treatment with intravenous hydrocortisone 50 mg every six hours was initiated, leading to complete resolution of symptoms within 72 hours. The patient was discharged on maintenance therapy with oral hydrocortisone (20 mg in the morning and 10 mg at night). Subsequent follow-ups showed undetectable cortisol levels. Currently, the patient has been followed up for 10 months post-event, showing persistent clinical and hormonal remission of her disease.

Discussion

CD represents approximately 80% of cases of endogenous hypercortisolism, and pituitary microadenomas are the most common cause of CD in all age groups [5]. CD prevalence is 0.3-6.2 cases per 100,000 people [3], which represents 4.4% of all pituitary adenomas [6], and it is up to five times more likely to occur in women than men. Spontaneous remission of CD is rare, and it is mainly due to the apoplexy of a pituitary tumor [7].

PA is a potentially fatal condition resulting from hemorrhage or necrosis of a pituitary adenoma that produces compression of the surrounding structures with symptoms that can be critical and even fatal [8]. PA affects between 2% and 12% of patients with pituitary adenomas, mainly in nonfunctional macroadenomas [9]. Although the main mechanism of PA is hemorrhage, it can also be due to a hemorrhagic infarction or an infarction without hemorrhage; this last scenario is clinically less aggressive [10]. Among the most important precipitating factors are craniocerebral trauma, pregnancy, thrombocytopenia, coagulopathies, pituitary stimulation tests, drugs such as anticoagulants and estrogens, surgeries that are complicated by hypotension, and radiotherapy [4,11,12].

There are three unique aspects of our case. First, the age of onset is 14 years old. This characteristic has been reported in less than 6% of cases of CD, with a mean age of onset between 12.3 and 14.1 years and a slightly higher incidence in men (63%) [13]. In this population, CD is the most common cause of hypercortisolism, accounting for 75-80% of all cases [14]. Furthermore, our patient presented a significant weight gain, severe compromise in her height, hypertension, depression, and diabetes mellitus, which is compatible with the classic profile described for CD in pediatric ages. It is important to clarify that although type 2 diabetes mellitus is common in adults, it is unusual in the pediatric population [13].

Second, spontaneous remission in CD due to apoplexy has been rarely reported in the past; hence, our case is an important addition to the scant literature on this unusual phenomenon. Although there are characteristics suggestive of PA, such as hyperdense lesions within the pituitary gland and the reinforcing ring, a CT scan has a low sensitivity for detecting pituitary hemorrhage (21-46%); therefore, a negative CT scan does not rule out PA in cases where there is infarction without hemorrhage, a situation that could correspond to our case [15].

The third unique feature of our case is that the stroke occurred in the context of a microadenoma, a situation reported in less than 10 cases in the literature. Despite being a microadenoma, the symptoms of PA were severe, with symptoms of meningism, an intense headache, vomiting, and the development of adrenal insufficiency. Taylor et al. [16] reported a similar case of a 41-year-old female with microadenoma whose PA was associated with severe headache and vomiting.

The main differential diagnosis in our case is cyclical CS (CCS), a disorder that occurs in 15% of CS cases, especially in CD [17]. The diagnosis of CCS is classically established with three peaks and two valleys in cortisol secretion, spontaneous fluctuations, and clinical features of CS [7]. The possibility of CCS was ruled out due to the typical presentation of the PA event and the persistence of hypocortisolism.

Finally, several cases of recurrence of their disease have been described after remission of CS due to AP. Those recurrences usually develop in follow-ups of up to seven years [18]. At the time of the last evaluation (10 months post-PA), the patient remained in remission, but long-term follow-up is required to detect both reactivation and hypopituitarism [19].

Conclusions

CD is a rare entity in the pediatric population, usually associated with a pituitary microadenoma. Spontaneous remission of this disease is very uncommon, but when it occurs, it is mainly due to PA. We describe a case with three unique aspects: CD with an early age of onset of symptoms, spontaneous remission of CD due to PA, which has been rarely reported in the medical literature, and the fact that there are less than 10 clinical case reports of PA associated with microadenoma. It is imperative for clinicians to be aware of this possible outcome in patients with CD.

References

  1. Fleseriu M, Auchus R, Bancos I, et al.: Consensus on diagnosis and management of Cushing’s disease: a guideline update. Lancet Diabetes Endocrinol. 2021, 9:847-75. 10.1016/S2213-8587(21)00235-7
  2. Bray DP, Rindler RS, Dawoud RA, Boucher AB, Oyesiku NM: Cushing disease: medical and surgical considerations. Otolaryngol Clin North Am. 2022, 55:315-29. 10.1016/j.otc.2021.12.006
  3. Giuffrida G, Crisafulli S, Ferraù F, et al.: Global Cushing’s disease epidemiology: a systematic review and meta-analysis of observational studies. J Endocrinol Invest. 2022, 45:1235-46. 10.1007/s40618-022-01754-1
  4. Briet C, Salenave S, Bonneville JF, Laws ER, Chanson P: Pituitary apoplexy. Endocr Rev. 2015, 36:622-45. 10.1210/er.2015-1042
  5. Newell-Price J, Bertagna X, Grossman A, Nieman L: Cushing’s syndrome. Lancet. 2006, 367:1605-17. 10.1016/S0140-6736(06)68699-6
  6. Daly AF, Beckers A: The epidemiology of pituitary adenomas. Endocrinol Metab Clin North Am. 2020, 49:347-55. 10.1016/j.ecl.2020.04.002
  7. Popa Ilie IR, Herdean AM, Herdean AI, Georgescu CE: Spontaneous remission of Cushing’s disease: a systematic review. Ann Endocrinol (Paris). 2021, 82:613-21. 10.1016/j.ando.2021.10.002
  8. Siwakoti K, Omay SB, Inzucchi SE: Spontaneous resolution of primary hypercortisolism of Cushing disease after pituitary hemorrhage. AACE Clin Case Rep. 2020, 6:e23-9. 10.4158/ACCR-2019-0292
  9. Dubuisson AS, Beckers A, Stevenaert A: Classical pituitary tumour apoplexy: clinical features, management and outcomes in a series of 24 patients. Clin Neurol Neurosurg. 2007, 109:63-70. 10.1016/j.clineuro.2006.01.006
  10. Semple PL, De Villiers JC, Bowen RM, Lopes MB, Laws ER Jr: Pituitary apoplexy: do histological features influence the clinical presentation and outcome?. J Neurosurg. 2006, 104:931-7. 10.3171/jns.2006.104.6.931
  11. Turgut M, Ozsunar Y, Başak S, Güney E, Kir E, Meteoğlu I: Pituitary apoplexy: an overview of 186 cases published during the last century. Acta Neurochir (Wien). 2010, 152:749-61. 10.1007/s00701-009-0595-8
  12. Wildemberg LE, Glezer A, Bronstein MD, Gadelha MR: Apoplexy in nonfunctioning pituitary adenomas. Pituitary. 2018, 21:138-44. 10.1007/s11102-018-0870-x
  13. Concepción-Zavaleta MJ, Armas CD, Quiroz-Aldave JE, et al.: Cushing disease in pediatrics: an update. Ann Pediatr Endocrinol Metab. 2023, 28:87-97. 10.6065/apem.2346074.037
  14. Ferrigno R, Hasenmajer V, Caiulo S, et al.: Paediatric Cushing’s disease: epidemiology, pathogenesis, clinical management and outcome. Rev Endocr Metab Disord. 2021, 22:817-35. 10.1007/s11154-021-09626-4
  15. Banerjee AK: Diagnostic imaging: Brain. 2nd edition. Br J Radiol. 2010, 83:450-1.
  16. Taylor HC, McLean S, Monheim K: Resolution of Cushing’s disease followed by secondary adrenal insufficiency after anticoagulant-associated pituitary hemorrhage: report of a case and review of the literature. Endocr Pract. 2003, 9:147-51. 10.4158/EP.9.2.147
  17. 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, 160:1011-8. 10.1530/EJE-09-0046
  18. Kamiya Y, Jin-No Y, Tomita K, et al.: Recurrence of Cushing’s disease after long-term remission due to pituitary apoplexy. Endocr J. 2000, 47:793-7. 10.1507/endocrj.47.793
  19. Machado MC, Gadelha PS, Bronstein MD, Fragoso MC: Spontaneous remission of hypercortisolism presumed due to asymptomatic tumor apoplexy in ACTH-producing pituitary macroadenoma. Arq Bras Endocrinol Metabol. 2013, 57:486-9. 10.1590/s0004-27302013000600012

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Unveiling the Uncommon: Cushing’s Syndrome (CS) Masquerading as Severe Hypokalemia

Posted on July 2, 2024 by MaryO

Abstract

Cushing’s syndrome (CS) arises from an excess of endogenous or exogenous cortisol, with Cushing’s disease specifically implicating a pituitary adenoma and exaggerated adrenocorticotropic hormone (ACTH) production. Typically, Cushing’s disease presents with characteristic symptoms such as weight gain, central obesity, moon face, and buffalo hump.

This case report presents an unusual manifestation of CS in a 48-year-old male with a history of hypertension, where severe hypokalemia was the primary presentation. Initial complaints included bilateral leg swelling, muscle weakness, occasional shortness of breath, and a general feeling of not feeling well. Subsequent investigations revealed hypokalemia, metabolic alkalosis, and an abnormal response to dexamethasone suppression, raising concerns about hypercortisolism. Further tests, including 24-hour urinary free cortisol and ACTH testing, confirmed significant elevations. Brain magnetic resonance imaging (MRI) identified a pituitary macroadenoma, necessitating neurosurgical intervention.

This case underscores the rarity of CS presenting with severe hypokalemia, highlighting the diagnostic challenges and the crucial role of a collaborative approach in managing such intricate cases.

Introduction

Cushing’s syndrome (CS), characterized by excessive cortisol production, is well-known for its diverse and often conspicuous clinical manifestations. Cushing’s disease is a subset of CS resulting from a pituitary adenoma overproducing adrenocorticotropic hormone (ACTH), leading to heightened cortisol secretion. The classic presentation involves a spectrum of symptoms such as weight gain, central obesity, muscle weakness, and mood alterations [1].

Despite its classic presentation, CS can demonstrate diverse and atypical features, challenging conventional diagnostic paradigms. This case report sheds light on a rare manifestation of CS, where severe hypokalemia was the primary clinical indicator. Notably, instances of CS prominently manifesting through severe hypokalemia are scarce in the literature [1,2].

Through this exploration, we aim to provide valuable insights into the diagnostic intricacies of atypical CS presentations, underscore the significance of a comprehensive workup, and emphasize the collaborative approach essential for managing such uncommon hormonal disorders.

Case Presentation

A 48-year-old male with a history of hypertension presented to his primary care physician with complaints of bilateral leg swelling, occasional shortness of breath, dizziness, and a general feeling of malaise persisting for 10 days. The patient reported increased water intake and urinary frequency without dysuria. The patient was diagnosed with hypertension eight months ago. He experienced progressive muscle weakness over two months, hindering his ability to perform daily activities, including using the bathroom. The primary care physician initiated a blood workup that revealed severe hypokalemia with a potassium level of 1.3 mmol/L (reference range: 3.6 to 5.2 mmol/L), prompting referral to the hospital.

Upon admission, the patient was hypertensive with a blood pressure of 180/103 mmHg, a heart rate of 71 beats/minute, a respiratory rate of 18 breaths/minute, and an oxygen saturation of 96% on room air. Physical examination revealed fine tremors, bilateral 2+ pitting edema in the lower extremities up to mid-shin, abdominal distension with normal bowel sounds, and bilateral reduced air entry in the bases of the lungs on auscultation. The blood work showed the following findings (Table 1).

Parameter Result Reference Range
Potassium (K) 1.8 mmol/L 3.5-5.0 mmol/L
Sodium (Na) 144 mmol/L 135-145 mmol/L
Magnesium (Mg) 1.3 mg/dL 1.7-2.2 mg/dL
Hemoglobin (Hb) 15.5 g/dL 13.8-17.2 g/dL
White blood cell count (WBC) 13,000 x 103/µL 4.5 to 11.0 × 109/L
Platelets 131,000 x 109/L 150-450 x 109/L
pH 7.57 7.35-7.45
Bicarbonate (HCO3) 46 mmol/L 22-26 mmol/L
Lactic acid 4.2 mmol/L 0.5-2.0 mmol/L
Table 1: Blood work findings

In order to correct the electrolyte imbalances, the patient received intravenous (IV) magnesium and potassium replacement and was later transitioned to oral. The patient was also started on normal saline at 100 cc per hour. To further investigate the complaint of shortness of breath, the patient underwent a chest X-ray, which revealed bilateral multilobar pneumonia (Figure 1). He was subsequently treated with ceftriaxone (1 g IV daily) and clarithromycin (500 mg twice daily) for seven days.

A-chest-X-ray-revealing-(arrows)-bilateral-multilobar-pneumonia
Figure 1: A chest X-ray revealing (arrows) bilateral multilobar pneumonia

With persistent abdominal pain and lactic acidosis, a computed tomography (CT) scan abdomen and pelvis with contrast was conducted, revealing a psoas muscle hematoma. Subsequent magnetic resonance imaging (MRI) depicted an 8×8 cm hematoma involving the left psoas and iliacus muscles. The interventional radiologist performed drainage of the hematoma involving the left psoas and iliacus muscles (Figure 2).

Magnetic-resonance-imaging-(MRI)-depicting-an-8x8-cm-hematoma-(arrow)-involving-the-left-psoas-and-iliacus-muscles
Figure 2: Magnetic resonance imaging (MRI) depicting an 8×8 cm hematoma (arrow) involving the left psoas and iliacus muscles

In light of the concurrent presence of hypokalemia, hypertension, and metabolic alkalosis, there arose concerns about Conn’s syndrome, prompting consultation with endocrinology. Their recommended workup for Conn’s syndrome included assessments of the aldosterone-renin ratio and random cortisol levels. The results unveiled an aldosterone level below 60 pmol/L (reference range: 190 to 830 pmol/L in SI units) and a plasma renin level of 0.2 pmol/L (reference range: 0.7 to 3.3 mcg/L/hr in SI units). Notably, the aldosterone-renin ratio was low, conclusively ruling out Conn’s syndrome. The random cortisol level was notably elevated at 1334 nmol/L (reference range: 140 to 690 nmol/L).

Furthermore, a low-dose dexamethasone suppression test was undertaken due to the high cortisol levels. Following the administration of 1 mg of dexamethasone at 10 p.m., cortisol levels were measured at 9 p.m., 3 a.m., and 9 a.m. the following day. The results unveiled a persistently elevated cortisol level surpassing 1655 nmol/L, signaling an abnormal response to dexamethasone suppression and raising concerns about a hypercortisolism disorder, such as CS.

In the intricate progression of this case, the investigation delved deeper with a 24-hour urinary free cortisol level, revealing a significant elevation at 521 mcg/day (reference range: 10 to 55 mcg/day). Subsequent testing of ACTH portrayed a markedly elevated level of 445 ng/L, distinctly exceeding the normal reference range of 7.2 to 63.3 ng/L. A high-dose 8 mg dexamethasone test was performed to ascertain the source of excess ACTH production. The baseline serum cortisol levels before the high-dose dexamethasone suppression test were 1404 nmol/L, which decreased to 612 nmol/L afterward, strongly suggesting the source of excess ACTH production to be in the pituitary gland.

A CT scan of the adrenal glands ruled out adrenal mass, while an MRI of the brain uncovered a 1.3×1.3×3.2 cm pituitary macroadenoma (Figure 3), leading to compression of adjacent structures. Neurosurgery was consulted, and they recommended surgical removal of the macroadenoma due to the tumor size and potential complications. The patient was referred to a tertiary care hospital for pituitary adenoma removal.

Magnetic-resonance-imaging-(MRI)-of-the-brain-depicting-a-1.3x1.3x3.2-cm-pituitary-macroadenoma-(star)
Figure 3: Magnetic resonance imaging (MRI) of the brain depicting a 1.3×1.3×3.2 cm pituitary macroadenoma (star)

Discussion

CS represents a complex endocrine disorder characterized by excessive cortisol production. While the classic presentation of CS includes weight gain, central obesity, and muscle weakness, our case highlights an uncommon initial manifestation: severe hypokalemia. This atypical presentation underscores the diverse clinical spectrum of CS and the challenges it poses in diagnosis and management [1,2].

While CS typically presents with the classic symptoms mentioned above, severe hypokalemia as the initial manifestation is exceedingly rare. Hypokalemia in CS often results from excess cortisol-mediated activation of mineralocorticoid receptors, leading to increased urinary potassium excretion and renal potassium wasting. Additionally, metabolic alkalosis secondary to cortisol excess further exacerbates hypokalemia [3,4].

Diagnosing a case of Cushing’s disease typically commences with a thorough examination of the patient’s medical history and a comprehensive physical assessment aimed at identifying characteristic manifestations such as central obesity, facial rounding, proximal muscle weakness, and increased susceptibility to bruising. Essential to confirming the diagnosis are laboratory examinations, which involve measuring cortisol levels through various tests, including 24-hour urinary free cortisol testing, late-night salivary cortisol testing, and dexamethasone suppression tests. Furthermore, assessing plasma ACTH levels aids in distinguishing between pituitary-dependent and non-pituitary causes of CS. Integral to the diagnostic process are imaging modalities such as MRI of the pituitary gland, which facilitate the visualization of adenomas and the determination of their size and precise location [1-4].

Treatment for Cushing’s disease primarily entails surgical removal of the pituitary adenoma via transsphenoidal surgery, with the aim of excising the tumor and restoring normal pituitary function. In cases where surgical intervention is unsuitable or unsuccessful, pharmacological therapies employing medications such as cabergoline (a dopamine receptor agonist) or pasireotide (a somatostatin analogue) may be considered to suppress ACTH secretion and regulate cortisol levels. Additionally, radiation therapy, whether conventional or stereotactic radiosurgery, serves as a supplementary or alternative treatment approach to reduce tumor dimensions and mitigate ACTH production [5,6]. To assess the effectiveness of treatment, manage any problem, and assure long-term illness remission, diligent long-term follow-up and monitoring are essential. Collaborative multidisciplinary care involving specialists such as endocrinologists, neurosurgeons, and other healthcare professionals is pivotal in optimizing patient outcomes and enhancing overall quality of life [2,4].

The prognosis of CS largely depends on the underlying cause, stage of the disease, and efficacy of treatment. Early recognition and prompt intervention are essential for improving outcomes and minimizing long-term complications. Surgical resection of the adrenal or pituitary tumor can lead to remission of CS in the majority of cases. However, recurrence rates vary depending on factors such as tumor size, invasiveness, and completeness of resection [2,3]. Long-term follow-up with endocrinologists is crucial for monitoring disease recurrence, assessing hormonal function, and managing comorbidities associated with CS.

Conclusions

In conclusion, our case report highlights the rarity of severe hypokalemia as the initial presentation of CS. This unique presentation underscores the diverse clinical manifestations of CS and emphasizes the diagnostic challenges encountered in clinical practice. A multidisciplinary approach involving endocrinologists, neurosurgeons, and radiologists is essential for the timely diagnosis and management of CS. Early recognition, prompt intervention, and long-term follow-up are essential for optimizing outcomes and improving the quality of life for patients with this endocrine disorder.

References

  1. Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM: The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008, 93:1526-40. 10.1210/jc.2008-0125
  2. Newell-Price J, Bertagna X, Grossman AB, Nieman LK: Cushing’s syndrome. Lancet. 2006, 367:1605-17. 10.1016/S0140-6736(06)68699-6
  3. Torpy DJ, Mullen N, Ilias I, Nieman LK: Association of hypertension and hypokalemia with Cushing’s syndrome caused by ectopic ACTH secretion: a series of 58 cases. Ann N Y Acad Sci. 2002, 970:134-44. 10.1111/j.1749-6632.2002.tb04419.x
  4. Elias C, Oliveira D, Silva MM, Lourenço P: Cushing’s syndrome behind hypokalemia and severe infection: a case report. Cureus. 2022, 14:e32486. 10.7759/cureus.32486
  5. Fleseriu M, Petersenn S: Medical therapy for Cushing’s disease: adrenal steroidogenesis inhibitors and glucocorticoid receptor blockers. Pituitary. 2015, 18:245-52. 10.1007/s11102-014-0627-0
  6. Pivonello R, De Leo M, Cozzolino A, Colao A: The treatment of Cushing’s disease. Endocr Rev. 2015, 36:385-486. 10.1210/er.2013-1048

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Is Cushing Syndrome More Common in the US Than We Think?

Posted on June 11, 2024 by MaryO

I think members of the Cushing’s Help boards have been saying this forever!  Cushing’s isn’t all that rare.  Just rarely diagnosed,

 

BOSTON — The prevalence of Cushing syndrome (CS) in the United States may be considerably higher than currently appreciated, new data from a single US institution suggest.

In contrast to estimates of 1 to 3 cases per million patient-years from population-based European studies, researchers at the University of Wisconsin, Milwaukee, estimated that the incidence of CS in Wisconsin is a minimum of 7.2 cases per million patient-years. What’s more, contrary to all previous studies, they found that adrenal Cushing syndrome was more common than pituitary adrenocorticotropic hormone (ACTH)– secreting tumors (Cushing disease), and that fewer than half of individuals with adrenal Cushing syndrome had classic physical features of hypercortisolism, such as weight gain, round face, excessive hair growth, and stretch marks.

“Cases are absolutely being missed…. Clinicians should realize that cortisol excess is not rare. It may not be common, but it needs to be considered in patients with any constellation of features that are seen in cortisol excess,” study investigator Ty B. Carroll, MD, Associate Professor of Medicine, Endocrinology and Molecular Medicine, and the Endocrine Fellowship Program Director at Medical College of Wisconsin in Milwaukee, told Medscape Medical News.

There are several contributing factors, he noted, “including the obesity and diabetes epidemics which make some clinical features of cortisol excess more common and less notable. Providers get used to seeing patients with some features of cortisol excess and don’t think to screen. The consequence of this is more difficult-to-control diabetes and hypertension, more advance metabolic bone disease, and likely more advanced cardiovascular disease, all resulting from extended exposure to cortisol excess,” he said.

Are Milder Cases the Ones Being Missed?

Asked to comment, session moderator Sharon L. Wardlaw, MD, professor of medicine at Columbia University College of Physicians and Surgeons, New York City, said “When we talk about Cushing [syndrome], we usually think of pituitary ACTH as more [common], followed by adrenal adenomas, and then ectopic. But they’re seeing more adrenal adenoma…we are probably diagnosing this a little more now.”

She also suggested that the Wisconsin group may have a lower threshold for diagnosing the milder cortisol elevation seen with adrenal Cushing syndrome. “If you screen for Cushing with a dexamethasone suppression test…[i]f you have autonomous secretion by the adrenal, you don’t suppress as much…. When you measure 24-hour urinary cortisol, it may be normal. So you’re in this in-between [state]…. Maybe in Wisconsin they’re diagnosing it more. Or, maybe it’s just being underdiagnosed in other places.”

She also pointed out that “you can’t diagnose it unless you think of it. I’m not so sure that with these mild cases it’s so much that it’s more common, but maybe it’s like thyroid nodules, where we didn’t know about it until everybody started getting all of these CT scans. We’re now seeing all these incidental thyroid nodules…I don’t think we’re missing florid Cushing.”

However, Wardlaw said, it’s probably worthwhile to detect even milder hypercortisolism because it could still have long-term damaging effects, including osteoporosis, muscle weakness, glucose intolerance, and frailty. “You could do something about it and normalize it if you found it. I think that would be the reason to do it.”

Is Wisconsin Representative of Cushing Everywhere?

Carroll presented the findings at the annual meeting of the Endocrine Society. He began by noting that most of the previous CS incidence studies, with estimates of 1.2-3.2 cases per million per year, come from European data published from 1994 to 2019 and collected as far back as 1955. The method of acquisition of patients and the definitions of confirmed cases varied widely in those studies, which reported CS etiologies of ACTH-secreting neoplasms (pituitary or ectopic) in 75%-85% and adrenal-dependent cortisol excess in 15%-20%.

The current study included data from clinic records between May 1, 2017, and December 31, 2022, of Wisconsin residents newly diagnosed with and treated for CS. The CS diagnosis was established with standard guideline-supported biochemical testing and appropriate imaging. Patients with exogenous and non-neoplastic hypercortisolism and those who did not receive therapy for CS were excluded.

A total of 185 patients (73% female, 27% male) were identified from 27 of the total 72 counties in Wisconsin, representing a population of 4.5 million. On the basis of the total 5.9 million population of Wisconsin, the incidence of CS in the state works out to 7.2 cases per million population per year, Carroll said.

However, data from the Wisconsin Hospital Association show that the University of Wisconsin’s Milwaukee facility treated just about half of patients in the state who are discharged from the hospital with a diagnosis of CS during 2019-2023. “So…that means that an actual or approximate incidence of 14-15 cases per million per year rather than the 7.2 cases that we produce,” he said.

Etiologies were 60% adrenal (111 patients), 36.8% pituitary (68 patients), and 3.2% ectopic (6 patients). Those proportions were similar between genders.

On biochemical testing, values for late-night salivary cortisol, dexamethasone suppression, and urinary free cortisol were highest for the ectopic group (3.189 µg/dL, 42.5 µg/dL, and 1514.2 µg/24 h, respectively) and lowest for the adrenal group (0.236 µg/dL, 6.5 µg/dL, and 64.2 µg/24 h, respectively). All differences between groups were highly statistically significant, at P < .0001, Carroll noted.

Classic physical features of CS were present in 91% of people with pituitary CS and 100% of those ectopic CS but just 44% of individuals with adrenal CS. “We found that adrenal-dependent disease was the most common form of Cushing syndrome. It frequently presented without classic physical features that may be due to the milder biochemical presentation,” he concluded.

Carroll reports consulting and investigator fees from Corcept Therapeutics. Wardlaw has no disclosures. 

Miriam E. Tucker is a freelance journalist based in the Washington DC area. She is a regular contributor to Medscape, with other work appearing in The Washington Post, NPR’s Shots blog, and Diatribe. She is on X (formerly Twitter) @MiriamETucker.

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Repeat Endoscopic Endonasal Transsphenoidal Surgery for Residual or Recurrent Cushing’s Disease: Safety, Feasibility, And Success

Posted on May 27, 2024 by MaryO

Abstract

Purpose

The success and outcomes of repeat endoscopic transsphenoidal surgery (ETS) for residual or recurrent Cushing’s disease (CD) are underreported in the literature. This study aims to address this gap by assessing the safety, feasibility, and efficacy of repeat ETS in these patients.

Methods

A retrospective analysis was conducted on 56 patients who underwent a total of 65 repeat ETS performed by a single neurosurgeon between January 2006 and December 2020. Data including demographic, clinical, laboratory, radiological, and operative details were collected from electronic medical records. Logistic regression was utilized to identify potential predictors associated with sustained remission.

Results

Among the cases, 40 (61.5%) had previously undergone microscopic surgery, while 25 (38.5%) had prior endoscopic procedures. Remission was achieved in 47 (83.9%) patients after the first repeat ETS, with an additional 9 (16.1%) achieving remission after the second repeat procedure. During an average follow-up period of 97.25 months, the recurrence rate post repeat surgery was 6.38%. Sustained remission was achieved in 48 patients (85.7%), with 44 after the first repeat ETS and 4 following the second repeat ETS. Complications included transient diabetes insipidus (DI) in 5 (7.6%) patients, permanent (DI) in 2 (3%) patients, and one case (1.5%) of panhypopituitarism. Three patients (4.6%) experienced rhinorrhea necessitating reoperation. A serum cortisol level > 5 µg/dL on postoperative day 1 was associated with a reduced likelihood of sustained remission.

Conclusion

Repeat ETS is a safe and effective treatment option for residual or recurrent CD with satisfactory remission rates and low rates of complications.

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Introduction

Cushing’s disease (CD) arises from an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma, leading to excessive endogenous glucocorticoid production [1]. The reported incidence of CD varies from 0.7 to 2.4 cases per million individuals annually [2,3,4,5,6]. Hypercortisolism impacts every bodily system and is linked to elevated morbidity and mortality risks [7, 8]. Therefore, prompt CD diagnosis and management are crucial to enhance patient outcomes.

Transsphenoidal surgery remains the primary treatment for CD, and have been associated with satisfactory remission rates ranging from 65 to 94% [2, 3, 5, 9,10,11]. Two surgical techniques are utilized: microscopic and endoscopic approaches. While both methods are effective, studies indicate that endoscopic transsphenoidal surgery (ETS) offers higher rates of complete tumor removal and lower complication rates [12,13,14]. ETS holds advantages over microscopic transsphenoidal surgery (MTS) due to superior tumor visualization, especially for laterally invasive tumors and macroadenomas [15]. Since its introduction in 1997, ETS has gained popularity and is now the standard surgical approach for managing CD [16].

Remission rates post-ETS for CD treatment range from 77 to 90% [17,18,19,20,21,22]. Despite ETS’s technical benefits and favorable outcomes, recurrence rates for Cushing’s disease after successful ETS range between 5.6% and 22.8% [17, 18, 22, 23]. Reoperating for residual or recurrent CD presents challenges due to altered surgical landmarks and scar tissue formation from previous surgeries, potentially elevating morbidity, and mortality risks [24, 25]. Limited literature exists on the success and outcomes of repeat endoscopic transsphenoidal surgery for residual or recurrent CD. This study aims to address this gap by assessing the safety, feasibility, and efficacy of repeat ETS in patients with residual or recurrent Cushing’s disease.

Methods

Study design

This is a retrospective cohort study of repeat endoscopic transsphenoidal surgery for residual or recurrent Cushing’s disease. All patients underwent endoscopic endonasal transsphenoidal surgery by the senior author between 2006 and 2020. The study protocol was approved by the local ethics committee for clinical studies.

Patient selection

The study participants were selected based on specific inclusion and exclusion criteria. Inclusion criteria were as follows: (i) a confirmed diagnosis of Cushing’s disease, (ii) prior transsphenoidal surgery, and (iii) confirmation of residual or recurrent CD through clinical, laboratory, and/or imaging assessments. Exclusion criteria included: (i) prior craniotomy without transsphenoidal surgery, (ii) previous radiotherapy before reoperation, (iii) inaccessible clinical, laboratory, or radiological data, and (iv) follow-up duration of less than 6 months.

Diagnostic criteria

Each patient underwent thorough screening for active Cushing’s disease. An increased 24-hour urine cortisol level > 45 µg/day or a serum fasting cortisol level exceeding 1.8 µg/dl following a low-dose (2 mg) dexamethasone suppression test was deemed abnormal. Subsequently, a high-dose (8 mg) dexamethasone test was administered, and a reduction of 50% or more from the baseline value was indicative of active Cushing’s disease. Due to the technical limitations of the institution that the research has been done, late-night salivary cortisol tests were not performed. Early remission was characterized by a fasting serum cortisol level below 5 µg/dl on the 1st and 7th postoperative days. Patients displaying a serum cortisol level below 1.8 µg/dl after the low-dose dexamethasone suppression test or those requiring continued corticosteroid replacement post-surgery were considered to maintain remission. The presence of a residual adenoma on postoperative magnetic resonance imaging (MRI) confirmed residual disease.

Routine follow-up protocol

Patients were evaluated for Cushing’s disease symptoms before surgery and monitored at 6 months after surgery, as well as during yearly check-ups for any changes in their condition. Fasting serum ACTH and cortisol levels were measured in the morning before surgery, on the 1st and 7th days after surgery, at the 1st, 3rd, and 6th months, and during yearly follow-up appointments. Prior to surgery, all patients underwent contrast-enhanced pituitary MRI and paranasal sinus CT scans. Follow-up pituitary MRI scans were conducted on the 1st day, at 3 and 12 months after surgery, and then annually thereafter.

Data collection

Data from electronic medical records were gathered, encompassing demographic, clinical, laboratory, radiological, and operative details. Laboratory assessments comprised an anterior pituitary hormone panel (Follicle-stimulating hormone [FSH], Luteinizing hormone [LH], Thyroid-stimulating hormone [TSH], Prolactin [PRL], Growth hormone [GH]), serum electrolytes, preoperative and postoperative serum ACTH, and cortisol levels. Patient records, along with CT and MRI scans, were scrutinized to document preoperative tumor characteristics such as size, multifocality, relationship with the cavernous sinus, Hardy-Wilson classification of sellar destruction, and suprasellar extension. Tumors larger than 10 mm were classified as macroadenomas. The operative database was examined to collect data on previous surgeries, including the number and dates of prior procedures, as well as the surgical techniques utilized. Outcome measures comprised remission rates and surgical complications.

Statistical analysis

Statistical analysis was conducted utilizing SPSS 23.0 software (IBM, New York). Two-group comparisons were performed using Chi-square and Fisher’s exact tests for categorical variables and Student’s t-test for continuous variables. Categorical variables were presented as numbers and percentages, while continuous variables were presented as means ± SD or median [IQR]. Logistic regression was performed to investigate potential predictors linked to sustained remission. A p-value of < 0.05 was deemed statistically significant.

Results

Baseline characteristics

Supplementary File 1 displays the demographic characteristics of the patient cohort.

A retrospective analysis was conducted on 190 patients who underwent a total of 212 operations for CD at our department between January 2006 and December 2020. Among them, 56 patients, comprising 65 repeat endonasal transsphenoidal surgeries due to either recurrence (n = 18, 27.7%) or residual disease (n = 47, 72.3%), were identified. The majority of patients were female (n = 48, 85.7%), with a mean age of 37.6 ± 12.4 years. Of the 56 patients, 43 (76.8%) were referred from another institution. Most patients (n = 42, 75%) had undergone only one prior surgery, while 12 patients (21.4%) had a history of two previous surgeries, and 2 patients (3.6%) had undergone three prior surgeries before referral to our center. The average follow-up duration since the first repeat ETS was 97.2 ± 36.8 months. The mean time to recurrence was 80.2 ± 61.1 months (median 75 months, range 23.2 to 103.5 months).

Hormonal data

Table 1 depicts the preoperative and postoperative serum ACTH and cortisol levels. The average preoperative serum cortisol levels for the entire patient cohort stood at 18.7 ± 11.1 µg/dL (median 17, range 12-24.6). The median preoperative 24-hour urine free cortisol level was 237 µg /day [188.5–425.5]. On the initial postoperative day, the mean serum cortisol levels for all patients were 13.4 ± 13.8 µg/dL (median 6.4, range 1.7–21). In 46.2% of cases (n = 30), cortisol levels on the first postoperative day were below 5 µg/dL (< 2 µg/dL in 33.8%). A comparison of the mean preoperative and postoperative serum ACTH and cortisol levels between the groups with residual disease and recurrence is detailed in Table 1.

Table 1 Cohort overview and comparison of recurrence and residual disease groups

Radiological findings

In the entire case cohort, there were 41 microadenomas (63.1%) and 24 macroadenomas (36.9%). Fifteen cases (23.1%) exhibited bifocal adenomas. Adenoma extension into the cavernous sinuses, indicated by cavernous sinus wall displacement, was present in 21 cases (32.3%), while invasion into the cavernous sinuses was observed in 10 cases (15.4%). Based on the Hardy-Wilson Classification, there were 38 Grade I adenomas (58.5%), 16 Grade II adenomas (24.6%), 6 Grade III adenomas (9.2%), and 5 Grade IV adenomas (7.7%). Thirty patients (46.2%) presented with Stage A adenoma, 7 (10.8%) with Stage B adenoma, 2 (3.1%) with Stage C adenoma, 1 (1.5%) with Stage D adenoma, and 25 (38.5%) with Stage E adenoma. As indicated in Table 1, there were no statistically significant differences between patients with residual disease and recurrence concerning radiological findings.

Surgical characteristics

A single surgeon conducted all 65 reoperations. Among these, 47 patients (72.3%) underwent repeat ETS due to residual disease, while 18 (27.7%) did so due to recurrence. The previous surgical technique was microscopic in 40 cases (61.5%) and endoscopic in 25 cases (38.5%). Microscopic transsphenoidal surgeries were exclusively performed at other institutions. There was a notable disparity between patients with residual disease and recurrence regarding the technique of the previous surgery. Residual disease occurrence following endoscopic transsphenoidal surgery was less frequent (n = 11/25, 44%) compared to after microscopic transsphenoidal surgery (n = 36/40, 90%; p < 0.001) (Table 1). Immunohistochemical staining of the specimens indicated that 55 cases (85%) exhibited ACTH-positive adenoma. Nevertheless, all patients with a negative pathology at the repeat surgery had a confirmed ACTH-adenoma at the first surgery. Of the 10 patients (15%) with a negative ACTH-positive adenoma pathology, two patients underwent inferior petrosal sinus sampling (IPSS) previously and were confirmed to have CD. Remaining patients did not undergo an additional inferior petrosal sinus sampling (IPSS) because all functional test results indicated a central source and MRI confirmed pituitary microadenoma in all cases. Notably, there are studies reporting that IPSS may not be required in patients with a sellar mass and a biochemical testing suggestive of CD [26, 27]. Additionally, we also explored both sides of the pituitary and confirmed the adenoma intraoperatively. Therefore, negative pathology in the repeat surgery is most likely due to sampling error.

Outcomes

As depicted in Fig. 1, among the 56 patients, 47 (83.9%) experienced initial remission following the first repeat ETS, while 9 (16.1%) still had residual adenoma. Within the group achieving initial remission, 44 patients (93.6%) maintained remission without the need for further surgeries, while 3 (6.4%) experienced recurrence during follow-up and required a second repeat ETS.

Fig. 1
figure 1

Outcomes of repeat endoscopic transsphenoidal surgery for residual or recurrent Cushing’s disease

Among the 9 patients with residual disease after the first repeat ETS, 1 (11.1%) opted to defer further treatment, 1 (11.1%) received radiotherapy, 1 (11.1%) chose adrenalectomy, and 6 (66.7%) underwent a second repeat ETS. Of the 9 patients who underwent a second repeat ETS due to residual disease or recurrence, 4 (44.4%) sustained remission, 5 (55.6%) still had residual disease, but 3 of them deferred further treatment, 1 received radiotherapy, while 1 achieved remission after adrenalectomy. Overall, 78.5% (n = 51) of the entire case cohort achieved remission following repeat ETS. Representative cases are presented in Fig. 2.

Fig. 2
figure 2

Case 1: Preoperative and postoperative magnetic resonance imaging (MRI) scans of a 49-year-old female who underwent repeat endoscopic transsphenoidal surgery (ETS) due to recurrent Cushing’s disease and achieved remission. The patient underwent initial surgery 14 years ago at an outside institution. Preoperative T2 (A), and T1 contrast-enhanced (B) MRI scans demonstrate a right-sided pituitary adenoma. Postoperative T2 (C), and T1 contrast-enhanced (D) MRI scans demonstrate total resection of the adenoma. Case 2: Preoperative and postoperative magnetic resonance imaging (MRI) scans of a 53-year-old female who underwent repeat endoscopic transsphenoidal surgery (ETS) due to recurrent Cushing’s disease and achieved remission. The patient underwent initial surgery 3 years ago at an outside institution. Preoperative T2 (E), and T1 contrast-enhanced (F) MRI scans demonstrate a left-sided pituitary adenoma, in close relation to ICA. Postoperative T2 (G), and T1 contrast-enhanced (H) MRI scans demonstrate total resection of the adenoma

Transient diabetes insipidus (DI) developed in 5 patients (7.6%), while 2 (3%) experienced permanent DI following repeat ETS. Intraoperative cerebrospinal fluid (CSF) leak occurred in 20 operations (30.7%). Three patients (4.6%) developed rhinorrhea and required reoperation. Five patients (7.6%) developed prolactin deficiency, 3 patients (4.6%) had GH deficiency, and another 3 patients (4.6%) had TSH deficiency requiring thyroxine replacement. Four patients (6.2%) had combined deficiencies in TSH, FSH, LH and prolactin, while one patient (1.5%) developed panhypopituitarism following the second repeat ETS.

Factors predisposing to unsuccessful repeat endoscopic transsphenoidal surgery

Among the 42 patients who underwent repeat ETS for residual disease, 9 (21.4%) still had residual disease after the first repeat ETS. We conducted a multivariable logistic regression analysis to explore potential risk factors for unsuccessful repeat ETS. However, the analysis did not reveal any significant association between the success of repeat ETS and factors such as extension or invasion into cavernous sinuses, sellar or parasellar extension, or tumor size (Supplementary File 1).

Potential predictors of sustained remission

We conducted a multivariable logistic regression analysis to investigate possible predictors of sustained remission. The variables included in the analysis are detailed in Table 5. The results indicated that having a serum cortisol level exceeding 5 µg/dL on postoperative day 1 was linked to a decreased likelihood of achieving sustained remission (Odds ratio [OR] 0.09, 95% confidence interval [CI] 0.01–0.52, p = 0.006) (Table 2).

Table 2 Logistic regression analysis of potential predictors for continued remission

Discussion

Transsphenoidal surgery remains the established standard for treating Cushing’s disease, with demonstrated remission rates ranging from 65 to 94%, contingent upon the surgeon’s expertise and remission criteria [2, 3, 5, 9,10,11]. The advent of endoscopic techniques has notably augmented this approach, offering wider visibility, reduced nasal trauma, and shorter hospital stays [16, 25, 28, 29]. While the effectiveness of ETS in managing CD is well-documented, literature on its efficacy in treating residual or recurrent cases is limited. Our study addresses this gap by assessing the safety, feasibility, and outcomes of repeat ETS for patients with persistent or recurrent Cushing’s disease.

In our study, 56 patients underwent 65 repeat ETS procedures for residual or recurrent Cushing’s disease. Mean follow-up duration was 97.2 ± 36.8 months, which is one of the longest follow-up durations that has been reported following repeat endoscopic transsphenoidal surgery [5, 30,31,32]. Of these patients, 40 (61.5%) had previously undergone microscopic surgery, while 25 (38.5%) had undergone prior endoscopic procedures. Importantly, a notable difference emerged between patients with residual disease and those experiencing recurrence regarding the prior surgical approach, with residual disease being less frequent after endoscopic surgery compared to microscopic surgery (p < 0.001). This variance was expected, as numerous studies have indicated that ETS yields a higher rate of complete resection compared to MTS [12,13,14].

After the first repeat ETS, 47 patients (83.9%) achieved remission, and 78.5% (n = 44) of them maintained remission at a mean follow-up of 97.2 months without requiring additional surgery. Limited data exists regarding the remission rates of CD following repeat transsphenoidal surgery, with reported rates ranging from 28.9 to 73% [33, 34, 35]. Burke et al. reported an immediate remission rate of 86.7% and a continued remission rate of 73.3% at follow-up after repeat ETS [36]. Among our patients who achieved remission after successful repeat ETS, 3 individuals (6.38%, n = 3/47) experienced recurrence after the first repeat ETS, with a mean time to recurrence of 45.6 months. The rates of CD recurrence following reoperation vary, with documented rates ranging between 22% and 63.2% [37, 38]. In our study, 9 patients required a second repeat ETS due to residual disease or recurrence. Of these, 4 (44.4%) achieved continued remission following the second repeat ETS, while 5 (55.6%) had residual disease; however, 4 of them deferred further treatment, and 1 achieved remission after adrenalectomy. In total, 47 patients (83.9%) in the entire patient cohort achieved remission following endoscopic transsphenoidal surgery and did not require further intervention.

Within our case cohort, among the 42 patients who underwent repeat ETS for residual disease, 9 individuals (21.4%) continued to exhibit residual disease following the first repeat ETS. We did not establish a significant association between the success of repeat ETS and factors such as extension or invasion into cavernous sinuses, sellar or parasellar extension, or tumor size.

The degree of hypocortisolism following transsphenoidal surgery is considered a potential indicator of remission in the postoperative period [3]. Numerous studies have indicated that patients with subnormal postoperative cortisol levels tend to experience a lower recurrence rate compared to those with normal or supranormal levels, although consensus on the precise cutoff level remains elusive [30,31,32, 39]. In a retrospective study involving 52 patients with CD, researchers reported a 100% positive predictive value of a postoperative nadir cortisol level < 2 µg/dL for achieving remission [5]. Additionally, Esposito et al. observed that a morning serum cortisol level ≤ 5 µg/dL on postoperative day 1 or 2 appears to serve as a reliable predictor of remission [11]. In our investigation, logistic regression analysis revealed that patients with a serum cortisol level > 5 µg/dL on postoperative day 1 were less inclined to achieve continued remission compared to those with a serum cortisol level < 5 µg/dL on postoperative day 1.

Repeat transsphenoidal surgery presents unique challenges due to distorted surgical landmarks and the presence of scar tissue from prior procedures, often resulting in lower cure rates and increased morbidity risk [24, 25, 28]. Non-surgical options such as radiotherapy and radiosurgery have been considered as an effective treatment option for recurrent or residual CD due to low rates of morbidity and acceptable remission rates [28, 40]. However, our findings suggest that the outcomes and complication rates associated with repeat ETS are comparable to primary ETS for CD and superior to other non-surgical options for residual or recurrent CD. Within our patient cohort, 5 (7.6%) individuals experienced transient diabetes insipidus (DI), while 2 (3%) developed permanent DI. Additionally, one patient (1.5%) experienced panhypopituitarism following the second repeat ETS. Similarly, various studies have reported DI rates ranging from 2 to 13% and panhypopituitarism rates between 2% and 9.7% [25, 28, 41,42,43]. In our series, 3 (5.3%) patients developed rhinorrhea and required reoperation, consistent with reported rates of postoperative CSF leak ranging from 1 to 5% following repeat endoscopic transsphenoidal surgery for residual or recurrent pituitary tumors [25, 28, 44]. While radiotherapy and radiosurgery are options for patients who have failed transsphenoidal surgery or experienced recurrence, the literature suggests remission rates ranging from 46 to 84%, with several studies indicating high recurrence rates (25-50%) following radiotherapy [40, 45,46,47]. In our study, among 56 patients, 47 (83.9%) achieved remission following the first repeat ETS, while 4 (17.8%) achieved remission after the second repeat ETS. Over a mean follow-up duration of 97.25 months, our recurrence rate following repeat ETS was 27.7%, with a mean time to recurrence of 45.62 months.

At our institution, we adhere to a specific algorithm (Fig. 3) for managing Cushing’s disease patients and implement a meticulous protocol for individuals undergoing repeat ETS for residual or recurrent CD. A thorough clinical and radiological assessment is conducted for all patients before surgery. Detailed radiological evaluation is particularly essential to identify any distortions in surgical landmarks from prior procedures, such as the course of sphenoidal septa and the location of the sellar floor opening, as well as other potential aberrations like internal carotid artery and optic nerve dehiscence. Imaging techniques should encompass dynamic pituitary MRI with and without contrast and paranasal CT scans. Our objective is to achieve extensive exposure during surgery, which is especially critical for managing bifocal adenomas or adenomas with cavernous sinus invasion or extension. The expanded visual field also facilitates the visualization of concealed parts of the adenoma, allowing the surgeon to achieve complete resection, which may be challenging or even impossible with limited exposure. We employ a multilayer closure technique to prevent CSF leaks, and if necessary, utilize a vascularized pedicled nasoseptal flap (Hadad-Bassagasteguy flap).

Fig. 3
figure 3

Specific algorithm for the management of Cushing’s disease patients

In summary, our findings suggest that in the hands of experienced surgeons, repeat ETS represents a safe and effective treatment option for managing residual or recurrent Cushing’s disease.

Strengths and limitations

Our study represents one of the largest case series in the literature examining the safety, feasibility, and efficacy of repeat ETS for managing recurrent or residual CD. Our findings underscore the safety and efficacy of repeat ETS in experienced centers, showcasing satisfactory remission rates and minimal complications. However, it is important to acknowledge the retrospective nature of our study, which inherently introduces potential biases such as selection bias. Lastly, our study exclusively focuses on patients undergoing surgical intervention for recurrent or residual CD, limiting our ability to compare the effectiveness of surgical treatment with alternative modalities like radiotherapy or radiosurgery.

Conclusion

Our study underscores the efficacy and safety of repeat endoscopic transsphenoidal surgery in managing residual or recurrent Cushing’s disease. Remarkably, 82.1% of patients achieved remission after their first reoperation, aligning closely with reported remission rates following primary endoscopic transsphenoidal surgery. Furthermore, the complication rates observed in our cohort were consistent with documented rates for both primary and repeat transsphenoidal surgeries. Notably, patients with serum cortisol levels < 5 µg/dL are more likely to maintain remission. Overall, our findings emphasize that in the hands of experienced surgeons, repeat endoscopic transsphenoidal surgery emerges as a reliable and safe treatment modality for residual or recurrent Cushing’s disease, offering satisfactory remission rates and minimal complications.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

ACTH:
adrenocorticotropic hormone
CD:
Cushing’s disease
CT:
computed tomography
DI:
diabetes insipidus
ETS:
endoscopic endonasal transsphenoidal surgery
MRI:
magnetic resonance imaging
MTS:
microscopic transsphenoidal surgery

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Acknowledgements

Not applicable.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Open access funding provided by the Scientific and Technological Research Council of Türkiye (TÜBİTAK).

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Authors and Affiliations

  1. Department of Neurosurgery, Faculty of Medicine, Hacettepe University, Ankara, Turkey

    Sahin Hanalioglu, Muhammet Enes Gurses, Neslihan Nisa Gecici, Baylar Baylarov & Ilkay Isikay

  2. Department of Neurosurgery, Miller School of Medicine, University of Miami, Miami, FL, USA

    Muhammet Enes Gurses

  3. Department of Endocrinology and Metabolism, Faculty of Medicine, Hacettepe University, Ankara, Turkey

    Alper Gürlek

  4. Department of Neurosurgery, Hacettepe University School of Medicine, Sihhiye, Ankara, 06230, Turkey

    Mustafa Berker

Contributions

Conceptualization: S.H, M.B; Methodology: S.H, M.E.G, N.N.G; Formal analysis and investigation: M.E.G, N.N.G, B.B; Writing – original draft preparation: N.N.G; Writing – review and editing: S.H, M.E.G, B.B, I.I, A.G, M.B; Supervision: S.H, I.I, A.G, M.B.

Corresponding author

Correspondence to Mustafa Berker.

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Hanalioglu, S., Gurses, M.E., Gecici, N.N. et al. Repeat endoscopic endonasal transsphenoidal surgery for residual or recurrent cushing’s disease: safety, feasibility, and success. Pituitary (2024). https://doi.org/10.1007/s11102-024-01396-x

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