Talus Avascular Necrosis as a Rare Complication of Cushing’s Disease

Posted on April 8, 2024 by MaryO

Abstract

Avascular necrosis (AVN), also called osteonecrosis, stems from blood supply interruption to the bone and is often idiopathic. It has risk factors like trauma, alcohol, and corticosteroids. AVN in the talus (AVNT) is less common than in the femoral head. Most cases of talar osteonecrosis are associated with trauma, while a smaller proportion is linked to systemic conditions such as sickle cell disease or prolonged prednisone use. Glucocorticoids are a key nontraumatic cause. We report a middle-aged woman with Cushing’s syndrome symptoms, such as hypertension and moon face, since her youth. A few years ago, she experienced pain and swelling in her ankle, which was diagnosed as atraumatic AVNT and treated with hindfoot fusion. Years later, she was diagnosed with Cushing’s disease caused by an adrenocorticotropic hormone (ACTH)-producing pituitary adenoma in laboratory tests and imaging, which was resected in 2020. She experienced significant weight loss, and her Cushing’s syndrome symptoms were relieved after tumor resection. Mechanisms behind AVN in hypercortisolism involve fat cell hypertrophy, fat embolization, osteocyte apoptosis, and glucocorticoid-induced hypertension. Traditional X-rays may miss early AVN changes; MRI is preferred for early detection. Although there are some cases of femoral AVN caused by endogenous hypercortisolism in the literature, as far as we know, this is the first case of AVNT due to Cushing’s disease. AVNT treatment includes conservative approaches, hindfoot fusion, and core decompression. Cushing’s disease is a rare cause of AVNT, and a multidisciplinary approach aids in the rapid diagnosis of elusive symptoms.

Introduction

Avascular necrosis (AVN), also known as osteonecrosis, is a condition arising from the temporary interruption or permanent cessation of blood supply to a bone, leading to tissue necrosis or its demise. While AVN is frequently idiopathic, certain established risk factors are known including trauma, alcohol abuse, and the use of exogenous corticosteroids [1]. While not as prevalent as in the femoral head, AVN of the talus (AVNT) in the ankle presents a painful and disabling issue for patients and poses a challenging dilemma for orthopedic surgeons [2]. About 75% of cases of talar osteonecrosis stem from traumatic injuries, while approximately 25% of nontraumatic instances are typically associated with systemic conditions such as sickle cell disease or prolonged use of prednisone, which impede blood flow. [3]

The use of glucocorticoids is one of the most important non-traumatic causes of AVN. Nevertheless, there are some case reports where AVN in the femoral head is reported as a manifestation of endogenous hypercortisolism, particularly associated with Cushing’s syndrome [4-12].

In this article, we describe the case of a middle-aged woman who was diagnosed with idiopathic severe progressive AVNT for two years. She had retrogradely diagnosed masked symptoms of Cushing’s disease since her youth, but the diagnosis was confirmed after undergoing ankle arthrodesis.

Case Presentation

A 43-year-old woman visited our office in June 2018 with a complaint of severe pain and swelling in her left ankle, which had persisted for the past two years. She had hypertension since her youth and blurry vision since 2013 but had no other significant medical or family history. She was also diagnosed with major depressive disorder (MDD) in 2015 when she lost her husband. She had no history of smoking, alcohol consumption, or addiction. She had not experienced any significant trauma during this period and sought consultations from various specialties, including neurology, psychology, internal medicine, nephrology, rheumatology, and orthopedics. She had received a platelet-rich plasma (PRP) injection in the ankle, but it did not improve her symptoms. Despite undergoing various diagnostic workups, no precise diagnosis had been established.

Back in 2013, she remembers suddenly experiencing blurry vision in her right eye. This condition underwent a misdiagnosis, which almost led to a loss of vision. She had been struggling with her eye problems until her last visit, during which she received intravitreal bevacizumab injections. Additionally, she previously had iron deficiency anemia, which was treated with ferrous sulfate before 2018.

In our first visit, during the physical examination, the pain was localized in the ankle mortise with some posterolateral pain along the course of the peroneal tendons posterior to the fibula. Based on the physical examination and available ankle radiographs, we diagnosed AVNT. The patient subsequently underwent ankle arthroscopy through the standard anterior portals, the joint was cleaned, the synovium was shaved, and a small incision was conducted for peroneal assessment; this procedure revealed a subchondral collapse and extensive necrosis in the talus. Following the procedure, she experienced a partial improvement in her symptoms. However, six months later, she returned with a recurrence of symptoms (Figure 1). Upon further inquiry, she mentioned that her symptoms had recurred a month ago when she was dancing at a family party. Radiographs showed a stress fracture in her fibula and extensive AVNT. This diagnosis was confirmed through a CT scan, MRI, and bone scan (Figure 2).

Ankle-X-ray-six-months-after-arthroscopy
Figure 1: Ankle X-ray six months after arthroscopy

Pain had reduced for four months, then pain increased with activity and disabled her after a night of dancing. Subchondral fracture and fibular stress fracture are evident (A and B, respectively).

MRI,-CT-scan,-and-technetium-99m-(Tc-99m)-bone-scan
Figure 2: MRI, CT scan, and technetium-99m (Tc-99m) bone scan

Coronal MRI confirmed avascular necrosis of the talar dome with subchondral fracture (A and B, respectively). CT scan (C) and Tc-99 bone scan (D) images also revealed the pathologies.

In the second visit after arthroscopy, upon confirmation of a fibular stress fracture and significant subchondral collapse, and following a discussion of the next available options with the patient, the second procedure was performed as an ankle arthrodesis with an anterior approach. A 6 cm longitudinal incision was made anteriorly, and through the plane between the tibialis anterior and extensor hallucis longus, the ankle joint was accessed. Joint preparation was done with an osteotome, ensuring a bleeding surface on both sides. Then, manual compression with provisional pin fixation in the corrective position was performed. The fusion was planned at less than 5 degrees of valgus, 10 degrees of external rotation, and approximately 10 degrees of plantar flexion, suitable for the high-heeled shoes that she was using in her daily living activities. After confirming fluoroscopy in two planes, final 6.5 mm cannulated cancellous screws were used, and fixation was augmented with an anterior molded 4.5 mm narrow dynamic compression plate (DCP), according to our previously published anterior ankle fusion technique [13]. The foot was placed in a splint for 10 days, after which stitches were removed, and a cast was applied for four weeks. Then, walking with gradual, as-tolerated weight-bearing was initiated (Figure 3). Three months after surgery, she was pain-free, and by the sixth month, she could walk without any boot or brace, only using high-heeled shoes.

Post-operative-radiographies
Figure 3: Post-operative radiographies

Six months after the ankle surgery, a huge osteonecrosis and fibular stress fracture were managed with an acceptable, painless ankle fusion (not solid) despite the remaining necrosis (A and B, respectively). In 2024, four years after the tumor resection, complete healing of talus necrosis and solid fusion were achieved (C and D, respectively).

In 2020, two years after her ankle surgery, she was referred to an endocrinologist due to excessive weight gain and hirsutism. The biochemical assessment revealed the following: cortisol (8 AM) (chemiluminescence immunoassay (CLIA)) was 96 µg/dl (normal range: 4.82 – 19.5 µg/dl), and it was 22.1 µg/dl after overnight dexamethasone (normal range: < 1.8 µg/dl). Adrenocorticotropic hormone (ACTH) (CLIA) was 44.4 pg/ml (normal range: 7.2-63.3 pg/ml), and cortisol measured 5.7 µg/dl after the 48-hour low-dose dexamethasone suppression test (normal < 5 µg/dl). The results, along with symptoms (Table 1), are documented in the laboratory tests (Table 2). She was diagnosed with Cushing’s syndrome, which was subsequently confirmed as Cushing’s disease due to an ACTH-producing pituitary adenoma observed in the MRI and Brain CT (Figure 4).

Sign/symptom Severity
Weight Gain Severe
Hirsutism Severe
Hypertension Severe
Easy bruising Severe
Depression Severe
Moon face Moderate (masked with makeup)
Lethargy Moderate
Headache Moderate
Peripheral edema       _
Buffalo hump       _
Myopathy       _
Acne       _
Purple striae       _
Table 1: Cushing’s disease symptoms and signs

The hyphens in the table indicate that the patient does not have those symptoms or signs.

Laboratory test Result Reference range
Cortisol (8 AM) (CLIA) 96 µg/dl 4.82-19.5 µg/dl
Cortisol (8 AM) (after overnight dexamethasone) (CLIA) 22.1 µg/dl <1.8 µg/dl
ACTH (CLIA) 44.4 pg/ml 7.2-63.3 pg/ml
Cortisol after 48 hours of LDDST (CLIA) 5.7 µg/dl < 5 µg/dl
Table 2: Laboratory tests

CLIA: chemiluminescence immunoassay; ACTH: adrenocorticotropic hormone; LDDST: low-dose dexamethasone suppression test

Brain-MRI
Figure 4: Brain MRI

Finally, a pituitary adenoma was diagnosed using a Brain MRI as the cause of Cushing’s disease symptoms (A and B).

Finally, she underwent a tumor resection and had a dramatic response after treatment (30 kg weight loss). She revealed that she had Cushing’s syndrome symptoms since she was young. These symptoms included a puffy face, which she covered with makeup, high blood pressure, and hirsutism. In January 2024, four years after her brain surgery, during our last visit, her symptoms had significantly improved. She reported no problems with her ankle, and talus necrosis was completely healed, with a solid fusion achieved in radiographs (Figure 3).

Discussion

As far as we are aware, this case presentation represents the first instance of AVNT attributed to Cushing’s disease in the existing literature. Nevertheless, some individuals with endogenous Cushing’s syndrome have been reported to experience AVN of the femoral head [4-12].

Cushing’s syndrome is an uncommon endocrine condition marked by manifestations of hypercortisolism. The predominant cause is often an adenoma in the anterior pituitary gland that produces ACTH, referred to as Cushing’s disease [14]. The presentation of Cushing’s syndrome can vary significantly in both adults and children, influenced by the extent and duration of hypercortisolemia. However, the typical signs and symptoms of Cushing’s syndrome are widely known [15]. Although some individuals may perceive these alterations as normal and physiological, the disease can go unnoticed for an extended period, as in our case, in which it remained undiagnosed for more than 20 years.

However, it is known that steroid use is a significant contributing factor to the occurrence of bone osteonecrosis, accounting for up to 40% of non-traumatic instances of AVN [16]. The mechanisms leading to AVN due to either endogenous hypercortisolism or excess exogenous glucocorticoids are not completely understood. There are just some hypotheses that suggest that the hypertrophy of fat cells, embolization of fat, and osteocytes’ apoptosis result in impaired blood flow in the bone, ultimately causing ischemic tissue necrosis [17]. An alternative proposed theory suggests that elevated levels of glucocorticoids may cause insulin resistance and subsequently contribute to AVN [18].

Traditional X-rays often fail to detect the initial changes of AVN (as observed in our case). MRI stands as the preferred method for identifying AVN in its early phases, providing an opportunity for timely therapeutic interventions [19,20].

In an analysis of 321 cases of AVNT, the predominant treatment modalities included conservative therapies (n = 104), hindfoot fusion (n = 62), and core decompression (n = 85) [21]. These approaches reflect the primary methods employed in contemporary clinical practice for addressing AVNT.

After all, we confirmed the AVNT diagnosis using MRI and bone scan and managed it with hindfoot fusion. Subsequently, the underlying issue, endogenous hypercortisolism due to an ACTH-producing pituitary adenoma, was identified and treated through resection of the tumor (Figure 5).

Case-report-timeline
Figure 5: Case report timeline

* Avascular necrosis in the talus

Conclusions

Cushing’s syndrome is a rare endocrine disorder characterized by excessive cortisol levels, commonly caused by an ACTH-producing adenoma in the pituitary gland, known as Cushing’s disease. Cushing’s disease may be one of the rare causes of AVNT. To the best of our knowledge, this is the first instance of AVNT due to Cushing’s disease described in the literature. Since atraumatic AVNT is rare in itself, a multidisciplinary approach can lead us to a more rapid and proper diagnosis, as each symptom may be masked or considered rare within its subspecialty field.

References

  1. Chang CC, Greenspan A, Gershwin ME: Osteonecrosis: current perspectives on pathogenesis and treatment. Semin Arthritis Rheum. 1993, 23:47-69. 10.1016/s0049-0172(05)80026-5
  2. Zhang H, Fletcher AN, Scott DJ, Nunley J: Avascular osteonecrosis of the talus: current treatment strategies. Foot Ankle Int. 2022, 43:291-302. 10.1177/10711007211051013
  3. Parekh SG, Kadakia RJ: Avascular necrosis of the talus. J Am Acad Orthop Surg. 2021, 29:e267-78. 10.5435/JAAOS-D-20-00418
  4. Belmahi N, Boujraf S, Larwanou MM, El Ouahabi H: Avascular necrosis of the femoral head: an exceptional complication of Cushing’s disease. Ann Afr Med. 2018, 17:225-7. 10.4103/aam.aam_75_17
  5. Salazar D, Esteves C, Ferreira MJ, Pedro J, Pimenta T, Portugal R, Carvalho 😧 Avascular femoral necrosis as part of Cushing syndrome presentation: a case report. J Med Case Rep. 2021, 15:287. 10.1186/s13256-021-02882-7
  6. Alaya Z, Braham M, Bouajina E: Aseptic femur head necrosis revealing Cushing’s disease: a rare presentation. J Clin Surg Res. 2020, 1:10.31579/2768-2757/002
  7. Phillips KA, Nance EP Jr, Rodriguez RM, Kaye JJ: Avascular necrosis of bone: a manifestation of Cushing’s disease. South Med J. 1986, 79:825-9. 10.1097/00007611-198607000-00011
  8. Koch CA, Tsigos C, Patronas NJ, Papanicolaou DA: Cushing’s disease presenting with avascular necrosis of the hip: an orthopedic emergency. J Clin Endocrinol Metab. 1999, 84:3010-2. 10.1210/jcem.84.9.5992
  9. Modroño N, Torán CE, Pavón I, Benza ME, Guijarro G, Navea 😄 Cushinǵs syndrome and avascular hip necrosis: presentation of two patients [Article in Spanish]. Rev Clin Esp (Barc). 2014, 214:e93-6. 10.1016/j.rce.2014.05.003
  10. Camporro F, Bulacio E, Gutiérrez Magaldi I: Bilateral osteonecrosis of the hip secondary to endogenous Cushing’s syndrome due to a recently-diagnosed carcinoid tumour of the lung [Article in Spanish]. Med Clin (Barc). 2016, 147:228. 10.1016/j.medcli.2016.03.042
  11. Ha JS, Cho HM, Lee HJ, Kim SD: Bilateral avascular necrosis of the femoral head in a patient with asymptomatic adrenal incidentaloma. Hip Pelvis. 2019, 31:120-3. 10.5371/hp.2019.31.2.120
  12. Anand A, Jha CK, Singh PK, Sinha U, Ganesh A, Bhadani PP: Avascular necrosis of femur as a complication of Cushing’s syndrome due to adrenocortical carcinoma. Am Surg. 2023, 89:2701-4. 10.1177/00031348221129510
  13. Gharehdaghi M, Rahimi H, Mousavian A: Anterior ankle arthrodesis with molded plate: technique and outcomes. Arch Bone Jt Surg. 2014, 2:203-9.
  14. Lindholm J, Juul S, Jørgensen JO, et al.: Incidence and late prognosis of cushing’s syndrome: a population-based study. J Clin Endocrinol Metab. 2001, 86:117-23. 10.1210/jcem.86.1.7093
  15. 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
  16. Konarski W, Poboży T, Konarska K, Śliwczyński A, Kotela I, Hordowicz M, Krakowiak J: Osteonecrosis related to steroid and alcohol use-an update on pathogenesis. Healthcare (Basel). 2023, 11:1846. 10.3390/healthcare11131846
  17. Chan KL, Mok CC: Glucocorticoid-induced avascular bone necrosis: diagnosis and management. Open Orthop J. 2012, 6:449-57. 10.2174/1874325001206010449
  18. Hartmann K, Koenen M, Schauer S, Wittig-Blaich S, Ahmad M, Baschant U, Tuckermann JP: Molecular actions of glucocorticoids in cartilage and bone during health, disease, and steroid therapy. Physiol Rev. 2016, 96:409-47. 10.1152/physrev.00011.2015
  19. Kaste SC, Karimova EJ, Neel MD: Osteonecrosis in children after therapy for malignancy. AJR Am J Roentgenol. 2011, 196:1011-8. 10.2214/AJR.10.6073
  20. Pierce TP, Jauregui JJ, Cherian JJ, Elmallah RK, Mont MA: Imaging evaluation of patients with osteonecrosis of the femoral head. Curr Rev Musculoskelet Med. 2015, 8:221-7. 10.1007/s12178-015-9279-6
  21. Gross CE, Haughom B, Chahal J, Holmes GB Jr: Treatments for avascular necrosis of the talus: a systematic review. Foot Ankle Spec. 2014, 7:387-97. 10.1177/1938640014521831

From https://www.cureus.com/articles/221491-talus-avascular-necrosis-as-a-rare-complication-of-cushings-disease-a-case-report?score_article=true#!/

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

PET/MRI may improve diagnosis of Cushing disease

Posted on April 5, 2024 by MaryO

PET/MRI could become the diagnostic method of choice over MRI alone for identifying small pituitary tumors associated with Cushing disease, according to a study published March 21 in the Journal of Nuclear Medicine.

In patients diagnosed with the disease yet who had inconclusive MRI results, PET/MRI was positive in 100% of cases, noted lead author Ilanah Pruis, a doctoral student at Erasmus University Medical Center in Rotterdam, Netherlands.

“This multimodal imaging technique provides a welcome improvement for diagnosis, planning of surgery, and clinical outcome in patients with Cushing disease,” the authors wrote.

Cushing disease is characterized by small tumors in pituitary glands, which causes them to secrete excess cortisol, the authors explained. While it is a rare disease, over time it can cause severely disabling conditions, such as high blood pressure or type II diabetes.

Currently, guidelines recommend the use of MRI and inferior petrosal sinus sampling (IPSS) to diagnose these tumors. IPSS is an invasive procedure in which cortisol hormone levels are sampled from the veins that drain the pituitary gland.

In up to 40% of patients, however, MRI is inconclusive, as the lesions are smaller than 10 millimeters in diameter. Even advanced MRI techniques, such as dynamic perfusion imaging, can leave small lesions undetected in up to one third of patients, the authors noted.

In preclinical work, PET imaging using a radiotracer named F-18 FET has been shown to bind with high affinity to a molecular target in pituitary tumors, and in this study, the researchers aimed to test this technique combined with MRI in a multimodal approach.

The researchers analyzed results from 22 patients (68% women; mean age 48 years) who underwent F-18 FET PET/MRI at Erasmus MC between February 2021 and December 2022. All patients showed a clear pituitary tumor F-18 FET-PET/MRI, whereas reading of the MRI alone yielded a suspected lesion in only 50%, the authors found.

T1-weighted postgadolinium MR images (A and C) and F-18 FET-PET/MR images (B and D) centered at pituitary before (A and B) and after (C and D) transsphenoidal surgery. This patient with Cushing disease showed clear focal uptake (B) but no clear lesion on previously obtained and accompanying MRI (A). Postoperative tissue analysis did confirm resection of small pituitary adenoma/PitNET, and postoperative F-18 FET-PET showed no residual uptake (D). Image courtesy of the Journal of Nuclear Medicine.T1-weighted postgadolinium MR images (A and C) and F-18 FET-PET/MR images (B and D) centered at pituitary before (A and B) and after (C and D) transsphenoidal surgery. This patient with Cushing disease showed clear focal uptake (B) but no clear lesion on previously obtained and accompanying MRI (A). Postoperative tissue analysis did confirm resection of small pituitary adenoma/PitNET, and postoperative F-18 FET-PET showed no residual uptake (D). Image courtesy of the Journal of Nuclear Medicine.

Importantly, 16 patients underwent treatment based on the results — either surgery, Gamma Knife, or CyberKnife therapy — with 12 of these patients achieving short-term remission, the authors noted.

“[F-18 FET-PET/MRI] is of great clinical value because it allows precision surgery and targeted Gamma Knife or CyberKnife therapy,” the group wrote.

The researchers noted that only one previous study evaluated F-18 FET-PET/MRI in these patients and that their study was limited, given the relatively small number of patients.

“Future studies will be directed at head-to-head comparisons of the performance of F-18 FET- PET and other diagnostic techniques, including advanced MRI sequences… preferably in patients at the time of initial clinical presentation,” the authors concluded.

A link to the full study can be found here.

From https://www.auntminnie.com/clinical-news/molecular-imaging/article/15667496/petmri-may-improve-diagnosis-of-cushing-disease

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Corcept Completes Enrollment in Phase 3 Gradient Trial of Relacorilant in Patients With Adrenal Cushing’s Syndrome

Posted on April 3, 2024 by MaryO

Corcept Therapeutics Incorporated (NASDAQ: CORT), a commercial-stage company engaged in the discovery and development of medications to treat severe endocrinologic, oncologic, metabolic and neurologic disorders by modulating the effects of the hormone cortisol, today announced completion of enrollment in GRADIENT, a Phase 3 trial of its proprietary selective cortisol modulator relacorilant in patients with Cushing’s syndrome (hypercortisolism) caused by an adrenal adenoma or adrenal hyperplasia.

“Hypercortisolism with adrenal etiology affects many patients and is associated with serious cardiometabolic comorbidities, including hypertension and hyperglycemia, and increased risk of premature death,” said Bill Guyer, PharmD, Corcept’s Chief Development Officer. “GRADIENT is the first prospective placebo-controlled study to be conducted exclusively in these patients with Cushing’s syndrome. We expect data from GRADIENT in the fourth quarter of this year.”

GRADIENT is a randomized, double-blind, placebo-controlled trial conducted at sites in the United States, Europe and Israel. One-hundred thirty-seven patients were randomized 1:1 to receive relacorilant or placebo for 22 weeks. Primary endpoints are improvement in glucose metabolism and hypertension.

About Cushing’s Syndrome (Hypercortisolism)
Cushing’s syndrome is caused by excessive activity of the hormone cortisol. Endogenous Cushing’s syndrome is an orphan disease that most often affects adults aged 20-50. Symptoms vary, but most patients experience one or more of the following manifestations: high blood sugar, diabetes, high blood pressure, upper-body obesity, rounded face, increased fat around the neck, thinning arms and legs, severe fatigue and weak muscles. Irritability, anxiety, cognitive disturbances and depression are also common. Cushing’s syndrome can affect every organ system and can be lethal if not treated effectively.

About Relacorilant
Relacorilant is a selective cortisol modulator that binds to the glucocorticoid receptor (GR), but does not bind to the body’s other hormone receptors. Corcept is studying relacorilant in a variety of serious disorders, including ovarian, adrenal and prostate cancer and Cushing’s syndrome. Relacorilant is proprietary to Corcept and is protected by composition of matter, method of use and other patents. Relacorilant has orphan drug designation in the United States and the European Union for the treatment of Cushing’s syndrome.

About Corcept Therapeutics
For over 25 years, Corcept’s focus on cortisol modulation and its potential to treat patients across a wide variety of serious disorders has led to the discovery of more than 1,000 proprietary selective cortisol modulators. Corcept’s advanced clinical trials are being conducted in patients with hypercortisolism, solid tumors, amyotrophic lateral sclerosis (ALS) and liver disease (NASH). In February 2012, the company introduced Korlym, the first medication approved by the U.S. Food and Drug Administration for the treatment of patients with Cushing’s syndrome. Corcept is headquartered in Menlo Park, California. For more information, visit Corcept.com.

Forward-Looking Statements
Statements in this press release, other than statements of historical fact, are forward-looking statements based on our current plans and expectations that are subject to risks and uncertainties that might cause our actual results to differ materially from those such statements express or imply. These risks and uncertainties include, but are not limited to, our ability to operate our business; risks related to the study and development of Korlym as well as relacorilant, miricorilant, dazucorilant and our other product candidates, including their clinical attributes, regulatory approvals, mandates, oversight and other requirements; and the scope and protective power of our intellectual property. These and other risks are set forth in our SEC filings, which are available at our website and the SEC’s website.

In this press release, forward-looking statements include those concerning the development of relacorilant as a treatment for Cushing’s syndrome, and design, timing and expectations regarding our GRADIENT trial. We disclaim any intention or duty to update forward-looking statements made in this press release.

From https://finance.yahoo.com/news/corcept-completes-enrollment-phase-3-120000179.html

Filed under: adrenal, adrenal crisis, Cushing's, Treatments | 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

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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

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Medium and Long-Term Data from a Series of 96 Endoscopic Transsphenoidal Surgeries for Cushing Disease

Posted on March 29, 2024 by MaryO

Objective

Postoperative data on Cushing’s disease (CD) are equivocal in the literature. These discrepancies may be attributed to different series with different criteria for remission and variable follow-up durations. Additional data from experienced centers may address these discrepancies. In this study, we present the results obtained from 96 endoscopic transsphenoidal surgeries (ETSSs) for CD conducted in a well-experienced center.

Methods

Pre- and postoperative data of 96 ETSS in 87 patients with CD were included. All cases were handled by the same neurosurgical team between 2014 and 2022. We obtained data on remission status 3−6 months postoperatively (medium-term) and during the latest follow-up (long-term). Additionally, magnetic resonance imaging (MRI) and pathology results were obtained for each case.

Results

The mean follow-up duration was 39.5±3.2 months. Medium and long-term remission rates were 77% and 82%, respectively. When only first-time operations were considered, the medium- and long-term remission rates were 78% and 82%, respectively. The recurrence rate in this series was 2.5%. Patients who showed remission between 3−6 months had higher longterm remission rates than did those without initial remission. Tumors >2 cm and extended tumor invasion of the cavernous sinus (Knosp 4) were associated with lower postoperative remission rates.

Conclusion

Adenoma size and the presence/absence of cavernous sinus invasion on preopera-tive MRI may predict long-term postoperative remission. A tumor size of 2 cm may be a supporting criterion for predicting remission in Knosp 4 tumors. Further studies with larger patient populations are necessary to support this finding.

Key Words: Complete remission · Neuroendoscopy · Pituitary-dependant Cushing syndrome · Treatment outcome.

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INTRODUCTION

Cushing’s disease (CD) is characterized by excessive secretion of adrenocorticotropic hormone (ACTH) by a corticotropic adenoma in the pituitary gland. In patients with CD whose hypercortisolism is inadequately corrected, morbidity and mortality can increase by up to 4.8 times due to Cushingrelated complications such as osteoporosis, hypertension, dyslipidemia, insulin resistance, and hypercoagulability [11,18].
Endoscopic transsphenoidal surgery (ETSS), the first-line treatment for CD [7], is performed to decrease complications while achieving remission and long-term disease control. Previous studies on CD have reported varying remission rates between 45% and 95% and recurrence rates ranging from 3−66% [2,4,9,16,21,30]. This wide range of differences can be primarily attributed to differences in surgical experience among centers: centers with higher surgical experience have fewer postoperative complications and higher remission rates [4,6]. However, despite initial remission, patients with CD may eventually experience recurrence. The mean recurrence rate at the 5-10-year follow-up is 23% for microadenomas and 33% for macroadenomas [19,23,30].
Since the postoperative rates in the literature are variable, additional data from experienced centers may be necessary to resolve these discrepancies. In this study, we present the medium- and long-term follow-up data from 96 operations for CD that were conducted in a center with a high level of experience for ETSS.
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MATERIALS AND METHODS

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of Basaksehir Cam and Sakura City Hospital (No. 2022185). Informed consent was obtained from all patients. The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
This retrospective study included pre and postoperative data of 96 ETSS performed in 87 patients with CD (Fig. 1). CD was diagnosed based on unsuppressed cortisol levels (>1.8 µg/dL) following the 1-mg dexamethasone suppression test, high levels of urinary free cortisol, or late night salivary cortisol and plasma ACTH levels >20 pg/mL [28]. Between 2014 and 2022, all surgeries were conducted by the experienced neurosurgical team (Ö.G., O.T., B.E., E.A.) responsible for endoscopic transsphenoidal procedures at the Pituitary Research Center. The surgeries were performed under perioperative glucocorticoid coverage.

jkns-2023-0100f1.jpg
Fig. 1.
Number of operations and patients included in the study.

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Size, cavernous sinus invasion, sellar and suprasellar infiltration of adenoma on preoperative magnetic resonance imaging (MRI) scans, residual tumor on postoperative MRI scans, postoperative complications, pathology results, remission and recurrence status, and additional postoperative management were evaluated in addition to patients’ demographic data. For follow-up assessments, data obtained 3−6 months postoperatively and during the latest follow-up were included. Three different classifications obtained during radiologic evaluation using MRI were used for pituitary adenomas : 1) maximum size of tumor (MST) : 0−5 mm (group 1), 6−10 mm (group 2), 11−20 mm (group 3), and >20 mm (group 4); 2) Knosp classification : for evaluation of cavernous sinus invasion [22]; and 3) modified Hardy classification : for evaluation of sellar and suprasellar infiltrations [20,39].
In cases of CD without a lesion or with a lesion <6 mm on MRI, confirmation of the central origin and lateralization was provided by inferior petrosal sinus sampling (IPSS) with corticotropin-releasing hormone stimulation [25,26,29]. Under neuronavigation guidance, pure ETSS surgical interventions were performed for all patients by a single surgical team using the Medtronic StealthStation™ S7 and S8 systems (Medtronic, Minneapolis, MN, USA) together with 4-mm 0°, 30°, and 45° rigid optical instruments and an endoscope. A nasal decongestant spray was administered 1 hour before the operation. The sphenoid ostium was detected from both nostrils, and a bi-nostril approach was used by resecting the posterior nasal septum. After sphenoidectomy, the standard sellar approach was used for lesions in the sellar region. The details of these surgical procedures are described in previous study [14]. Selective adenectomy with ETSS was performed for preoperatively localized and visible tumors, whereas hemihypophysectomy was performed for non-lesional cases. In cases with cavernous sinus-invading tumors, particularly Knops 3-4, the defect which was created by the tumor on the medial wall of anterior cavernous sinus was identified and, it was expanded for resection of the tumor tissue within the cavernous sinus. If a defect was not visible, blunt-ended hook-shaped dissectors were used to create a defect on the medial wall, allowing access for the tumor to enter the cavernous sinus. Hematoxylin and Eosin (H&E) and immunohistochemistry staining were performed for the specimens obtained during ETSS. Adenomas showing positive immunohistological staining for ACTH were diagnosed histologically as corticotropinomas.
CD was considered to be in remission when the cases showed basal cortisol levels <5 µg/dL or suppressed cortisol levels (≤1.8 µg/dL) following the 1-mg dexamethasone suppression test, 3-6 months postoperation, and during the latest follow-up. The study protocol was approved by the ethics committee of our institution.
Data were statistically analyzed using the SPSS 15.0 package (IBM Corp., Armonk, NY, USA). The chi-square test was used for categorical variables. Sample distribution was evaluated with the Kolmogorov-Smirnov test. Continuous independent variables with a normal distribution were compared using the Student’s t-test. Continuous variables with non-normal distributions were compared using the Mann-Whitney U test. p<0.05 was considered statistically significant. A Kaplan-Meier survival analysis was conducted to determine probability and time to recurrence in cases with initial remission.
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RESULTS

Demographic data

A total of 96 ETSS were performed for 87 patients with CD. Of the 87 patients, 68 (79%) were female, and 19 (21%) were male. The mean patient age was 42.2±12.9 years, and the mean duration of follow-up was 39.5±3.2 months. Of the 96 surgeries, 79 (82%) were performed for the first time, six (6%) were performed for residual tumors, and 11 (12%) were performed following a recurrence of the disease. Eight of the 17 patients who underwent reoperations had undergone their first operation at another center.

Preoperative imaging

Table 1 shows the maximum tumor size on preoperative pituitary MRI before each surgical procedure. Preoperative IPSS for lateralization was performed in 42 operations (44%), all of which were first-time cases. Knosp classification based on preoperative pituitary MRI and the modified Hardy classification is presented in Table 1.

Table 1.

Preoperative pituitary magnetic resonance imaging scans

Number of tumors (n=96)
Maximum tumor size
 Group 1, 0−5 mm 41 (42.7)
 Group 2, 6−10 mm 24 (25.0)
 Group 3, 11−20 mm 20 (20.8)
 Group 4, >20 mm 11 (11.5)
Knosp classification
 Grade 0 52 (54.2)
 Grade 1 22 (22.9)
 Grade 2 6 (6.3)
 Grade 3 8 (8.3)
 Grade 4 8 (8.3)
Modified Hardy classification
 0
  A 41 (42.8)
  B –
  C –
  D –
  E –
 1
  A 14 (14.6)
  B –
  C –
  D –
  E 4 (4.2)
 2
  A 5 (5.2)
  B –
  C –
  D –
  E 5 (5.2)
 3
  A 1 (1.0)
  B 2 (2.1)
  C –
  D –
  E 1 (1.0)
 4
  A 1 (1.0)
  B –
  C –
  D 1 (1.0)
  E 3 (3.1)
 NA 18 (18.8)

Values are presented as number (%). Invasion : 0, sella normal; 1, sella focally expanded and tumor ≤10 mm; 2, sella enlarged and tumor ≥10 mm; 3, localized perforation of the sellar floor; 4, diffuse destruction of the sellar floor. Suprasellar extension : A, no suprasellar extension; B, anterior recesses of the third ventricle obliterated; C, floor of the third ventricle grossly displaced with parasellar extension; D, intracranial (intradural) : anterior, middle or middle fossa; E, into/beneath the cavernous sinus (extradural).

NA : not available

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Postoperative results

Remission was achieved between the 3rd and 6th months in 74 (77%) of the 96 operations, and long-term remission in 79 operations (82%). Among all 96 operations, eight (8%) concluded with a residual tumor. Regarding only first-time operations, five (6%) of the 79 concluded with a postoperative residual tumor. Of the 79 first-time operations, there were 62 cases (78%) of remission between 3 and 6 months. Two (2.5%) of these 79 operations involved recurrence during follow-up, while 60 (97%) showed sustained remission. Those with sustained remission had a median disease-free survival time of 31 months (interquartile range, 14-64) during long-term followup, two cases with recurrence had their recurrence 49 and 54 months after their operation. Survival analysis of cases with remisson and recurrence is presented in Fig. 2. CD persisted after 17 (21.5%) of the 79 first operations.

jkns-2023-0100f2.jpg
Fig. 2.
Survival analysis after the first operation in cases with remission at 3-6 months. Dashed line represents cases with recurrence and, straight line represents cases with sustained remission during long-term follow-up.

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Ten (13%) of the 79 cases underwent reoperation; two were due to recurrence, and eight due to disease persistence. In five cases (29%), the patients were initially unresponsive but showed remission later during the long-term follow-up. Remission was achieved with stereotactic radiosurgery (STRS) and medical treatment in one of these cases, with only STRS in two and only medical treatment in two cases. At the latest follow-up visit, the total number of cases showing remission after the first operation was 65 (82%). Additional details regarding the results of the first operations are provided in Fig. 3.

jkns-2023-0100f3.jpg
Fig. 3.
Results of the cases who had operation for the first time.

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Of the 18 reoperations, the results for one case were excluded since the patient was operated at another center. After the reoperation (n=17), the medium and long-term remission rates were 71% (n=12) and 77% (n=13), respectively. The 3-6-month remission rate did not differ significantly between first-time and reoperations (p=0.5). Residual tumors were present in three cases (18%) after reoperation. Of the early non-responders, one case showed remission after STRS, and none of the responders showed recurrence during long-term follow-up. Additional details regarding the results of reoperations are provided in Fig. 4.

jkns-2023-0100f4.jpg
Fig. 4.
Results of the reoperations in our center.

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Remission rates based on tumor size are presented in Table 2. The initial remission rates of the tumors in MST group 4 were significantly lower than those in the other MST groups (MST 1 vs. 4, p=0.01; MST 2 vs. 4, p=0.001; and MST 3 vs. 4, p=0.006). Comparisons of the other MST groups showed no significant differences. When adenomas were stratified using the 10-mm cut-off, the remission rates did not differ significantly (remission rate, 81% for adenomas <10 mm and 68% for adenomas ≥10 mm; p=0.2). Postoperative residual tumors were observed in five of the 11 tumors (46%) >2 cm (MST group 4) and in one tumor in each of MST groups 1-3 (2%, 4%, and 5%, respectively, p<0.001). Reoperation rate was 17% (n=7) for adenomas ≤5 mm, 18% (n=10) for adenomas ≥6 mm (p=0.9), and 27% (n=3) for adenomas >20 mm (among all grades, p=0.3).

Table 2.

Comparison of remission rates in preoperative pituitary magnetic resonance imaging scans

3−6-month remission Long-term remission
Maximum tumor size
 Group 1, 0−5 mm (n=41) 31 (75.6) 33 (80.5)
 Group 2, 6−10 mm (n=24) 22 (91.7) 22 (91.7)
 Group 3, 10−20 mm (n=20) 17 (85.0) 17 (85.0)
 Group 4, >20 mm (n=11) 4 (36.4) 7 (63.6)
 p-value 0.003* 0.200
Knops classification
 0 (n=52) 41 (78.8) 44 (84.6)
 1 (n=22) 21 (95.5) 21 (95.5)
 2 (n=6) 4 (66.7) 3 (50.0)
 3 (n=8) 7 (87.5) 7 (87.5)
 4 (n=8) 1 (12.5) 4 (50.0)
 p-value <0.001* 0.010*
Modified Hardy classification
 0
  A (n=41) 32 (78.0) 34 (82.9)
 1
  A (n=14) 12 (85.7) 12 (85.7)
 2
  E (n=4) 3 (75.0) 3 (75.0)
  A (n=5) 5 (100.0) 5 (100.0)
 3
  E (n=5) 2 (40.0) 2 (40.0)
  A (n=1) 1 (100.0) 1 (100.0)
  B (n=2) 2 (100.0) 2 (100.0)
 4
  E (n=1) 0 (0.0) 0 (0.0)
  A (n=1) 1 (100.0) 1 (100.0)
  D (n=1) 0 (0.0) 0 (0.0)
  E (n=3) 1 (33.3) 3 (100.0)
 p-value 0.10 0.06
Pathology result
 Corticotropinoma (+) (n=71) 58 (81.7) 60 (84.5)
 Corticotropinoma (-) (n=25) 16 (64.0) 19 (76.0)
 p-value 0.07 0.30

Values are presented as number (%). Invasion : 0, sella normal; 1, sella focally expanded and tumor ≤10 mm; 2, sella enlarged and tumor ≥10 mm; 3, localized perforation of the sellar floor; 4, diffuse destruction of the sellar floor. Suprasellar extension : A, no suprasellar extension; B, anterior recesses of the third ventricle obliterated; D, intracranial (intradural) with anterior, middle, or middle fossa; E, into/beneath the cavernous sinus (extradural).

* Statistically significant p-value

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Remission rates based on Knosp and Hardy classifications are presented in Table 2, respectively. The medium-term remission rates in Knosp group 4 were significantly lower than the rates in the other groups (Knosp 0 vs. 4, p<0.001; Knosp 1 vs. 4, p<0.001; Knosp 2 vs. 4, p=0.04; and Knosp 3 vs. 4, p=0.003). Additionally, the medium-term remission rate of tumors in Knosp group 2 was lower than that in Knosp group 1 (p=0.04). However, remission rates did not differ significantly among the other groups. Comparing invasive (Knosp 3 and 4) and noninvasive (Knosp 0, 1, and 2) tumors, remission rates within 3-6 months were 50% and 83% in the invasive and noninvasive groups, respectively. We further stratified cases with tumor size ≥20 mm (n=11) using Knosp classification; one case (9%) was Knosp 0, one case (9%) was Knosp 1, two cases (18%) were Knosp 3, and seven cases (64%) were Knosp 4 tumors. For ≥20 mm, all cases with Knosp 0, 1, and 3 tumors achieved remission within 3-6 months postoperatively, while none of the cases with Knosp 4 tumors had remission (p=0.01). All the cases with Knosp 0, 1, and 3 tumors sustained remission, and three cases with Knosp 4 tumor later achieved long-term remission (p=0.3). Of the cases that achieved long-term remission, two underwent STRS, and one had medical therapy with additional STRS.
Of the 96 tissue specimens obtained during ETSS, 71 (74%) stained positive for ACTH and were histologically identified as corticotropic adenomas, while 25 (26%) were negative. Remission rates based on the pathology results are compared in Table 2. Of the lesions with conclusive findings on MRI (≥6 mm lesions), 89% (n=49) were pathologically confirmed as corticotropinomas, whereas 54% (n=22) of those with inconclusive MRI f indings were pathologically conf irmed (p<0.001). Among the lesions that showed negative results for both conclusive MRI findings (≤5 mm) and pathologic confirmation (negative for a corticotropinoma) (n=19), 12 (63%) showed remission at 3-6 months and 14 (74%) showed remission during long-term follow-up.
During the exploration of the cavernous sinus in one patient (1%), postoperative lateral gaze paralysis of the eye developed due to right abducens nerve palsy. The patient was treated with anti-inflammatory doses of steroids, and the symptom completely resolved within 1 month. In three other patients (3%), severe epistaxis was observed in the postoperative period, 1 to 3 weeks after surgery. Nasal packing was applied for 3 days. Additionally, three patients (3%) experienced postoperative rhinorrhea. To address this issue, a reconstruction of the skull base was performed using fat tissue harvested from the leg, fascia lata graft, and tissue adhesive material. These patients were monitored with a lumbar drain for 1 week. Among the patients who developed rhinorrhea, one patient also developed meningitis and received intravenous antibiotic therapy for about 3 weeks and, the situation compeletly resolved during follow-up. The postoperative complications are summarized in Table 3. Comparison of various characteristics of the cases with and without medium and long-term remission are presented in Table 3, respectively.

Table 3.

Comparison of cases with and without remission, postoperative complications

3−6-month remission

 Long-term remission

 Number of cases (n=96)
Remission (+) (n=74) Remission (-) (n=22) p-value Remission (+) (n=79) Remission (-) (n=17) p-value
Operation 0.500 0.08
 First time 62 (83.8) 17 (77.3) 66 (83.5) 13 (76.5)
 Re-operation 12 (16.2) 5 (22.7) 13 (16.5) 4 (23.5)
Tumor characteristics 0.003* 0.20
 MST
  Grade 1 31 (42.0) 10 (45.0) 33 (41.8) 8 (47.1)
  Grade 2 22 (30.0) 2 (9.0) 22 (27.8) 2 (11.8)
  Grade 3 17 (23.0) 3 (14.0) 17 (21.5) 3 (17.6)
  Grade 4 4 (5.0) 7 (32.0) 7 (8.9) 4 (23.5)
 Knosp classification <0.001* 0.01*
  0 41 (56.0) 11 (50.0) 44 (55.5) 9 (53.0)
  1 21 (28.0) 1 (4.5) 21 (26.5) 2 (12.0)
  2 4 (5.0) 2 (9.0) 3 (4.0) 1 (6.0)
  3 7 (10.0) 1 (4.5) 7 (9.0) 1 (6.0)
  4 1 (1.0) 7 (32.0) 4 (5.0) 4 (23.0)
 Hardy classification 0.09 0.06
  0A 32 (43.2) 9 (41.0) 34 (43.0) 7 (41.0)
  1A 12 (16.2) 2 (9.0) 12 (15.0) 2 (12.0)
  1E 3 (4.0) 1 (4.5) 3 (4.0) 1 (6.0)
  2A 5 (6.7) 0 (0.0) 5 (6.0) 0 (0.0)
  2E 2 (2.7) 3 (14.0) 2 (3.0) 3 (17.0)
  3A 1 (1.4) 0 (0.0) 1 (1.0) 0 (0.0)
  3B 2 (2.7) 0 (0.0) 2 (3.0) 0 (0.0)
  3E 0 (0.0) 1 (4.5) 0 (0.0) 1 (6.0)
  4A 1 (1.4) 0 (0.0) 1 (1.0) 0 (0.0)
  4D 0 (0.0) 1 (4.5) 0 (0.0) 1 (6.0)
  4E 1 (1.4) 2 (9.0) 3 (4.0) 0 (0.0)
  NA 15 (20.3) 3 (13.5) 16 (20.0) 2 (12.0)
Postoperative
 Complication 0.900 0.30
  (+) 10 (13.5) 3 (13.6) 12 (15.2) 1 (5.9)
  (-) 64 (86.5) 19 (86.4) 67 (84.8) 16 (94.1)
 Pathologic diagnosis 0.070 0.30
  Corticotropinoma 58 (78.4) 13 (59.1) 60 (75.9) 11 (64.7)
  Negative 16 (21.6) 9 (40.9) 19 (24.1) 6 (35.3)
 Remission during long-term F/U <0.001*
  (+) 72 (97.3) 7 (31.8)
  (-) 2 (2.7) 15 (68.2)
 Residual tumor 0.001*
  (+) 3 (3.8) 5 (29.4)
  (-) 76 (96.2) 12 (70.6)
 Remission during long-term F/U <0.001*
  (+) 72 (91.1) 2 (11.8)
  (-) 7 (8.9) 15 (88.2)
Postoperative complication
 DI-temporary 4 (4.2)
 DI-permanent 4 (4.2)
 Meningitis 1 (1.0)
 CSF leak 3 (3.1)
 Epistaxis 3 (3.1)
 Cranial nerve palsy, transient 1 (1.0)
Hypopituitarism 4 (4.2)
 Hypocortisolism 2 (2.1)
 Hypothyroidisim 2 (2.1)

Values are presented as number (%). *Statistically significant p-values. MST : maximum size of tumor, NA : not available, F/U : follow up, DI : diabetes insipidus, CSF : cerebrospinal fluid

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DISCUSSION

This study reported an overall postoperative 3-6 month remission rate of 77% and a long-term remission rate of 82% after 3 years of follow-up. The initial and long-term remission rates after first operations were 78% and 82%, respectively, with a recurrence rate of 2.5% over a follow-up period of 3-3.5 years. Additionally, our findings revealed that tumor size >2 cm and extended tumor invasion of the cavernous sinus (Knosp 4) might be associated with lower postoperative remission rates. Patients who showed remission within 3-6 months showed higher rates of long-term remission than those in patients without initial remission.
Pituitary surgery is the first-line treatment modality for CD. ETSS is a safe and less invasive method for treating pituitary adenomas; therefore, it has been increasingly preferred in CD [5,15]. However, the postsurgical outcomes in patients with CD have shown variable remission and recurrence rates [2,4,9,16,17,21,30]. These discrepancies may be attributable to differences in population and number of cases involved in the studies, tumor characteristics, criteria for remission and recurrence used by the centers, laboratory parameters, time of evaluation and followup durations, surgical and imaging techniques used by different centers, and neurosurgical expertise.
In this study, we present the medium- and long-term postoperative results of 96 ETSS procedures performed in 87 patients. The medium-term results (obtained 3-6 months postoperation) were preferred to immediate results since a subset of cases may show delayed remission, and immediate postoperative results could be misleading in almost 6% of cases [37]. The overall medium-term remission rate was 77%, consistent with the results published by Serban et al. [34], who reported an overall remission rate of 77% 2 months postoperation. A larger series of 1106 cases reported an immediate remission rate of 72.5% within 7 days postoperation; however, this rate decreased to 67% after delayed remission rates and recurrences 56 months postoperation were considered [12]. The long-term remission rate obtained over a median period of 3 years was 82% in our series. The increased long-term remission rate was attributed to reoperations, additional medical therapies, and the use of STRS in those who did not show remission initially.
Of the 96 procedures, 79 were performed for the first time. The medium-term remission rate after first operations was 78%. Recent studies have reported remission rates of 74-82% after first operations [12,34]. The recurrence rates reported previously varied between 3% and 66% [5,12,34]. However, the duration of follow-up differed among the studies. Dai et al. [12] and Brady et al. [5] reported recurrence rates of 12% and 3%, respectively, after a follow-up period of 2 years. In contrast, Serban et al. [34] reported a recurrence rate of 17% after a longer followup duration of 6 years. In this series, after a median follow-up period of 3 years, the overall recurrence rate was 2.5%. Residual tumors were observed in five cases (6%), and the reoperation rate after the first operation was 13%. Including the eight patients admitted for reoperation after having undergone their first surgery in another center, 17 cases involved reoperations in our center. Of these cases, 71% (n=12) showed remission between 3-6 months postoperation, while none showed recurrence; thus, the long-term remission rate was 77%. Residual tumors were detected in three cases (18%), and the disease persisted in four (24%) of these 17 reoperated cases. Previous studies have reported remission rates of 22-75% after repeated surgery in CD [5,12,34,38]. Although the success rates after reoperations were lower than those in first-time operations in some studies [38], the remission rates after the first and reoperations did not differ significantly in our study.
Tumor size has been reported to contribute to the success of transsphenoidal surgery [12,34], with microadenomas showing a higher success rate after surgery [5,12,34]. Our remission rates for micro- and macroadenomas were similar to those reported by Dai et al. [12] : 81% for adenomas <10 mm and 68% for adenomas ≥10 mm. However, the statistical significance of our study differed from that in the series presented by Dai et al. [12] (p=0.2 vs. p=0.002). This may be due to the large difference in the number of cases included in the two studies and the differences in size scales for tumors ≥10 mm. In our series, when the tumors were stratified further by the tumor size, the medium-term remission rate further decreased to 36% for tumors ≥20 mm in size, although the remission rates for other groups <20 mm were all above 75% (p=0.003). Sharifi et al. [35] classified pituitary MRI scans in CD showing a tumor size <6 mm as “inconclusive” because incidentalomas are frequent among tumors in this size range, and this size is not indicative of CD. Previously published series reported that the rate of inconclusive MRI scans in CD was 36-64%, and the remission rates varied between 50% and 71% for those with an inconclusive MRI scan [10,24,27,32,33]. In our series, 54% of the preoperative MRI scans were inconclusive. In the series presented by Sharifi et al. [35] and some other series [8,12,32,36], no significant difference was observed between the remission rates of CD cases with and without a conclusive MRI.This finding is controversial since other studies showed decreased remission rates with preoperative inconclusive MRIs [13,40]. Similar to the results reported by Sharifi et al. [35], we did not find a statistically significant difference between the remission rates of tumors <6 mm and those between 6-20 mm. However, a significant difference was observed between tumors <6 mm and those ≥20 mm. Residual tumors were more frequent after operating tumors >20 mm compared to those <20 mm, but the number of reoperations did not differ among the groups. Additionally, tumors >20 mm were primarily Knosp 4 (64%), probably contributing to lower remission rates in this group. Interestingly, two Knosp 3 cases had postoperative remission within 3-6 months without additional intervention. In these two cases, the surgical team explored the cavernous sinus and could resect the tumor. However, complete excision was not feasible with Knosp 4 tumors, where there is a complete encasement of the intracavernous internal carotid artery. Thus, a tumor size of 20 mm may be supportive data in predicting non-remission in the presence of complete cavernous sinus infiltration.
Cavernous sinus invasion, determined by the Knosp classification, and sellar invasion and/or suprasellar extension, determined by the Hardy-Wilson classification, indicate the radiologic status of local invasion in cases of pituitary tumors [20,22,39]. Invasion to surrounding structures and tissues may be a limiting factor for postoperative remission of pituitary tumors. In the series presented by Dai et al. [12], remission rates of corticotropinomas with Knosp grade 4 (definitive cavernous sinus invasion) dropped to 53% from a remission rate of 77% for corticotropinomas with less likely or no cavernous sinus invasion (p<0.001). Similarly, our results showed that both medium- and long-term remission rates for Knosp grade 4 tumors decreased to 13% and 50%, respectively, and were lower than the remission rates in other grades (p<0.001 and p=0.01, respectively). While remission rates in Knosp group 3 were not inferior to noninvasive tumors, remission rates in Knosp group 4 were lower than all the other groups. In this regard, the extent of invasion may be more determinative. In contrast, in our series, the modified Hardy classification did not show a significant effect on postoperative remission rates in medium- and long-term follow-up assessments. Araujo-Castro et al. [3] had previously shown that for pituitary adenomas, the Hardy-Wilson classification lacked utility in predicting postoperative remission compared to the Knosp classification. The difference in the utility of these classifications for predicting postoperative remission may be due to differences in accessing tissues during surgery.
In the present series, 74% (n=71) of tissues were histologically proven to be corticotropinomas, while 26% (n=25) did not show histologic confirmation. Medium- and long-term remission rates did not differ between histologically proven and unproven CD cases (medium-term remission rates, 82% vs. 64%, p=0.07; long-term remission rates, 85% vs. 76%, p=0.3). A conclusive finding of an adenoma on MRI increased the rate of histologic proof of corticotropinoma in our series, implying that adenomas showing a ≥6-mm lesion on MRI more frequently stained positive for ACTH. In previous studies 12-53% of CD did not have postoperative pathologic identification and the rate increased in those with a preoperative inconclusive MRI [25,31,38]. However, this did not have a significant influence on our remission rates. The remission rates did not decrease even for CD cases that were not conclusively detected on MRI and could not be histologically proven. On the other hand, in previous studies, ACTH positivity was higher, and the lack of proof for a corticotropinoma decreased the remission rates [1,12,31,32,34]. The higher remission rates despite reduced localization with MRI and/or lower rates of histologic confirmation in our series may be explained by the successful preoperative IPSS lateralization, surgical exploration, and hemi-hypophysectomy procedure. Furthermore, tumor tissues might have been aspirated along with blood and other materials through the suction tube, potentially resulting in less histological confirmation despite postoperative remission of CD.
Additionally, tumor tissues might have been aspirated along with blood and other materials through the suction tube, potentially resulting in less histological confirmation despite postoperative remission of CD.
The total rate of complications in this series was 20%, and the most frequent complication was diabetes insipidus (DI; 8%, both permanent and temporary). The incidence of hypopituitarism was relatively lower (4%), mainly involving hypocortisolism and hypothyroidism. Recent studies have shown postoperative DI rates of 25-66% and hypothyroidism rates of 11-23% [5,34]. Although our neurosurgical team was experienced in conducting pituitary surgeries, other factors may have resulted in these differences. Since not all the cases were postoperatively followed in our center, with some patients lost to follow-up, there may be missing data.
Comparing cases with and without remission in the medium term, cases of remission frequently involved adenomas >20 mm and less cavernous sinus invasion. Additionally, cases that achieved medium-term remission showed long-term remission more frequently. In the long term, those showing remission had less cavernous sinus invasion and residual tumors compared to those without remission. Therefore, we may conclude that a tumor size of 20 mm may predict medium-term remission, while the absence of/less cavernous sinus invasion, early remission, and absence of residual tumor may predict long-term remission.
This study had limitations. First, the retrospective nature of the study and the limited number of cases, which was inevitable due to the low incidence of CD, may have distorted our results. Although the same neurosurgical team operated on all patients, they were followed up pre and postoperatively at different endocrinology centers, causing difficulty in obtaining the full postoperative data of certain cases. Lastly, some patients recently underwent ETSS; thus, they had a shorter follow-up period. However, we intend to present the longer-term outcomes of all patients in a separate study.
Although ETSS is the first-line treatment for CD, previous studies on the use of ETSS for CD have reported a wide range of remission and recurrence rates, which can be primarily attributed to differences in the surgical experience levels among centers. This trend highlights the need for additional data from experienced centers to resolve the discrepancies in the existing data. Therefore, we present medium- and long-term follow-up data from 96 operations for CD conducted in a center with a high level of experience for ETSS. We believe our study makes a significant contribution to the literature because the findings reconfirm the usefulness of ETSS for the treatment of CD and highlight the importance of the size of the adenoma and presence/absence of cavernous sinus invasion on preoperative MRI in predicting long-term remission postoperatively.
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CONCLUSION

ETSS is a safe and effective method for the treatment of CD. Some characteristics of adenomas, such as size, cavernous sinus invasion, and postoperative residue, may predict long-term remission. A tumor size of 2 cm may be a supporting criterion for predicting remission status in the presence of complete cavernous sinus infiltration. Further studies with larger patient populations are necessary to support this finding.
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Notes

Conflicts of interest

No potential conflicts of interest relevant to this study exist.

Informed consent

Informed consent was obtained from all individual participants included in this study.

Author contributions

Conceptualization : BE, MB, EH; Data curation : EA, OH, DT, MM; Formal analysis : LŞP, DAB, DT, İÇ; Funding acquisition : OT, ÖG, DAB; Methodology : LŞP, İÇ, MM, ÖG; Project administration : BE, SÇ, EH; Visualization : EA, OT, OH; Writing – original draft : BE, MB, SÇ; Writing – review & editing : BE, EH

Data sharing

None

Preprint

None

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Acknowledgements

This manuscript was edited by a certified English Proofreading Service (Editage).
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