Clinical and Surgical Outcomes of Pediatric Cushing's Disease Following Endoscopic Transsphenoidal Surgery

doi:10.21203/rs.3.rs-4937982/v1

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Clinical and Surgical Outcomes of Pediatric Cushing's Disease Following Endoscopic Transsphenoidal Surgery

https://doi.org/10.21203/rs.3.rs-4937982/v1

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Background

Cushing's disease (CD) is characterized by hypercortisolism due to excessive adrenocorticotropic hormone (ACTH) secretion from a pituitary adenoma. Though more common in adults, pediatric cases constitute approximately 5% of those seen in adults. Early diagnosis and treatment are critical due to the severe impacts on growth and development in children. Endoscopic transsphenoidal surgery (ETSS) is the preferred first-line treatment for both children and adults.

Methods

From 2011 to 2024, 3,280 patients with pituitary adenoma underwent surgery using the ETSS technique at Loghman Hospital of Tehran, including 213 CD cases, of which 22 were pediatric (under 18 years old). This retrospective study analyzed clinical data such as age, gender, presenting symptoms, family and medical history, imaging characteristics, surgical findings, pathology, follow-up, and postoperative outcomes. Diagnostic criteria included biochemical tests, MRI imaging, and inferior petrosal sinus sampling.

Results

Out of 22 pediatric patients, 16 were females and 6 males, with an average age of 14.73 years. Obesity was the initial clinical manifestation in 59% of the patients. According to the Hardy-Wilson classification, 18.2% of patients were stage E, 9.09% stage C, and the rest (excluding MRI-negative patients) stage A. ETSS was performed on all patients, with total hypophysectomy in 18.2% and hemi-hypophysectomy in 9.09%. Postoperative complications included cerebrospinal fluid leakage in 13.63% of patients. Remission was achieved in 95.45% of patients, with a recurrence rate of 4.54%. Hormone imbalances post-surgery included hypocortisolism (50%), hypothyroidism (45.45%), and hypogonadism (13.63%).

Conclusion

ETSS is an effective and safe treatment for pediatric CD, achieving high remission rates and minimal complications. This study highlights the importance of specialized surgical care in managing pediatric CD and underscores the need for early diagnosis and intervention. Further studies are warranted to evaluate long-term outcomes and optimize treatment protocols.

Cushing's disease

Pediatric endocrinology

Endoscopic transsphenoidal surgery

Pituitary adenoma

Hypercortisolism

Surgical outcomes

Cushing's disease (CD) is a pathological state characterized by hypercortisolism, occurring when a pituitary adenoma secretes an excessive amount of adrenocorticotropic hormone (ACTH). Hypercortisolemia, marked by elevated cortisol secretion, is attributed to the presence of a pituitary corticotrophic adenoma. While predominantly reported in adults, this phenomenon can also occur in children, albeit rarely [1, 2]. The occurrence of CD in children is estimated to be around 5% of that observed in adults [3]. CD accounts for 70% of cases of adult-onset endogenous Cushing’s syndromes and 75–80% of cases of pediatric-onset endogenous Cushing’s syndromes [2, 4–6]. It is associated with severe illness in both pediatric and adult patients; hence, early diagnosis and treatment are crucial for optimal therapeutic outcomes [7].

Pituitary radiotherapy and transsphenoidal pituitary surgery are considered the most effective therapeutic options for these patients. The clinical presentations of hypercortisolemia can exhibit substantial variation across all age groups, frequently complicating the establishment of a precise diagnosis. Moreover, the initial symptoms of pediatric CD may be underestimated and differ from those observed in adult patients [7–9]. Typical observations in pediatric CD include growth retardation with weight gain, a higher occurrence in males, and abnormal puberty [10–12]. Although there are documented differences in the onset of CD in adults and children, the diagnostic criteria and investigation methodologies for pediatric cases are typically derived from established practices for adults.

The primary goal of treating CD is to quickly normalize cortisol levels, especially in children, due to the adverse effects of prolonged high cortisol levels on growth and development [7]. Endoscopic Transsphenoidal Surgery (ETSS) is the recommended first-line treatment for both children and adults with CD, involving the targeted surgical removal of the adenoma. ETSS in children presents technical challenges and requires specialized care from a highly trained pediatric neurosurgeon [8, 13]. Consistently undetectable serum cortisol levels (less than 50 nmol/l) within a week post-surgery are regarded as the most reliable indicator of successful treatment for CD [8]. The primary aim of this study is to evaluate the clinical and surgical outcomes in pediatric patients with CD, a rare condition with limited prior investigations.

From 2011 to 2024, a total of 3,280 patients with pituitary adenoma underwent surgery using the ETSS technique at Loghman Hospital of Tehran. Among these patients, 213 were diagnosed with CD, and 22 were pediatric cases with age not exceeding 18-years-old (Fig. 1). A retrospective investigation was conducted on 22 consecutive pediatric patients with CD who underwent transsphenoidal microsurgery. The clinical data collected included age, gender, presenting symptoms, family and medical history, imaging characteristics, operative findings such as Hardy-Wilson classification and adenoma size, pathology results, follow-up, and postoperative outcomes, including diabetes insipidus, complications, and current endocrine status.

The Hardy-Wilson classification assessed the level of damage to the sellar region (grade) and the extent of expansion beyond the sellar region (stage) [1]. Extrasellar extension, according to the Hardy-Wilson modified scale, is categorized into different stages: Stage 0 indicates no suprasellar extension, Stages A-C represent progressive suprasellar extension (A indicates occupation of the cistern, B indicates destruction of the recess of the third ventricle, and C indicates gross displacement of the third ventricle), and Stages D-E represent parasellar extension (D indicates intracranial extension and E indicates cavernous sinus extension).

All patients provided written informed consent before enrolment. Institutional review board approval was waived as deidentified information of patients was retrospectively collected.

Diagnostic Evaluation:

A multidisciplinary panel comprising members from the Departments of Endocrinology, Neurosurgery, Radiology, and Pathology established the diagnosis of CD. The diagnosis was confirmed through biochemical tests, including urine free cortisol (UFC), daytime serum ACTH, and low-dose and high-dose dexamethasone suppression tests (LDSST and HDDST). The diagnostic criteria included tumor detection via contrast-enhanced MRI or dynamic gadolinium-enhanced MRI, sustained hypercortisolism confirmed by morning and evening plasma cortisol levels, 24-hour UFC levels, LDDST, HDDST, or contrast-enhanced MRI, along with positive results from inferior petrosal sinus sampling (IPSS) to rule out the presence of a tumor. If no tumors were identified or if there were suspicions, IPSS was performed according to the protocol described by Feng [5].

Operation and Post-operation

All ETSS operations were performed by the same surgical team supervised by the senior author (G.Sh). The surgical techniques and informed consent were discussed, considering the patient's age, history, and disease severity. Upon the discovery of an adenoma during surgery, expanded adenomectomy (removal of both the adenoma and the surrounding pituitary tissue) was performed.

Postoperative clinical and endocrinological evaluations were conducted within 7 days after surgery to assess remission and within 6 months after surgery to determine residual disease. Patients were classified as being in remission if they exhibited clinical adrenal insufficiency and had serum cortisol levels below 2.5 µg/dL at 48 hours after surgery or below 1.8 µg/dL with a low-dose dexamethasone suppression test in the third month postoperative. Additionally, they needed to show a restoration of their circadian rhythm, improvement in symptoms, and no evidence of an adenoma in MR imaging.

Persistent illness was characterized by higher postoperative cortisol levels and a requirement for further CD therapy within a 6-month period. Additionally, gadolinium-enhanced and/or dynamic gadolinium-enhanced MRI of the pituitary gland was employed to validate the reappearance of the condition [6, 7].

Out of the 22 patients, 16 were young females and 6 were young males, with an average age of 14.73 years (range 11–17). Obesity was the initial clinical manifestation in 59% of the patients, while menstrual problems and striae were reported in 18.2% of the patients. None of the patients had a family history of MEN Syndrome, but 4.54% had a family history of CD. Regarding their medical history, 22.72% had a history of fatty liver, 13.63% had dyslipidemia, 9.09% had diabetes mellitus, and 4.54% were in a pre-diabetic state. Detailed demographic and medical history information is provided in Table 1.

Table 1

Patient Demographic and Clinical Characteristics
Patient ID	Age	Gender	Duration of Symptoms (months)	First Manifestation	Family History of Pituitary Adenoma	Family History of MEN	Past Medical History
X 1	17	Male	18	Obesity (28 Kg)	No	No	No
X 2	15	Female	12	Menstural disorder	No	No	No
X 3	16	Female	15	Menstural disorder	No	No	Fat Liver, Dyslipidemia
X 4	11	Female	24	Obesity (12 Kg)	No	No	No
X 5	15	Female	6	Obesity (12 Kg)	No	No	No
X 6	12	Female	50	Obesity (30 Kg)	No	No	HTN, Fat Liver
X 7	14	Female	36	Striae	Yes (her cousin)	No	Fat Liver
X 8	15	Female	9	Obesity (30 Kg)	No	No	No
X 9	14	Male	12	Obesity (12 Kg)	No	No	No
X 10	17	Female	24	Headache	No	No	No
X 11	14	Female	12	Menstural disorder	No	No	HTN, Fat Liver, Dyslipidemia
X 12	17	Male	6	Obesity (30 Kg)	No	No	No
X 13	16	Female	2	Striae	No	No	No
X 14	16	Male	18	Obesity (13 Kg)	No	No	HTN
X 15	15	Female	12	Obesity (24 Kg)	No	No	HTN, DM
X 16	15	Male	24	Blurred vision	No	No	No
X 17	14	Female	24	Obesity (30 Kg)	No	No	Fat Liver, Dyslipidemia
X 18	17	Female	12	Striae	No	No	DM
X 19	12	Female	3	Obesity (15 Kg)	No	No	No
X 20	14	Female	12	Obesity (15 Kg)	No	No	No
X 21	16	Female	48	Menstural disorder	No	No	Pre DM
X 22	12	Male	24	Obesity (28 Kg)	No	No	No
TOTAL	(11–17)	Female: % (16/22) Male: % (6/22)	Mean 18.3	Blurred vision: (1/21) Obesity: (13/22) Menstural disorder: (4/22) Striae: (3/22) Headache: (1/21)	Family History of Pituitary Adenoma: % (1/22)	FH MEN: 0% (0/22)	HTN: (4/22) DM: (2/22) Pre DM: (1/22) Fat Liver: (5/22) Dyslipidemia: (3/22)

According to the Hardy-Wilson classification, 18.2% of patients were classified as stage E, 9.09% as stage C, and the rest (excluding MRI-negative patients) as stage A. Additionally, 18.2% of patients exhibited invasion into the cavernous sinus, and 9.09% showed evidence of hemorrhagic sella on their imaging.

All patients underwent ETSS surgical treatment (Table 2 and Fig. 1). Among them, 18.2% also underwent total hypophysectomy, and 9.09% underwent hemi-hypophysectomy. Radiation therapy was performed in 9.09% of patients, with one patient eligible for bilateral adrenalectomy. No surgical complications developed except for cerebrospinal fluid (CSF) leakage, which was observed in 13.63% of patients. Further details on the surgical treatments are provided in Table 2.

Table 2

Surgical and Treatment Details
Patient ID	Size of Adenoma	Multifocality	Invasion	Hardy-Wilson Classification	Additional Findings	Number of surgeries	Surgical Approach	Resection
X 1	Micro	Unifocal	No	1A		1	ETSS	Adenomectomy
X 2	Micro	Multifocal	No	1A		1	ETSS	Adenomectomy
X 3	Macro	Unifocal	Cavernous Sinus Knosb 2	First Op: 3E 2nd Op: 3E		2 ( Same surgeon)	ETSS	Adenomectomy
X 4	Micro	Unifocal	No	1A		1	ETSS	Adenomectomy
X 5	Micro	Unifocal	No	1A	Hemorrhagic	1	ETSS	Adenomectomy
X 6	Micro	Unifocal	No	1A		1	ETSS	Adenomectomy
X 7	2nd Op: Micro	Unifocal	Cavernous Sinus Knosb 1	2nd Op: 1E		2 (Other surgeon)	ETSS	Adenomectomy
X 8	Micro	Unifocal	No	1A		1	ETSS	Hemi-hypophysectomy
X 9	MRI Neg.	-	No	0		1	ETSS	Adenomectomy
X 10	Macro	Unifocal	No	1A		1	ETSS	Adenomectomy
X 11	Micro	Unifocal	No	1A		1	ETSS	Adenomectomy
X 12	MRI Neg.	-	No	0		1	ETSS	Adenomectomy
X 13	Micro	Unifocal	No	1A		1	ETSS	Total-hypophysectomy
X 14	Macro	Unifocal	Cavernous Sinus Knosb 1	2E	Empty sella, Hemorragic	1	ETSS	Adenomectomy
X 15	Micro	Unifocal	No	1A		1	ETSS	Hemi-hypophysectomy
X 16	Macro	Multifocal	No	2C		1	ETSS	Total-hypophysectomy, Stalkectomy
X 17	First Op: Micro 2nd Op: MRI Neg.	First Op: Multifocal 2nd Op: 0	First Op: Cavernous Sinus Knosb 1	First Op:2E 2nd Op: 0		2 ( Same surgeon)	ETSS	Adenomectomy
X 18	2nd Op: Micro	Unifocal	No	2nd Op : 1A		2 (Other surgeon)	ETSS	Adenomectomy
X 19	Macro	Multifocal	No	2C		1	ETSS	Total-hypophysectomy, Stalkectomy
X 20	Micro	Unifocal	No	1A		1	ETSS	Total-hypophysectomy
X 21	Micro	Unifocal	No	1A		1	ETSS	Adenomectomy
X 22	2nd Op: Micro	Unifocal	No	2nd Op : 1A		2 (Other surgeon)	ETSS	Adenomectomy
TOTAL	Last Op; Micro: (14/22) Macro: (5/22) MRI Neg: (3/22)	Last Op; Unifocal: % (16/22) Multifocal: % (3/22)	Last Op; Cavernous Sinus Invasion: Knosb 1: % (2/22) Knosb 2: % (1/22)	Last Op; 1A: % (14/22) 2C: % (2/22) 1E: % (1/22) 2E: % (1/22) 3E: % (1/22)	Hemorrhagic Tumor: % (2/22) Empty Sella: % (1/22)	1 Op : % (17/22) 2 Op: % (5/22)	ETSS: 100% (22/22)	Last Op: Adenomectomy: % (16/22) Hemihypophysectomy: % (2/22) Total Hypophysectomy: % (4/22) Stalkectomy : % (2/22)

Overall, 95.45% of patients went into remission, while the rest did not respond to the surgical treatment. Additionally, 4.54% of patients experienced a recurrence of CD after achieving remission and required re-operation. Temporary diabetes insipidus occurred in 40.09% of patients. Most patients experienced hormone imbalances following surgery, with 50% experiencing hypocortisolism, 45.45% hypothyroidism, and 13.63% hypogonadism. Table 3 provides more details on surgical outcomes.

Table 3

Postoperative Complications & Outcomes
Patient ID	Immediate Complications	Additional Treatment	Follow-up Period (months)	Long-Term Complications	Outcomes	Post Op DI (No, Temporary, Permanent)	Last Endocrine Status
X 1	0	0	105	No	Remission	No	NL
X 2	0	0	102	HTN	Remission	No	NL
X 3	0	Radiotherapy, Bilateral Adrenalectomy	91	No	Remission	Temporary	Hypocortisolism
X 4	0	0	90	No	Remission	No	Hypothyroidism, Hypocortisolism
X 5	0	0	78	No	Remission	No	Hypocortisolism
X 6	0	0	78	Menstural disorder	Remission	Temporary	Hypothyroidism, Hypocortisolism
X 7	0	0	78	No	Remission	Temporary	Hypogonadism
X 8	0	0	66	No	Remission	Temporary	NL
X 9	CSF Leak	0	63	No	Remission
X 10	0	0	60.5	No	Remission	No	NL
X 11	0	0	54	Menstural disorder, Insulin Resistance, Dyslipidemia	Remission	No	NL
X 12	CSF Leak	0	51	No	Remission	No	Hypothyroidism, Hypocortisolism
X 13	Epistaxis	0	50	Infertility	Remission	No	Hypothyroidism, Hypogonadism, Hypocortisolism
X 14	0	0	45	HTN, Dyslipidemia, Depression	Remission	No	NL
X 15	CSF Leak	0	44	Menstural disorder	Remission	Temporary	Hypothyroidism, Hypocortisolism
X 16	0	Radiotherapy	36	No	Remission	Temporary	Hypocortisolism
X 17	Electrolyte Imbalance	0	22	Insulin Resistance	Recurrence after Remission (after 2 years of Op)	Temporary	Hypothyroidism
X 18	0	0	20.5	Osteopenia	Remission	No	Hypothyroidism, Hypocortisolism
X 19	0	0	18	No	Remission	Temporary	Hypothyroidism, Hypocortisolism
X 20	0	0	10	No	Remission	No	NL
X 21	0	0	6	No	Remission	Temporary	Hypothyroidism, Hypogonadism, Hypocortisolism
X 22	0	0	6	No	No Response	No	Hypothyroidism
TOTAL	CSF Leak: % (3/22) Epistaxis: % (1/22) Electrolyte Imbalance: % (1/22)	Radiotherapy: % (2/22) Bilateral Adrenalectomy: % (1/22)	53.3 Months	HTN : % (2/22) Dyslipidemia: % (2/22) Osteopenia: % (1/22) Insulin Resistance: % (2/22) Menstural disorder: % (3/22) Depression: % (1/22)	Remission: % (19/22) No Response: % (1/22) Recurrence after Remission: % (1/22)	DI No: % (13/22) Temporary: % (9/22)	Hypocortisolism: % ( 11/22 ) Hypogonadism: % ( 3/22 ) Hypothyroidism: % ( 10/22 )

In the past, bilateral adrenalectomy was commonly used as the first-line treatment. While the method successfully reduced cortisol levels, there was still a danger of developing Nelson's syndrome after undertaking adrenalectomy for pituitary adenoma. Medical intervention aimed at reducing cortisol levels is a potential short-term treatment option, but it is not advisable as the primary therapy for Cushing's disease [1]. Transsphenoidal pituitary surgery is the preferred option for young patients with CD, as it allows for the targeted excision of the microadenoma [2]. Both transsphenoidal microscopic surgery (TSMS) and ETSS offer a safe and effective approach to accessing the sellar fossa, with a minimal incidence of complications and morbidity.

The introduction of endoscope has led to significant advancements in transsphenoidal surgery. Currently, ETSS is the preferred procedure for pituitary surgery. We made the switch to ETSS in 2006 because it is less invasive than TSMS, while still achieving the same rates of full tumor removal. Additionally, patients who have ETSS have shorter hospital stays, both in adults and children [3].

The clinical manifestations of CD typically result from elevated cortisol production. The presentation exhibits significant variability. The diagnosis is often delayed due to the reason that growth failure may be the sole symptom for an extended period of time. Our series indicates that obesity and weight gain are the most common and initial symptoms of CD in pediatric patients. This finding is further supported by earlier research [4, 5]

Several elements of CD exhibit variations in the pediatric population. The frequency is greater in males than in females. Unlike prior works [6], our dataset exhibited an obvious female dominance, with females accounting for 72.72% of the total population compared to males at 23%. The significance of gender is evident in a study where it was shown that out of 102 pediatric patients, male participants had greater body mass index (BMI), potentially shorter height, and elevated plasma ACTH levels. This suggests that boys may have a more aggressive type of CD [7]

In our study, 95.45% of patients experienced remission during the initial follow-up period and one patient experienced recurrence. One of our patients, who did not experience a successful recovery following their second surgery follow-up, was considered as a candidate for bilateral adrenalectomy. Out of these patients, 5 (22.72%) have previously undergone endoscopic operations, following the repeated ETSS procedure on these 5 patients, 4 of them successfully attained remission. There is a lack of evidence on the rates of remission of CD after undergoing repeat transsphenoidal surgery, with reported proportions varying between 28.9% and 73% [8–10]. The rates of recurrent CD after reoperation exhibit variability, with presented incidences ranging from 22–63.2% [11, 12]. However, it is important to note that this data specifically pertains to adult patients with CD. Additionally, there is insufficient evidence about the rate of remission and recurrence after repeating ETSS in pediatric patients.

Two patients had radiotherapy for the treatment of CD. Non-surgical alternatives, such as radiotherapy and radiosurgery, have been regarded useful for recurring or residual CD due to their low morbidity rates and appropriate remission rates [13, 14]. However, for radiosurgery the remission rate varies across individuals. Therefore, it is important to acknowledge that ETSS provides much higher remission rate for microadenomas [15].

However, our research, similar to the study conducted by Hanalioglu et.al [16], indicates that the results and rates of complications related to repeated ETSS are similar to those of the initial ETSS for CD and better than alternative non-surgical treatments for persistent or recurring CD. Within our study, a total of 3 patients (13.63%) experienced rhinorrhea and required reoperation. This aligns with previously reported rates of CSF leakage, which typically ranges from 1 to 5%, after repeating endoscopic transsphenoidal surgery for residual or recurrent pituitary tumors [13, 17, 18].

Out of the patients we studied, 9 individuals (40.09%) had temporary diabetes insipidus (DI), Similarly, other studies have documented rates of DI ranging from 2 to 13% [13, 17]. However, none of them acquired persistent DI. In addition, 50% of patients acquired hypocortisolism and 13.63% of patients had hypogonadism. While hypothyroidism developed in 45.45% of patients. According to a prior study, it is found that all four axis of preoperative pituitary deficit showed recovery, with an average recovery rate of 29.7%. The cortisol axis exhibited the most significant recovery, while the thyroid axis shown the least recovery, with cumulative recovery rates of 44.3% and 6.1% respectively, over the course of one year. Postoperative hypopituitarism was observed in 17.2% of cases, with the highest incidence in the thyroid axis (24.3%, 27 out of 111) and the lowest incidence in the cortisol axis (9.7%, 16 out of 165) [19].

Based on our results, 13.63% of our patients had negative MRI findings. However, all of these children obtained remission after undergoing surgery. In contrast, a study conducted by Tatsi et.al. [20] suggests that the remission rate in these MRI-negative patients is significantly lower compared to pediatric patients with positive MRI results. Also, it is important to note that empty sella is a condition commonly associated with pituitary adenomas especially somatotropic adenomas, as reported by Sharifi et al. [21] in their previous series.

Strength and Limitation

Our study is one of the largest case series in the existing literature that investigates the safety, feasibility, and effectiveness of ETSS for the management of recurring and diagnosed pediatric Cushing’s disease. The results of our study emphasize the safety and effectiveness of ETSS at specialized medical facilities, demonstrating high rates of successful treatment and minimal complication rates. Nevertheless, it is crucial to acknowledge the retrospective nature of our work, which automatically brings about potential biases such as selection bias.

Our study specifically examines individuals who have undergone surgery for residual CD in pediatric. This limits our capacity to evaluate the effectiveness of surgical treatment with alternative methods like as radiation or radiosurgery.

This study highlights the effectiveness and safety of endoscopic transsphenoidal surgery in the management of Cushing's disease. Surprisingly, a significant proportion of patients (95.45%) experienced remission following their reoperation. In addition, the rates of complications observed in our study group were in line with the recorded rates for both initial and repeated transsphenoidal procedures. Endoscopic transsphenoidal surgery is a dependable and secure therapy method for Cushing's disease in pediatric patients, providing acceptable rates of remission along with minimal complications.

Conflict of interest

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

Author Contribution

G.SH ConceptualizationEP and MMMN writing the manuscriptEM Review editing NS and MRMT: investigationNAD: Supervision

Acknowledgment

Authors declare that they used OpenAI’s ChatGPT in a supervised manner only to revise the language and readability of current are very grateful for the patience and trust of our patients and their families. Also, we appreciate the hard works of our coworkers and other researchers.

Availability of data

All data used in this manuscript are available as deidentified material through direct request sent to corresponding author.

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Clinical and Surgical Outcomes of Pediatric Cushing's Disease Following Endoscopic Transsphenoidal Surgery

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Results

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Strength and Limitation

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Author Contribution

Acknowledgment

Availability of data

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