Radiation-induced Undifferentiated Malignant Pituitary Tumor After 5 Years of Treatment for Cushing Disease

Posted on December 11, 2023 by MaryO

Abstract

The occurrence of a second neoplasm possibly constitutes an adverse and uncommon complication after radiotherapy. The incidence of a second pituitary tumor in patients irradiated for adrenocorticotropic hormone secreting pituitary adenoma is rare. We report a case of a 40-year-old female with Cushing disease who underwent surgical management followed by radiotherapy. After 5 years of initial treatment, an increase in tumor size was evident at the same location, with a significant interval growth of the parasellar component of the lesion. Histology revealed an undifferentiated highly malignant sarcoma. In the span of next 2 years, the patient was followed with 2 repeat decompression surgeries and radiotherapy because of significant recurrent compressive symptoms by locally invasive malignant tumor. Despite the best efforts, the patient remained unresponsive to multiple treatment strategies (eg, surgical resections and radiotherapy) and succumbed to death.

Introduction

Radiation therapy is a commonly used modality for primary or adjuvant treatment of pituitary adenoma. It is also used as an adjuvant therapy for Cushing disease with persistent or aggressive tumor growth or recurrent disease after surgery. The immediate sequelae of radiotherapy for pituitary tumors include nausea, fatigue, diminished taste and olfaction, and hair loss [1]. One frequent long-term side effect is hypopituitarism. The incidence rate of new-onset hypopituitarism after conventional radiotherapy is approximately 30% to 100% after a follow-up of 10 years, whereas after stereotactic radiosurgery or fractionated radiotherapy, the incidence is approximately 10% to 40% at 5 years [2].

The occurrence of a second neoplasm after cranial radiotherapy constitutes possibly one of the most adverse complications. Tumors such as meningioma, glioma, and sarcoma are the most frequently reported secondary neoplasms after pituitary irradiation [3]. The cumulative probability of a second brain tumor in patients irradiated for pituitary adenoma and craniopharyngioma is approximately 4% [4].

We report 1 such case with detailed clinical, histopathological, and radiological characteristics because of its rarity and associated high mortality of radiation-induced sarcoma.

Case Presentation

The patient first presented at 40 years of age with complaints of weight gain, new-onset diabetes mellitus, hypertension, and cushingoid features in 2014. She was diagnosed with Cushing disease (24-hour urinary cortisol 1384 mcg/24 hours [3819 nmol/24 hours; reference >2 upper limit of normal], low-dose dexamethasone suppression test serum cortisol 16.6 mcg/dL [457.9 nmol/L], ACTH 85 pg/mL [18.7 pmol/L; reference range, <46 pg/mL, <10 pmol/L]) caused by invasive adrenocorticotropic hormone-secreting giant adenoma. The initial imaging revealed a homogenously enhanced pituitary macroadenoma with a size of 42 × 37 × 35 mm with suprasellar extension and encasing both the internal carotid arteries with mass effect on optic chiasma and sellar erosion. The patient underwent tumor excision by endoscopic transsphenoidal transnasal approach. Partial excision of the tumor was achieved because of cavernous sinus invasion. Histopathology and immunohistochemical stains demonstrated a corticotrophin-secreting (ACTH-staining positive) pituitary adenoma with MIB labeling index of 1% to 2%. Because biochemical remission was not achieved (urinary cortisol 794 mcg/24 hours [2191 nmol/24 hours]; ACTH 66 pg/mL [14.5 pmol/L; reference range, <46 pg/mL, <10 pmol/L]), the patient was started on ketoconazole and was received fractionated radiotherapy with a dose of 5040 cGy in 28 fractions.

Diagnostic Assessment

For the next 5 years, at yearly follow-up, 400 mg ketoconazole was continued in view of insufficient control of ACTH secretion. During follow-up, the size of the tumor was stable at approximately 23 × 16 × 33 mm after radiotherapy with no significant clinical and biochemical changes.

Five years after surgery and radiotherapy, the patient developed cerebrospinal fluid rhinorrhea; imaging revealed a cystic transformation of the suprasellar component and increase in the size of the tumor to 39 × 22 × 26 mm, which included visualization of a parasellar component of size 29 × 19 × 15 mm. The patient continued on ketoconazole. The patient was also advised to undergo hypofractionated radiotherapy but did not return for follow-up.

Treatment

In 2021, 1.5 years after the last visit, the patient developed severe headache, altered sensorium, ptosis, focal seizures, and left-sided hemiparesis. During this episode, the patient had an ACTH of 66 pg/mL (14.53 pmol/L; reference range, <46 pg/mL [<10 pmol/L]) and baseline cortisol of 25 mcg/dL (689 nmol/L; reference range, 4-18 mcg/dL [110-496 nmol/L]). Repeat imaging revealed a significant decrease in the suprasellar cystic component but an increase in the size of the parasellar component to 38 × 21 × 25 mm from 29 × 19 × 15 mm, which was isointense on T1 and T2 with heterogeneous enhancement. Significant brain stem compression and perilesional edema was also visible. The patient underwent urgent frontotemporal craniotomy and decompression of the tumor. On pathological examination, the tumor tissue was composed of small pleomorphic round cells arranged in sheets and cords separated by delicate fibrocollagenous stroma. Cells had a round to oval hyperchromatic nucleus with scanty cytoplasm. Areas of hemorrhage, necrosis, and a few apoptotic bodies were seen. The tumor tissue had very high mitotic activity of >10/10 hpf and MIB labeling index of 70%. Immunohistochemistry demonstrated positivity for vimentin, CD99, and TLE-1. Dot-like positivity was present for HMB 45, synaptophysin. INI-1 loss was present in some cells. Ten percent patchy positivity was present for p53. The tumor cells, however, consistently failed to express smooth muscle actin, CD34, Myf-4, epithelial membrane antigen, desmin, LCA, SADD4, CD138, and S-100 protein. ACTH and staining for other hormones was negative. Based on the immunological and histochemical patterns, a diagnosis of high-grade poorly differentiated malignant tumor with a probability of undifferentiated sarcoma was made.

Because of the invasion of surrounding structures and surgical inaccessibility, repeat fractionated radiotherapy was given with a dose of 4500 cGy over 25 fractions at 1.8 Gy daily to the planned target volume via image-guided fractionated radiotherapy. During the next 1.5 years, patient improved clinically with no significant increase in the size of tumor (Fig. 1). The patient was gradually tapered from ketoconazole and developed hypopituitarism requiring levothyroxine and glucocorticoid replacement. There was a significant improvement in the power of the left side and ptosis.

 

Figure 1.

Contrast-enhanced T1 magnetic resonance imaging dynamic pituitary scan (A, sagittal; B, axial; C, coronal sections) reveals postoperative changes with residual enhancing tumor in the right lateral sella cavity with extension into the right cavernous sinus and parasellar region encasing the cavernous and inferiorly extends through the foramen ovale below the skull base up to approximately 1.5 cm. Anteriorly, it extends up to the right orbital apex and posteriorly extends along the right dorsal surface of clivus.

Outcome and Follow-up

After 1.5 years of reradiation in 2022, the patient again developed palsies of the abducens, trigeminal, oculomotor, and trochlear cranial nerve on the right side and left-sided hemiparesis. A significant increase in tumor size to 50 × 54 × 45 mm with anterior, parasellar, and infratentorial extension was seen (Fig. 2). Again, repeat decompression surgery was done. Two months after surgery, there was no improvement in clinical features and repeat imaging suggested an increased size of the tumor by 30%, to approximately 86 × 68 × 75 mm. Nine years after initial presentation, the patient had an episode of aspiration pneumonia and died.

 

Figure 2.

Contrast-enhanced T1 magnetic resonance imaging dynamic pituitary images (A, sagittal; B, axial; C, coronal sections) after 1.5 years of a second session of radiotherapy reveal a significant interval increase in size of heterogeneously enhancing irregular soft tissue in sellar cavity with extension into the right cavernous sinus and parasellar region when compared with previous imaging. Superiorly, it extends in the suprasellar region, causing mass effect on the optic chiasma with encasement of the right prechiasmatic optic nerve and right-sided optic chiasma. Inferiorly, the lesion extends into the sphenoid sinus. Posteriorly, there is interval increase in the lesion involving the clivus and extending into the prepontine and interpeduncular cistern. Anteriorly, mass has reached up to the right orbital apex optic nerve canal, which shows mild interval increase.

Discussion

Radiation-induced tumors were initially described by Cahan et al in 1948. They also described the prerequisites for a tumor to be classified as a radiation-induced sarcoma [5]. The modified Cahan criteria state that (1) the presence of nonmalignancy or malignancy of a different histological type before irradiation, (2) development of sarcoma within or adjacent to the area of the radiation beam, (3) a latent period of at least 3 years between irradiation and diagnosis of secondary tumor, and (4) histological diagnosis of sarcoma, can be classified as radiation-induced sarcoma [5].

Our patient fulfilled the criteria for a radiation-induced sarcoma with a highly malignant tumor on histopathology. Radiation-induced sarcomas after functional pituitary tumors, especially Cushing disease, are rarely reported. One of the case reports revealed a high-grade osteoblastic osteosarcoma 30 years after treatment for Cushing disease with transsphenoidal resection and external beam radiotherapy [6]. In our case, there was a lag period of approximately 5 years before the appearance of a second highly undifferentiated, malignant, histologically distinct tumor. The cellular origin of this relatively undifferentiated tumor cannot be determined with certainty. However, the interlacing sarcomatous and adenomatous components resulting from distinct positive immunohistochemistry may indicate that the sarcomatous component may be derived from the preexisting pituitary adenoma.

A hormonally functional pituitary tumor is not itself expected to be associated with an increased risk of secondary malignancy, except in the case of GH-secreting tumors and those with a hereditary cancer syndrome. Although not proven, immunosuppression from hypercortisolism in Cushing disease has been proposed as a contributor to secondary tumor development [7]. Other mechanisms causing increased risk of secondary malignancy can be double-stranded DNA damage and genomic instability caused by ionizing radiation and germline mutations in tumor suppressor genes such as TP53 and Rb [7].

Radiation-induced intracranial tumors were studied in a multicenter, retrospective cohort of 4292 patients with pituitary adenoma or craniopharyngioma. Radiotherapy exposure was associated with an increased risk of a second brain tumor with a rate ratio of 2.18 (95% CI, 1.31-3.62, P < .0001). The cumulative probability of a second brain tumor was 4% for the irradiated patients and 2.1% for the controls at 20 years [7]. In another study including 426 patients irradiated for pituitary adenoma between 1962 and 1994, the cumulative risk of second brain tumors was 2.0% (CI, 0.9-4.4) at 10 years and 2.4% (95% CI, 1.2-5.0) at 20 years. The relative risk of a second brain tumor compared with the incidence in the normal population is 10.5 (95% CI, 4.3-16.7) [8].

The incidence of radiation-induced sarcomas has been estimated at 0.03% to 0.3% of patients who have undergone radiation therapy. The risk of radiation-induced sarcomas increases with field size and dose. In a systemic review and analysis of 180 cases of radiation-induced intracranial sarcomas, the average dose of radiation delivered was 51.4 ± 18.6 Gy and latent period of sarcoma onset was 12.4 ± 8.6 years. A total of 49 cases were developed after radiation treatment of pituitary adenomas (27.2%). The median overall survival time for all patients with sarcoma was 11 months, with a 5-year survival rate of 14.3% [9].

Our patient received approximately 50 Gy twice through fractionated radiotherapy, resulting in larger field size and significantly higher dose than one would expect with a modern stereotactic treatment. Such a high dose of radiation is indeed a risk factor for secondary malignancy. In our patient, in a period of 2 months, there was already >30% tumor growth after recent repeat decompression surgery.

The risk of secondary malignancy is thought to be much lower with stereotactic radiosurgery than conventional external beam radiation therapy, with an estimated cumulative incidence of 0.045% over 10 years (95% CI, 0.00-0.34) [10]. However, long-term follow-up data for patients receiving stereotactic radiation therapy are shorter and thus definitive conclusions cannot be made at this stage.

Our case highlights a rare but devastating long-term complication of pituitary tumor irradiation after Cushing disease. The limited response to various available treatment options defines the aggressive nature of radiation-induced malignancy.

Learning Points

  • The occurrence of a second neoplasm constitutes possibly one of the most adverse and rare complication after radiotherapy.
  • The incidence of radiation-induced sarcomas has been estimated at 0.03% to 0.3% of patients, but cases after Cushing disease are rarely reported.
  • Patients often present with advanced disease unresponsive to various treatment modalities because of aggressive clinical course.
  • New modalities with stereotactic radiosurgery and proton beam therapy are to be reviewed closely for risk assessment of secondary tumor.

Acknowledgments

The authors acknowledge Dr. Ishani Mohapatra for her support with histopathology and interpretation.

Contributors

All authors made individual contributions to authorship. G.B., S.K.M., and V.A.R. were involved in diagnosis and management of the patient. G.B. was involved in the writing of this manuscript and submission. V.P.S. was responsible for patient surgeries. All authors reviewed and approved the final draft.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Disclosures

The authors have nothing to disclose.

Informed Patient Consent for Publication

Signed informed consent could not be obtained from the patient or a proxy but was approved by the treating institute.

Data Availability Statement

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

© The Author(s) 2023. 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 License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

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Intensity-Modulated Radiotherapy for Cushing’s Disease: Single-Center Experience in 70 Patients

Posted on October 16, 2023 by MaryO

Context: Intensity-modulated radiotherapy (IMRT) is a modern precision radiotherapy technique for the treatment of the pituitary adenoma.

Objective: Aim to investigate the efficacy and toxicity of IMRT in treating Cushing’s Disease (CD).

Methods: 70 of 115 patients with CD treated with IMRT at our institute from April 2012 to August 2021 were included in the study. The radiation doses were usually 45-50 Gy in 25 fractions. After IMRT, endocrine evaluations were performed every 6 months and magnetic resonance imaging (MRI) annually. Endocrine remission was defined as suppression of 1 mg dexamethasone test (DST) or normal 24-hour urinary free cortisol level (24hUFC). The outcome of endocrine remission, endocrine recurrence, tumor control and complications were retrieved from medical record.

Results: At a median follow-up time of 36.8 months, the endocrine remission rate at 1, 2, 3 and 5 years were 28.5%, 50.2%, 62.5% and 74.0%, respectively. The median time to remission was 24 months (95%CI: 14.0-34.0). Endocrine recurrence was found in 5 patients (13.5%) till the last follow-up. The recurrence-free rate at 1, 2, 3 and 5 years after endocrine remission was 98.2%, 93.9%, 88.7% and 88.7%, respectively. The tumor control rate was 98%. The overall incidence of new onset hypopituitarism was 22.9%, with hypothyroidism serving as the most common individual axis deficiency. Univariate analysis indicated that only higher Ki-67 index (P=0.044) was significant favorable factors for endocrine remission.

Conclusion: IMRT was a highly effective second-line therapy with low side effect profile for CD patients. Endocrine remission, tumor control and recurrence rates were comparable to previous reports on FRT and SRS.

Introduction

Cushing’s disease (CD) is characterized by hypersecretion of adrenocorticotropic hormone (ACTH) from pituitary adenoma. As the state of hypercortisolemia considerably increases morbidity and mortality, normalizing cortisol levels is regarded as the major treatment goal in patients with CD (1). Transsphenoidal selective adenomectomy (TSS) is now established as the first-line treatment of CD. Despite the satisfactory remission rate that can be achieved with TSS (ranging from 59-97%), delayed recurrences have also been reported in up to 50% of patients (2).

The Endocrine Society guidelines suggest a shared decision-making approach in patients who underwent a noncurative surgery or for whom surgery was not possible (3). Second-line therapeutic options include repeat transsphenoidal surgery, medical therapy, radiotherapy and bilateral adrenalectomy. Radiotherapy (RT) is generally used in patients who have failed TSS or have recurrent CD, as well as in progressively growing or invasive corticotroph tumors (3, 4).

Both stereotactic radiosurgery(SRS)and fractionated radiotherapy (FRT) have been used in the treatment of CD. Conventional radiotherapy as one of the technique for FRT has been used with a long experience, but its benefits were hindered by high risk of toxicity, mainly attributed to the harm to healthy surrounding structures (4). Previous studies on conventional RT in treating CD showed high efficacy (tumor control rate of 92-100% and hormonal control rate of 46-89%), but RT-induced hypopituitarism (30-58%) and recurrence (16-21%) were also commonly reported (1, 4–7). Modern precise radiotherapy, especially intensity-modulated radiotherapy (IMRT), can spare the surrounding normal structure better by a more conformal and precise dose distribution (8). However, a large cohort study on long-term efficacy and toxicity of IMRT for CD is still lacking. Therefore, in the current study, we aim to analyze the efficacy and toxicity of intensity-modulated radiotherapy (IMRT) in treating CD. We also investigated the predictors of endocrine remission in aid of further management.

Methods

Patient

We collected 115 cases of Cushing’s disease treated at our center from April 2012 to August 2021. Patients were excluded under the following conditions: (1) follow-up time less than 3 months, (2) lacking evaluation of serum cortisol (F), adrenocorticotropic hormone (ACTH) or 24-hour urinary free cortisol (24hUFC) before or after RT, (3) underwent uni or bilateral adrenalectomy, (4) having received RT at other institutes before admitted to our center. At last, a total of 70 cases were included in this study.

Radiotherapy parameters

RT was administrated by a linear accelerator (6 MV X-ray). Intensity-modulated radiation therapy was applied for all patients. Including fix-filde IMRT (FF-IMRT), volumetric modulated arc therapy (VMAT) or Tomotherapy. We immobilized the patient with an individualized thermoplastic head mask and then conducted a computed tomography (CT) simulation scan at 2- to 3-mm intervals. The target volume and organs at risks (OARs) were delined with a contrast enhanced T1-weighted image (T1WI) magnetic resonance imaging (MRI) fusing with planning CT. The gross tumor volume (GTV) was defined with the lesion visible on MRI or CT. The clinical target volume (CTV) included microscopic disease, especially when the tumor invaded cavernous sinus and surrounding bones. The planning target volume (PTV) was defined as CTV plus a margin of 2- to 3-mm in three dimensions. The prescription dose was defined at 100% isodoseline to cover at least 95% PTV. The maximum dose was limited to less than 54 Gy for the brain stem and optic pathway structures. Radiotherapy was performed once a day and five fractions a week during five to six weeks. The total dose was 45-60 Gy, delivered in 25-30 fractions, with most patients (78.6%) receiving 45-50 Gy in 25 fractions. The fractionated dose was 1.8-2.0 Gy.

Data collection and clinical evaluation

Baseline characteristics were collected at the last outpatient visit before RT, including demographic characteristics, biochemical data, tumor characteristics and details of previous treatments. After RT, endocrine evaluations were performed every 6 months. Endocrine remission was considered when 1 mg dexamethasone suppression test (DST)<1.8 mg/dl. If 1mg DST results were lacking, then 24hUFC within the normal range was used as a remission criterion. Patients who regained elevated hormone levels after achieving remission were considered to have endocrine recurrence. For patients receiving medications that could interfere with the metabolism of cortisol, hormonal evaluation was performed at least 3 months after the cessation of the therapy.

Tumor size was measured on magnetic resonance imaging (MRI) before RT and annually after the completion of RT. Any reduction in or stabilization of tumor size was considered as tumor control. Tumor recurrence was defined as an increase of 2 millimeters in 2 dimensions comparing to MRI before RT, or from invisible tumor to a visible tumor on MRI (9).

Anterior pituitary function was assessed before RT and every 6 months during the follow-up after RT. RT-induced hypopituitarism was defined as the development of new onset hormone deficiency after RT. The diagnostic criteria for growth hormone deficiency (GHD), central hypothyroidism and hypogonadotropic hypogonadism (HH) refer to previous literature (10–12). Panhypopituitarism referred to three or more anterior pituitary hormone deficiencies (13).

Statistical analysis

Statistical analysis was performed with SPSS version 25.0. Longitudinal analysis was performed with Kaplan-Meier method. For time-dependent variable, Log rank test was used for univariate analysis and Cox regression for multivariate analysis. The cut-off of F, ACTH and 24hUFC were defined as their median value. All variants in the univariate analysis were included in the model of multivariate analysis. P value < 0.05 was considered statistically significant. Plot was created with GraphPad Prism version 9.4.

Results

Patient characteristics

Of 70 cases included in the study, the median age was 32 years (range, 11-66 years). 60 (85.7%) were female and 10 (14.3%) were male (F:M= 6:1). The median follow-up time was 36.8 months (range, 3.0-111.0 months). 68 patients received RT as a second-line treatment because of incomplete tumor resection, failure to achieve complete endocrine remission or recurrence postoperative, and 2 were treated with RT alone because of contraindication of surgery. The frequency of surgical treatment was 1 for 42 patients, 2 for 21 and more than 3 for 5. A total of 8 patients received medical treatment before RT. 5 of them used pasireotide, 2 used ketoconazole and 1 used mifepristone. The median ACTH level was 58.7 pg/ml (range 14.9-265 pg/ml), F, 26.2μg/dl (range 11.8-72.6 μg/dl) and 24hUFC, 355.7 μg/24hr (range 53.5-3065 μg/24hr) before RT. Tumor size evaluation was performed in all 70 patients before RT. Among them, 36 patients showed no visible residual tumor identified on MRI and only 5 patients showed tumor size more than 1 cm. Hypopituitarism was found in 31 patients (38.8%) before RT. HH was the most common (21 patients, 26.3%), followed by central hypothyroidism (13 patients, 16.3%) and GHD (9 patients, 11.3%). Panhypopituitarism was found in 4 patients (5.0%). (Table 1).

Table 1
www.frontiersin.orgTable 1 Patient characteristics.

Endocrine remission

Endocrine remission was achieved in 37 of 70 patients during the follow-up. Six of them were evaluated by 1mg DST. The hormonal remission rate at 1, 2, 3 and 5 years were 28.5%, 50.2%, 62.5% and 74.0%, respectively, gradually increasing with follow-up time (Figure 1). The median time to remission was 24.0 months (95%CI: 14.0-34.0 months). Univariate analysis indicated that only higher Ki-67 index (P=0.044) was significant favorable factors for endocrine remission. There was no significant correlation between remission and age, sex, tumor size, the frequency of surgery, medication prior RT. The hormone levels (F, ACTH and 24hUFC prior RT) were divided into high and low groups by the median value, and were also not found to be associated with endocrine remission (Table 2). Since only Ki-67 was significant in the univariate analysis and all other parameters were far from significant, a multivariate analysis was no longer performed.

Figure 1
www.frontiersin.orgFigure 1 Endocrine remission rate during the follow-up after RT.

Table 2
www.frontiersin.orgTable 2 Univariate predictors of endocrine remission.

Endocrine recurrence was found in 5 patients till the last follow-up, with an overall recurrence rate of 13.5% (5/37). The median time to recurrence after reaching endocrine remission was 22.5 months. The recurrence-free rate at 1, 2, 3 and 5 years after endocrine remission was 98.2%, 93.9%, 88.7% and 88.7%, respectively (Figure 2).

Figure 2
www.frontiersin.orgFigure 2 Recurrence free rate after endocrine emission.

Tumor control

A total of 51 patients had repeated MRI examinations before and after treatment. During the follow-up, 20 patients showed reduction and 30 patoents remained stable in tumor size, with a tumor control rate of 98%. Only 1 patient showed enlargement tumor 1 year after RT, with F, ACTH and 24hUFC increase continuously.

Complications

At the last follow-up, 16 patients developed new onset hypopituitarism after RT. The overall incidence of RT-induced hypopituitarism was 22.9%. Hypothyroidism was the most common of hypopituitarism (8 patients), followed by HH (7 patients), adrenal insufficiency (4 patients) and GHD (3 patients). Only 1 patient (1.3%) with systemic lupus erythematosus (SLE) comorbidity complained of progressively worsening visual impairment during the follow up. No cerebrovascular event or radiation associated intracranial malignancy was found in our cohort.

Discussion

Efficacy and radiotherapy techniques

RT has been emerged as an effective second-line treatment for CD for many years. Although conventional fractionated RT has been used for a long experience in patients with CD, study on the modern precise radiotherapy, particularly IMRT, is rare and reports limited evidence on its long-term treatment outcome. IMRT can be implemented in many different techniques, such as fixed-field intensity-modulated radiotherapy (FF-IMRT), volumetric-modulated arc therapy (VMAT) and tomotherapy. Compared with conventional RT, IMRT allows a better target volume conformity while preserves adequate coverage to the target (14, 15). Our study reported that IMRT for CD has an endocrine remission rate of 74.0% at 5 years, with a median time to remission of 24.0 months (95%CI: 14.0-34.0 months). The endocrine remission rate at 5 years was comparable to those reported in previous series of FRT, with a median time to remission within the reported range (4.5-44 months) (9, 16–18) (Table 3). Compared with SRS in treating CD, the endocrine remission rate and median time to remission were also similar. Pivonello et al (19) summarized 36 studies of SRS for CD between 1986 to 2014, the mean endocrine remission rate was 60.8% and the median time to remission was 24.5 months. Tumor control rate was 98% in our cohort, only one patient showed enlargement tumor with elevating hormones. This local control rate was also comparable to that reported in a series of pituitary adenoma treated with FRT (93-100%) and SRS(92-96%) (9, 16–18, 20, 21). Indeed, despite the lack of controlled studies about SRS and FRT in treating CD, many reviews that summarize the biochemical control and tumor contral of both are similar (2, 6, 19).

Table 3
www.frontiersin.orgTable 3 Literature review of FRT and SRS in patients with CD published in recent years.

The overall endocrine recurrence rate in our study was 13.5%, with a median time to recurrence of 22.5 months. We, for the first time, reported the actuarial recurrence free rate at 1, 2, 3 and 5 years in CD patients treated with IMRT. The recurrence free rate at 3 and 5 years was 88.7% in our study. Outcomes were comparable to those reported in patients treated with conventional RT or SRS, with a mean recurrence rate and a median recurrence time of 15.9% (range, 0-62.5%) and 28.1 months, or 12.3% (range, 0-100%) and 33.5 months, according to a review conducted by Pivonello et al (19).

At 2020, we reported the outcomes of pituitary somatotroph adenomas treated with IMRT at our institution (20). Compared with pituitary somatotroph adenomas, CD has a similar 5-year remission rate (74.0% vs 74.3%) but a shorter median time to remission (24.0m vs 36.2m) (Figure 3). The tumor contral rates were similar, at 98% and 99%, respectively. The endocrine recurrence rate was significantly different, with CD being about one-fold higher than the pituitary somatotroph adenoma (13.8% vs 6.1%). This may be due to the majority of microadenomas in CD and that of macroadenomas in pituitary somatotroph adenomas.

Figure 3
www.frontiersin.orgFigure 3 Endocrine remission rate of CD and pituitary somatotroph adenoma.

Predictors of endocrine remission

In the univariate analysis, we found that only Ki-67 index ≥ 3% was correlated with better endocrine remission (p=0.044). Cortisol levels before RT and tumor size were not predictors of endocrine remission. For surgery in treating CD, higher preoperative ACTH level was considered as unfavorable prognostic factor for endocrine remission in a few studies (22, 23). For radiotherapy, some previous studies also have reported a faster endocrine remission in patients with lower serum cortisol level. Minniti et al. reported that hormone level was normalized faster in patients with lower urinary and plasma cortisol level at the time of RT (16). Apaydin also reported that low postoperative cortisol and 1mg DST was a favorable factors for faster remission in patients treated with gamma knife surgery (GKS) and hypofractionated radiotherapy (HFRT), although no significant relationship was found between remission rate and plasma cortisol level prior RT in both studies (9, 16). Castinetti et al. found that initial 24hUFC was a predicative factor of endocrine remission in patients treated with GKS, which was not reported in our cohort treated with IMRT (24). However, the discrepancy between the results can be attributed to various factors, including selection bias of retrospective study, duration of follow-up, endocrine remission criteria and cut-off value.

Tumor size before RT was considered as a significant predictor for endocrine remission in some published series of patients treated with SRS. Jagannathan et al. reported a significant relationship between preoperative tumor volume and endocrine remission in patients with CD treated with GKS (25). However no significant correlation between tumor size and endocrine remission was found in series of patients treated with FRT (5, 9, 16, 17). But our study found no significant correlation between tumor size (visible or no-visible residual tumor on MRI) before RT and endocrine remission. The frequency of surgery before RT was also not found to be associated with endocrine remission in our study, which reached a similar conclusion with some previous studies (9, 17, 18, 26). Abu Dabrh et al. reported a higher remission rate in patients receiving TSS prior RT in their meta-analysis (5). Similar result was also reported in a review on the treatment outcome of GKS in patients with CD, that postoperative GKS was more effective than primary GK (19). However, analysis on this parameter was difficult in our cohort considering the low number of patients who received IMRT as the first-line treatment.

Reports on the effect of medical treatment on endocrine remission have been controversial. Some studies reported a negative effect of medical treatment at the time of SRS on endocrine remission in patients with CD. Castinetti et al. showed a significant higher rate of endocrine remission in patients who were not receiving ketoconazole at the time of GKS, compared to those who were (27). Sheehan et al. also found a significantly shorter time to remission in patients who discontinued ketoconazole at the time of GKS (28). However, no such correlation was found in patients treated with FRT (9, 17). Like previous studies on FRT, we also noted no significant relationship between preradiation use of medication and endocrine remission, but our statistical analysis may be hindered by the low proportion of patients undergoing medical treatment before RT. Moreover, the anticortisolic drugs used in previous studies were mainly ketoconazole or cabergoline, while most of our patient have received pasireotide, whose effect have not been well-studied yet. Further studies are necessary to understand the effect of somatostatin receptor ligands on the outcome of radiotherapy in patients with CD.

Complications

Hypopituitarism is the most common complication secondary to radiotherapy, with the rate of new-onset hypopituitarism ranging widely in previous report. Pivonello et al. reviewed series of CD patients who were treated with conventional RT with a follow-up of at least 5 years (19). The reported mean and median rates of hypopituitarism were 50% and 48.3%, respectively (range, 0-100%). As regards FRT, the overall rate of new-onset hypopituitarism was 22.2-40% at a median follow-up ranging from 29-108 months, with both incidence and severity increasing with longer follow-up (9, 16–19). The incidence of hypopituitarism in our series was 22.9%, which was within the reported range of new onset hypopituitarism after FRT. Lower rate of hypopituitarism after SRS compared to conventional RT has been recognized in previous reviews (2, 6). Our study showed that new onset hypopituitarism was less prevalent after IMRT than after conventional RT. This can be attributed to a higher precision in contouring the target volume and OARs, allowing these modern radiotherapy techniques to provide a better protection to hypothalamus-pituitary axes. In previous studies, potential risk factors for new onset hypopituitarism included suprasellar extension, higher radiation dose to the tumor margin and lower isodose line prescribed (29, 30). Sensitivity of individual hormonal axes to RT varies in different series. In our study, central hypothyroidism was the most common individual axis deficiency, followed by HH, adrenal insufficiency and GHD. This sequence was similar to that reported by Sheehan et al., whose series included 64 CD patients treated with SRS, as well as some other series (29, 31). It is noted in some studies that GHD is the most vulnerable axes (19, 32, 33). Limited number of patients undergoing stimulation test may underestimate the prevalence of GHD in our study and some previous series, and longer follow-up is needed to generate a more accurate, time-dependent rate of new onset hypopituitarism.

In our study, only one patient complained of mild visual impairment, which was comparable to the rate ranging from 0-4.5% in previous series of FRT treating pituitary adenoma (9, 16–18, 26, 32, 34, 35). This patient had concomitant SLE and the associated microangiopathy may render the optic nerve intolerant to radiotherapy. Cranial nerve damage was acknowledged as an uncommon complication, with an estimated risk of vision deterioration below 1% if single radiation dose was no more than 2.0 Gy and total dose no more than 45-50 Gy (2, 36). The actuarial rate of optic neuropathy at 10 years was 0.8% in a series containing 385 patients with pituitary adenoma (37). No patient in our cohort developed cerebrovascular accident or secondary brain tumor. This finding was consistent with the low actuarial prevalence of these complications reported in other published series of FRT. Secondary brain tumor was extremely rare after SRS, with an overall incidence of 6.80 per patients-year, or a cumulative incidence of 0.00045% over 10 years in a multicenter cohort study containing 4905 patients treated with GKS (38). Ecemis et al. reviewed cohort studies of conventional RT in treating pituitary adenoma from 1990 to 2013 and found that 1.42% of patients developed secondary brain tumor, with a latency period of 19.6 years for meningioma, 11 years for glioma and 9 years for astrocytoma (39). As for cerebrovascular accident, Minniti et al. reported two patients (in a total of 40 patients) who had stroke 6 and 8 years after FRT (16). Data was still limited for FRT. Considering the low incidence and long latency period, large, controlled cohort study with long follow-up of FRT is still needed to accurately evaluate these complications.

Limitations

Our study has several limitations. First, not all patients rigorously followed regular follow-up time points, making time-dependent statistical analysis less accurate. In addition, the excessively low number of cases with 1mg DST as the endocrine remission criterion may affect the accuracy of the remission rate.Moreover, a median follow-up time of about 3 years hampered evaluation on some late complications, including cerebrovascular events and secondary brain tumor.

In conclusion, our study revealed that IMRT was a highly effective second-line therapy with low side effect profile for CD patients, and it’s endocrine remission, tumor control and recurrence rates were comparable to previous reports on FRT and SRS.

Data availability statement

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

Author contributions

1. Conceptualization: FZ and HZ 2. Data curation: XL and ZX. 3. Funding acquisition: FZ. 4. Investigation: XL and ZX 5. Methodology: WW 6. Resources: XL, SS and XH 7. Validation: LL and HZ. 8. Writing – original draft: ZX 9. Writing – review and editing: XL. All authors contributed to the article and approved the submitted version.

Funding

Supported by grants National High Level Hospital Clinical Research Funding (No.2022-PUMCH-B-052) and National Key R&D Program of China, Ministry of Science and Technology of the People’s Republic of China.(Grant No. 2022YFC2407100, 2022YFC2407101).

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.

Publisher’s note

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

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Keywords: cushing’s disease, intensity-modulated radiotherapy, radiotherapy, pituitary adenoma, ACTH

Citation: Lian X, Xu Z, Sun S, Wang W, Zhu H, Lu L, Hou X and Zhang F (2023) Intensity-modulated radiotherapy for cushing’s disease: single-center experience in 70 patients. Front. Endocrinol. 14:1241669. doi: 10.3389/fendo.2023.1241669

Received: 17 June 2023; Accepted: 31 August 2023;
Published: 26 September 2023.

Edited by:

Luiz Augusto Casulari, University of Brasilia, Brazil

Reviewed by:

Luiz Eduardo Armondi Wildemberg, Instituto Estadual do Cérebro Paulo Niemeyer (IECPN), Brazil
Carolina Leães Rech, Federal University of Health Sciences of Porto Alegre, Brazil

Copyright © 2023 Lian, Xu, Sun, Wang, Zhu, Lu, Hou and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Fuquan Zhang, zhangfq@pumch.cn

†These authors have contributed equally to this work

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

From https://www.frontiersin.org/articles/10.3389/fendo.2023.1241669/full

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Long-Term Obesity Persists Despite Pituitary Adenoma Treatment In Childhood

Posted on January 5, 2020 by MaryO

Sethi A, et al. Clin Endocrinol. 2019;doi:10.1111/CEN.14146.

January 5, 2020

Obesity is common at diagnosis of pituitary adenoma in childhood and may persist despite successful treatment, according to findings published in Clinical Endocrinology.

“The importance of childhood and adolescent obesity on noncommunicable disease in adult life is well recognized, and in this new cohort of patients, we report that obesity is common at presentation of pituitary adenoma in childhood and that successful treatment is not necessarily associated with weight loss,” Aashish Sethi, MD, MBBS, a pediatric endocrinologist in the department of endocrinology at Alder Hey Children’s Hospital in Liverpool, United Kingdom, and colleagues wrote. “We have reported obesity, and obesity-related morbidity in a mixed cohort of children and young adults previously, but [to] our knowledge, this is the first time this observation has been reported in a purely pediatric cohort.”

In a retrospective study, Sethi and colleagues analyzed clinical and radiological data from 24 white children from Alder Hey Children’s Hospital followed for a median of 3.3 years between 2000 and 2019 (17 girls; mean age at diagnosis, 15 years). Researchers assessed treatment modality (medical, surgical or radiation therapy), pituitary hormone deficiencies and BMI, as well as results of any genetic testing.

Within the cohort, 13 girls had prolactinomas (mean age, 15 years), including 10 macroadenomas between 11 mm and 35 mm in size. Children presented with menstrual disorders (91%), headache (46%), galactorrhea (46%) and obesity (38%). Nine children were treated with cabergoline alone, three also required surgery, and two were treated with the dopamine agonist cabergoline, surgery and radiotherapy.

Five children had Cushing’s disease (mean age, 14 years; two girls), including one macroadenoma. Those with Cushing’s disease presented with obesity (100%), short stature (60%) and headache (40%). Transsphenoidal resection resulted in biochemical cure; however, two patients experienced relapse 3 and 6 years after surgery, respectively, requiring radiotherapy. One patient also required bilateral adrenalectomy.

Six children had a nonfunctioning pituitary adenoma (mean age, 16 years; two girls), including two macroadenomas. These children presented with obesity (67%), visual field defects (50%) and headache (50%). Four required surgical resections, with two experiencing disease recurrence after surgery and requiring radiotherapy.

During the most recent follow-up exam, 13 children (54.1%) had obesity, including 11 who had obesity at diagnosis.

“The persistence of obesity following successful treatment, in patients with normal pituitary function, suggests that mechanisms other than pituitary hormone excess or deficiency may be important,” the researchers wrote. “It further signifies that obesity should be a part of active management in cases of pituitary adenoma from diagnosis.” – by Regina Schaffer

Disclosures: The authors report no relevant financial disclosures.

From https://www.healio.com/endocrinology/adrenal/news/online/%7Bde3fd83b-e8e0-4bea-a6c2-99eb896356ab%7D/long-term-obesity-persists-despite-pituitary-adenoma-treatment-in-childhood

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Cushing’s Syndrome Eludes Treatment Paradigm or Standard Approach to Care

Posted on July 7, 2018 by MaryO

Results of two systematic reviews indicate that while surgery is the preferred treatment, many patients present with contraindications without an accepted management paradigm leaving clinicians to follow a patient-centric approach to care.

Written by 

With commentary by Eliza B. Geer, MD

Cushing’s syndrome may arise from an endogenous glucocorticoid excess is either adrenocorticotropic hormone (ACTH)-dependent or ACTH-independent; each variation has numerous underlying causes, including pituitary tumor, adrenal tumor, or other unknown causes.

Although rare, ectopic Cushing’s syndrome results from a non-pituitary ACTH-producing source. Cushing’s disease, a type of Cushing’s syndrome, affects an estimated 1.2 to 2.4 million people each year, and is caused by an ACTH-secreting pituitary adenoma.1

While surgery is preferred for treatment of Cushing's syndrome many patients need a medical approach instead.

Gaining insights into treatment preferences and efficacy for Cushing’s syndrome were the focus of two separate systematic reviews and meta-analyses, both published in the journal, Pituitary: one regarding medical treatments for Cushing’s syndrome,2 and the other comparing endoscopic versus microscopic transsphenoidal surgery for Cushing’s disease.3

Assessing Medical Management of Cushing’s Syndrome

The meta-analysis examining medical care of individuals with Cushing’s syndrome encompassed 1520 total patients across 35 studies, most of whom had Cushing’s disease.2 However, only 2 of the 35 studies were randomized trials, highlighting the lack of and clear need for controlled clinical trials on medical therapies for Cushing’s syndrome.

Surgery is typically first-line treatment—whether transsphenoidal pituitary adenomectomy for Cushing’s disease,4 removal of the ACTH-producing tumor in ectopic Cushing’s syndrome or adrenalectomy in ACTH-independent Cushing’s syndrome.5

However, many patients require medical therapy owing to contraindications for surgery, for recurrent disease, or to control cortisol secretion prior to surgery or radiotherapy. Results of the meta-analysis reflected wide-ranging normalization of cortisol levels depending upon the agent used– from 35.7% for cabergoline to nearly 82% for mitotane in Cushing’s disease.2 Combination therapy (medications used either together or sequentially) was shown to increase effectiveness in normalizing cortisol levels.2

In an interview with EndocrineWeb, Eliza B. Geer, MD, medical director of the Multidisciplinary Pituitary and Skull Base Tumor Center at Memorial Sloan Kettering Cancer Center in New York City, noted that most medical therapies for Cushing’s syndrome are used off-label (in the US), and thus may lack clinical trial efficacy and safety data; consequently, this review provides useful information for treatment selection. However, Dr. Geer said there was substantial diversity of treatments reviewed in this paper – including tumor-directed therapies, cortisol synthesis inhibitors, an adrenolytic therapy, and a receptor blocker, used alone or in combination.

Further, treatments used in the studies addressed a range of Cushing’s etiologies and reflected heterogeneous study designs (for example follow-up ranged from 2 weeks to 11.5 years).2  As such, she said, “findings provided by this review should be viewed in the context of a broader clinical understanding of Cushing’s treatment.”

Specifically, Dr. Geer said, “Dr. Broersen’s analysis found that efficacy of medical therapy was improved by prior radiotherapy. But we know that radiotherapy is recommended on an individualized basis in only a fraction of Cushing’s patients, depending on tumor behavior and treatment history. Also, the fact that mitotane was shown here to have the highest efficacy of all therapies does not make this the appropriate treatment for all, or even most, Cushing’s patients; mitotane is adrenolytic and has a high rate of significant adverse effects.”

Too Many Questions Persist, Necessitating Focus on Attaining Management Paradigm

Dr. Geer also highlighted the need for answers to basic questions when investigating Cushing’s treatments: How do we define ‘successful’ treatment? What goals of care can patients expect? Which cortisol measurements and cut-offs can be used? How do we define clinical remission—resolution of which symptoms and comorbidities? She said Cushing’s syndrome is one of the most challenging endocrine diseases to treat because of the lack of an accepted, universal treatment or management paradigm.

“Treatment is often multimodal and always multidisciplinary, with patient-specific decision trees that must consider many factors, including goals of care, treatment history, disease etiology and severity, tumor behavior, and individual responses to medical therapies,” she told EndocrineWeb.

She concluded, “While Broersen et al’s study provides a useful review of available medical therapies, it reinforces something we already know about the treatment of Cushing’s: Expertise is required.”

Pituitary surgery is first-line treatment for Cushing’s disease. Currently, there are two main techniques for transsphenoidal pituitary surgery: microscopic and endoscopic. The operating microscope provides three-dimensional vision and may be advantageous in identifying small tumors; the broader field of vision afforded by the endoscope may be advantageous for complete resection of large tumors.3  Generally, despite an absence of studies directly comparing relative remission and complication rates between microscopic versus endoscopic approaches, most surgical centers choose to use one or the other; few have both.3

Examining the Surgical Options to Manage Cushing’s Disease

The second systematic review is the first to compare remission and recurrence rates, and mortality after microscopic versus endoscopic transsphenoidal pituitary surgery for Cushing’s disease.3 The review included 97 studies of 6695 patients: 5711 individuals having the microscopic procedure and 984 undergoing endoscopic surgery.

Results of the meta-analysis found no clear difference between the two techniques in overall remission (80%) or recurrence (10%).3 Short-term mortality for both techniques was < 0.5%. However, endoscopic surgery was associated with a greater occurrence of cerebrospinal fluid leak (12.9 vs 4.0%) but a lesser occurrence of transient diabetes insipidus (11.3 vs 21.7%).3

The authors reported a higher percentage of patients in remission (76.3 vs. 59.9%) and lower percentage recurrence rates (1.5 vs 17.0%) among patients undergoing endoscopic surgery for macroadenomas.3

When interviewed regarding the second meta-analysis,3 Dr. Geer said that the potential benefit of endoscopy over microscopy has been questioned for ACTH-secreting tumors specifically since most are microadenomas.

“With the caveat that few studies (four of the 97 reviewed) compared techniques directly, Broersen et al3 found that endoscopic surgery was associated with higher remission rates compared to microscopic surgery for large tumors, but the two techniques were comparable for small tumors,” said Dr. Geer, however, “one limitation of these data is the lack of standardized criteria to define diagnosis and remission of Cushing’s among the studies reviewed.”

Need for Consistency in Clinical Trials and Surgical Expertise

The study investigators concluded, “endoscopic surgery for patients with Cushing’s disease reaches comparable results for microadenomas, and probably better results for macroadenomas than microscopic surgery,” despite the greater learning curve associated with endoscopic surgery.3 As such, based on their findings, the authors concluded that “endoscopic surgery may thus be considered the current standard of care. Microscopic surgery can be used based on neurosurgeon’s preference.” They did not respond to EndocrineWeb for a request for comment.

As more neurosurgeons receiving training with the endoscope, the preferred technique for pituitary surgery is changing. Dr. Geer said, “Broersen’s review provides reassurance that the newer endoscopic technique is at least equal to the microscope for microadenomas and may be preferred for macroadenomas.”

“However, [conclusions based on the systematic review] do not change our role as endocrinologists treating Cushing’s disease, which is to refer, when indicated, to the available neurosurgeon with the most favorable outcomes and lowest rate of complications, both of which depend directly on level of experience with the procedure and the instrument being used, whether endoscope or microscope,” she said.

The authors had no financial conflicts to declare.

From https://www.endocrineweb.com/professional/cushings/cushings-syndrome-eludes-treatment-paradigm-standard-approach-care

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Postsurgical treatment often necessary in persistent, recurrent Cushing’s disease

Posted on March 30, 2017 by MaryO

Nearly half of adults with Cushing’s disease that persists or recurs after surgical treatment require second and sometimes third therapeutic interventions, including pituitary surgical reintervention, radiotherapy, pharmacotherapy or bilateral adrenalectomy, study data from Mexico show.

Moisés Mercado, MD, FRCPC, of the ABC Hospital Neurological and Cancer Centers in Mexico City, and colleagues evaluated 84 adults (median age, 34 years; 77 women) with Cushing’s disease to determine the long-term efficacy of secondary interventions for persistent and recurrent Cushing’s disease. Median follow-up was 6.3 years.

Overall, 81 participants were primarily treated with transsphenoidal surgery. More than half experienced long-lasting remission (61.7%); disease remained active in 16%, who were diagnosed with persistent Cushing’s disease; and 22% experienced relapse after remission and were diagnosed with recurrent Cushing’s disease.

After the initial procedure, 18 participants required pituitary surgical reintervention, including 10 with recurrent and eight with persistent disease. Radiation therapy was administered to 14 participants, including two as primary therapy and 12 after failed pituitary surgery. Pharmacologic treatment with ketoconazole was prescribed for 15 participants at one point during the course of disease. Bilateral adrenalectomy was performed in 12 participants.

Pituitary surgical reintervention was the most commonly used secondary treatment (22.2%), followed by pharmacologic therapy with ketoconazole (16%), radiotherapy (14.8%) and bilateral adrenalectomy (14.8%). More than half of participants experienced early remissions after a second operation (66.6%) and radiotherapy (58.3%), whereas long-lasting remission was reached in only 33.3% of participants who underwent a second surgery and 41.6% of participants who underwent radiotherapy. Half of participants who underwent bilateral adrenalectomy were diagnosed with Nelson’s syndrome.

Overall, 88% of participants achieved remission, and disease was biochemically controlled with pharmacologic treatment in 9.5% of participants after their initial, secondary and third-line treatments.

“The efficacy of treatment alternatives for recurrent or persistent [Cushing’s disease] vary among patients, and often, more than one of these interventions is required in order to achieve a long-lasting remission,” the researchers wrote. – by Amber Cox

Disclosure: The researchers report no relevant financial disclosures.

From http://www.healio.com/endocrinology/adrenal/news/in-the-journals/%7B5519b312-5912-4c65-b2ed-2ece3f68e83f%7D/postsurgical-treatment-often-necessary-in-persistent-recurrent-cushings-disease

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