Uncommon adrenal rest tumors and massive adrenal enlargement in adult with congenital adrenal hyperplasia mimicking metastasis from pleomorphic sarcoma.

BACKGROUND: Congenital adrenal hyperplasia (CAH) encompassed a bunch of autosomal recessive disorders characterized by impaired cortisol levels due to an enzymatic deficiency in steroid synthesis. In adult male patients with CAH, a frequent complication related to poor disease control is the development of ectopic adrenocortical tissue in the testes, named testicular adrenal rest tumors (TART). Conversely, ovarian adrenal rest tumors (OART) in females are extremely rare and adrenal rests in sites other than gonads are so uncommon to have been described only few times in literature. CASE PRESENTATION: We report a case of a male patient with untreated CAH and oncologic history of pleomorphic sarcoma who presented with massive bilateral adrenal enlargement and adrenal rest tumors in peri-lumbar and peri-cecal sites, which mimicked metastasis from sarcoma. CONCLUSIONS: The development of massive adrenal enlargement and ectopic adrenal rest tumors in sites other than gonads, even if very uncommon, should be suspected in patients with CAH and prolonged periods of undertreatment.

Long-term disease-free survival after MIBG therapy for metastatic pheochromocytoma.

Pheochromocytomas are rare tumours originating in chromaffin cells, representing 0.1%-1% of all secondary hypertension cases. The majority are benign and unilateral, characterised by the production of catecholamines and other neuropeptides. Mainly located in the adrenal gland, they are more frequent between the third and fifth decades of life. Iodine-131 metaiodobenzylguanidine (131I-MIBG), a radiopharmaceutical agent used for scintigraphic localisation of pheochromocytomas, has been employed to treat malignant pheochromocytomas since 1983 in a few specialised centres around the world. We reviewed our clinical experience in one such case of a young lady who presented with history of abdominal pain, headache and lower back pain. On evaluation, ultrasonography revealed a right adrenal mass and elevated urine vanillylmandelic acid levels. Following surgical resection and histopathological confirmation of pheochromocytoma, MIBG scintigraphy revealed osseous metastases and hence, she underwent 131I-MIBG therapy.

Case report: A challenging case of severe Cushing's syndrome in the course of metastatic thymic neuroendocrine carcinoma with a synchronous adrenal tumor.

Ectopic ACTH syndrome (EAS) remains one of the most demanding diagnostic and therapeutic challenges for endocrinologists. Thymic neuroendocrine tumors account for 5%-10% of all EAS cases. We report a unique case of a 31-year-old woman with severe EAS caused by primary metastatic combined large-cell neuroendocrine carcinoma and atypical carcinoid of the thymus. The patient presented with severe hypercortisolemia, which was successfully controlled with continuous etomidate infusion. Complex imaging initially failed to detect thymic lesion; however, it revealed a large, inhomogeneous, metabolically active left adrenal mass infiltrating the diaphragm, suspected of primary disease origin. The patient underwent unilateral adrenalectomy, which resulted in hypercortisolemia resolve. The pathology report showed an adenoma with adrenal infarction and necrosis. The thymic tumor was eventually revealed a few weeks later on follow-up imaging studies. Due to local invasion and rapid progression, only partial resection of the thymic tumor was possible, and the patient was started on radio- and chemotherapy.

Bilateral Adrenal Metastasis of Prostatic Adenocarcinoma on 68 Ga-PSMA PET/CT Imaging.

ABSTRACT: An 84-year-old man with prostate adenocarcinoma underwent 68 Ga-PSMA PET/CT due to PSA recurrence. Foci of 68 Ga-PSMA uptake were observed in bilateral adrenal glands. Adrenal MRI showed metastasis only in the left adrenal gland. Metastatic 68 Ga-PSMA uptake was also observed in the mediastinum and bone. Enzalutamide treatment was started. Follow-up 68 Ga-PSMA PET/CT scan showed regression in both adrenal gland metastases and other metastases.

Cabozantinib in patients with unresectable and progressive metastatic phaeochromocytoma or paraganglioma (the Natalie Trial): a single-arm, phase 2 trial.

BACKGROUND: Metastatic phaeochromocytomas and paragangliomas (MPPGs) are orphan diseases. Up to 50% of MPPGs are associated with germline pathogenic variants of the SDHB gene. These tumours and many non-familial MPPGs exhibit a phenotype that is characterised by abnormal angiogenesis. We aimed to assess the activity and safety of cabozantinib, an antiangiogenic multi-tyrosine kinase inhibitor, in patients with MPPGs. METHODS: The Natalie Trial is a single-arm, phase 2 clinical trial being conducted at The University of Texas MD Anderson Cancer Center (Houston, TX, USA). Patients aged 18 years or older with histologically confirmed, progressive, and unresectable MPPGs, with an Eastern Cooperative Oncology Group performance status of 0-2, were treated with oral cabozantinib 60 mg/day. The primary endpoint was the investigator-assessed overall response rate per the Response Evaluation Criteria in Solid Tumours version 1.1 criteria. All outcomes were assessed in all evaluable participants who received any amount of study treatment. The trial is registered with ClinicalTrials.gov (NCT02302833) and is active but not recruiting. FINDINGS: From March 10, 2015, to May 11, 2021, 17 patients (13 male participants and four female participants) were enrolled. The median follow-up was 25 months (IQR 18-49). The overall response rate was 25·0% (95% CI 7·3-52·4; four of 16 patients). Seven grade 3 adverse events were reported in six patients, including single cases of hand-and-foot syndrome, hypertension, rectal fistula, QT prolongation, and asymptomatic hypomagnesaemia, and two cases of asymptomatic elevations of amylase and lipase. There were no grade 4 adverse events and no patient died on-study. INTERPRETATION: Cabozantinib shows promising activity in patients with MPPGs. FUNDING: Team NAT Foundation, Margaret Cazalot, and Clarence P Cazalot.

Adrenal tumors in patients with neuroendocrine neoplasms.

PURPOSE: To study the prevalence of primary adrenal tumors and adrenal metastases in patients with neuroendocrine neoplasms (NENs) and describe these in detail. NENs can be further divided into neuroendocrine tumor (NET) and neuroendocrine carcinoma (NEC). METHODS: A review of medical files was conducted for all patients who underwent a 68Gallium-DOTATOC-PET/CT during 2010-2023 or adrenalectomy during 1999-2023 at the Karolinska University Hospital. RESULTS: In total, 68Gallium-DOTATOC-PET/CT was performed on 1750 individuals with NEN, among whom 12 (0.69%) had adrenal tumors. Of these, 9 (0.51%) were NEN metastases. Out of 1072 adrenalectomies, 4 (0.37%) showed evidence of NEN metastases. Thus, 16 patients with NEN exhibited adrenal tumors. The adrenal tumors were found on average 5 years after the NEN diagnosis and 19% of the adrenal tumors with simultaneous NEN were benign. Few had all adrenal hormones measured. None had an adrenal insufficiency nor an adrenal biopsy. Another synchronous metastasis was found in 69% at the time of the adrenal tumor discovery. During the median 2-year follow-up, 38% of the subjects had deceased (with the exclusion of individuals presenting supposedly benign adrenal tumors 31%) all due to tumor complications. A comparison between individuals identified through 68Gallium-DOTATOC-PET/CT and those who underwent adrenalectomy revealed a higher prevalence of NETs in the former group and NECs in the latter group. CONCLUSION: Adrenal primary tumors and adrenal metastases are infrequent occurrences in patients with NEN. Most cases involved the presence of NEN metastasis upon the initial discovery of adrenal tumors. The overall prognosis was found to be favorable.

Cutaneous, Subcutaneous, and Bilateral Adrenal Gland Metastases in Progressive Prostate Carcinoma: Theranostic Potential of 68 Ga-PSMA-11 PET/CT Imaging and 177 Lu-PSMA-617 Therapy.

ABSTRACT: Prostate carcinoma (PC) is the second most common malignant tumor in males globally. The metastatic spread of PC usually involves the pelvic and abdominal lymph nodes and the skeletal system. Cutaneous metastases are exceedingly uncommon and typically manifest themselves late in the disease course, considered as ominous sign with limited treatment options and a poor prognosis. We describe a patient wherein 68 Ga-PSMA-11 PET/CT detected multiple uncommon metastatic sites in the cutaneous region of the scrotum, penis, and thigh, as well as in the subcutaneous region of anterior abdominal wall, and in bilateral adrenal glands. These findings served as a theranostic tool for selecting 177 Lu-PSMA-617 treatment for these extremely rare metastatic sites.

Practical Considerations for the Treatment of an Adrenal Metastasis With Stereotactic Body Radiation Therapy.

The purpose of this paper is to summarize 3 methods for treating adrenal metastases with stereotactic body radiation therapy. This article is not meant to provide consensus guidelines but rather to present 4 practical examples of treatment techniques using different treatment platforms from 3 institutions.

Novel alternative tools for metastatic pheochromocytomas/paragangliomas prediction.

OBJECTIVE: The existing prediction models for metastasis in pheochromocytomas/paragangliomas (PPGLs) showed high heterogeneity in different centers. Therefore, this study aimed to establish new prediction models integrating multiple variables based on different algorithms. DESIGN AND METHODS: Data of patients with PPGLs undergoing surgical resection at the Peking Union Medical College Hospital from 2007 to 2022 were collected retrospectively. Patients were randomly divided into the training and testing sets in a ratio of 7:3. Subsequently, decision trees, random forest, and logistic models were constructed for metastasis prediction with the training set and Cox models for metastasis-free survival (MFS) prediction with the total population. Additionally, Ki-67 index and tumor size were transformed into categorical variables for adjusting models. The testing set was used to assess the discrimination and calibration of models and the optimal models were visualized as nomograms. Clinical characteristics and MFS were compared between patients with and without risk factors. RESULTS: A total of 198 patients with 59 cases of metastasis were included and classified into the training set (n = 138) and testing set (n = 60). Among all models, the logistic regression model showed the best discrimination for metastasis prediction with an AUC of 0.891 (95% CI, 0.793-0.990), integrating SDHB germline mutations [OR: 96.72 (95% CI, 16.61-940.79)], S-100 (-) [OR: 11.22 (95% CI, 3.04-58.51)], ATRX (-) [OR: 8.42 (95% CI, 2.73-29.24)] and Ki-67 ≥ 3% [OR: 7.98 (95% CI, 2.27-32.24)] evaluated through immunohistochemistry (IHC), and tumor size ≥ 5 cm [OR: 4.59 (95% CI, 1.34-19.13)]. The multivariate Cox model including the above risk factors also showed a high C-index of 0.860 (95% CI, 0.810-0.911) in predicting MFS after surgery. Furthermore, patients with the above risk factors showed a significantly poorer MFS (P ≤ 0.001). CONCLUSIONS: Models established in this study provided alternative and reliable tools for clinicians to predict PPGLs patients' metastasis and MFS. More importantly, this study revealed for the first time that IHC of ATRX could act as an independent predictor of metastasis in PPGLs.

Treatment of metastatic paraganglioma: experience of a single center.

PURPOSE: Data regarding treatment options and their efficacy for metastatic paragangliomas (mPPGL) is limited. This study aims to report a single center experience in treating mPPGL, comparing the efficacy and safety of various treatment approaches. METHODS: Retrospective analysis of patients with mPPGL treated at an Endocrinology Department of a cancer institute between January 2000 and October 2022. RESULTS: We analyzed 25 patients with mPPGL, 8 pheochromocytomas and 20 paragangliomas (12% multifocal), followed for a median of 9 [4; 14] years. Surgical approach, aimed at the primary tumor or at debulking of metastases, was the only treatment achieving complete response: 87% in primary tumor and 87.5% with debulking of metastases. These were long-lasting results with a duration of 69 (23.8; 136.8) months in primary tumor removal and 35.1 (15.3; 41) months in metastases debulking. As for other therapeutic approaches, such as radioactive isotopes, tyrosine kinase inhibitors, chemotherapy and external beam radiotherapy, the main outcome was stable disease, with few partial responses. At the last follow-up, 66% of the patients were alive, 15.4% were in remission and 84.6% had stable disease. Median overall survival was 14 years. The 5-year and 10-year survival rates from primary tumor diagnosis were 77.9% and 66.9% respectively, and from metastasis diagnosis were 67.4% and 55.6%, respectively. CONCLUSION: This is the only European single center analysis addressing outcomes of different therapies in mPGL. The results support surgery as a first-line treatment, being the only approach that may achieve complete response with satisfactory and long-lasting results.

Performance of EUS-FNA and EUS-B-FNA for the diagnosis of left adrenal glands metastases in patients with lung cancer: A systematic review and meta-analysis.

OBJECTIVES: For diagnosing left adrenal gland metastasis in lung cancer, clinical guidelines recommend to perform EUS, but EUS-B (EUS using an EBUS-scope) is increasingly being used. We evaluated the diagnostic performance of both procedures. MATERIALS AND METHODS: We did a systematic review (PROSPERO, CRD42023416205) and searched MEDLINE and EMBASE on 04-July-2023 for studies evaluating EUS and/or EUS-B in diagnosing left adrenal gland metastases in adults with (suspected) lung cancer. Outcomes were: (1) ability to visualize the left adrenal gland, (2) ability to sample (in those with successful visualization and in whom sampling was attempted), (3) ability to obtain adequate material (in those with successful sampling), (4) malignancy detection rate (in those with successful sampling), and (5) remaining risk of malignancy (in those with a negative EUS(-B)-FNA and undergoing a reference standard). We performed random-effects meta-analyses. RESULTS: We included 19 studies (EUS: n = 11, EUS-B: n = 6, both: n = 2), covering 1712 patients. All studies had high (n = 18) or unclear (n = 1) risk of bias (QUADAS-2). Average ability to visualize the left adrenal gland was 0.94 (95 %CI 0.82-0.98; n = 7 studies). Average ability to sample was 1.00 (95 %CI 0.99-1.00; n = 9). Average ability to obtain adequate material was 0.96 (95 %CI 0.93-0.98; n = 18). Average malignancy detection rate was 0.42 (95 %CI 0.34-0.49; n = 18). Remaining risk of malignancy was 0.07 (95 %CI 0.04-0.12; n = 8). Ability to visualize was slightly higher for EUS (0.99; 95 %CI 0.90-1.00) than EUS-B (0.84; 95 %CI 0.70-0.92; p = 0.025), but the other performance characteristics were similar. No major complications were reported. CONCLUSION: Both EUS and EUS-B have good performance and are safe for left adrenal gland analysis in patients with lung cancer, but the number of high-quality studies is limited and further well-constructed prospective studies are needed.

Adrenal Metastasectomy in the Era of Immuno- and Targeted Therapy.

Adrenal metastasectomy has an increasing role in multimodality oncologic care for diverse primary cancer types. In this review, we discuss the epidemiology, evaluation, and contemporary best practices in the management of adrenal metastases from various primaries. Initial evaluation of suspected adrenal metastases should include diagnostic imaging to assess the extent of tumor involvement and determine surgical resectability, as well as biochemical evaluation for hormone secretion. Biopsy has a minimal role and should only be performed in tumors that are established to be non-hormone secreting and when the biopsy results would change clinical management. Adrenal metastasectomy is associated with survival benefit in selected patients. We suggest that adrenal metastasectomy has the greatest benefit in four clinical scenarios: (1) disease limited to the adrenal gland in which adrenalectomy renders the patient disease-free; (2) isolated progression in the adrenal gland in the setting of otherwise controlled metastatic extra-adrenal disease; (3) need for palliation of symptoms related to adrenal metastases; or (4) in the context of tissue-based clinical trials. Both minimally invasive and open adrenalectomy techniques are safe and appear to have equivalent oncologic outcomes. Minimally invasive approaches are favored when technically feasible while maintaining oncologic principles. A multidisciplinary evaluation including clinicians with expertise in the primary cancer type is essential to the successful management of adrenal metastases.

Machine learning analysis of adrenal lesions: preliminary study evaluating texture analysis in the differentiation of adrenal lesions

PURPOSE: This study aimed to determine the accuracy of texture analysis in differentiating adrenal lesions on unenhanced computed tomography (CT) images. METHODS: In this single-center retrospective study, 166 adrenal lesions in 140 patients (64 women, 76 men; mean age 56.58 ± 13.65 years) were evaluated between January 2015 and December 2019. The lesions consisted of 54 lipid-rich adrenal adenomas, 37 lipid-poor adrenal adenomas (LPAs), 56 adrenal metastases (ADM), and 19 adrenal pheochromocytomas (APhs). Each adrenal lesion was segmented by manually contouring the borders of the lesion on unenhanced CT images. A texture analysis of the CT images was performed using Local Image Feature Extraction software. First-order and second-order texture parameters were assessed, and 45 features were extracted from each lesion. One-Way analysis of variance with Bonferroni correction and the Mann-Whitney U test was performed to determine the relationships between the texture features and adrenal lesions. Receiver operating characteristic curves were performed for lesion discrimination based on the texture features. Logistic regression analysis was used to generate logistic models, including only the texture parameters with a high-class separation capacity (i.e., P < 0.050). SPSS software was used for all statistical analyses. RESULTS: First-order and second-order texture parameters were identified as significant factors capable of differentiating among the four lesion types (P < 0.050). The logistic models were evaluated to ascertain the relationships between LPA and ADM, LPA and APh, and ADM and APh. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of the first model (LPA vs. ADM) were 85.7%, 70.3%, 81.3%, 76.4%, and 79.5%, respectively. The sensitivity, specificity, PPV, NPV, and accuracy of the second model (LPA vs. APh) were all 100%. The sensitivity, specificity, PPV, NPV, and accuracy of the third model (ADM vs. APh) were 87.5%, 82%, 36.8%, 98.2%, and 82.7%, respectively. CONCLUSION: Texture features may help in the characterization of adrenal lesions on unenhanced CT images.

Radiation Therapy in the Management of Adrenal Metastases.

Adrenal glands represent a common site of metastases from several primary tumors, including lung cancer, breast cancer and melanoma. Surgical resection is considered the standard of care, but surgery is not always feasible given the challenges related to anatomical site and/or due to patient and/or disease characteristics. Stereotactic body radiation therapy (SBRT) represents a promising treatment for oligometastases, though the literature on its role for adrenal metastases is still heterogeneous. Herein are summarized the most relevant published studies on the efficacy and safety of SBRT for adrenal gland metastases. The preliminary data suggests that SBRT yields high local control rates and symptom relief with a mild pattern of toxicity. Advanced radiotherapy techniques including IMRT and VMAT, a BED10 > 72 Gy and the use of 4DCT for motion control should be considered for a high quality ablative treatment of adrenal gland metastases.

Robotic stereotactic body radiotherapy for the management of adrenal gland metastases: a bi-institutional analysis.

PURPOSE: Adrenal gland metastases (AGMs) are a common manifestation of metastatic tumor spread, especially in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). In patients with a limited systemic tumor burden, effective treatments for AGMs are needed. Due to varying fractionation schemes and limited reports, short-course treatment results for stereotactic body radiotherapy (SBRT) for AGMs are lacking. This work analyzes the outcomes of short-course SBRT for AGMs. METHODS: Patients who underwent robotic SBRT for AGMs with one to five fractions were eligible for analysis. RESULTS: In total, data from 55 patients with 72 AGMs from two institutions were analyzed. Most AGMs originated from renal cell carcinoma (38%) and NSCLC (35%). The median follow-up was 16.4 months. The median prescription dose and isodose line were 24 Gy and 70%, respectively. Most patients (85%) received SBRT with just one fraction. The median biologically effective dose assuming an α/ß ratio of 10 (BED10) was 80.4 Gy. The local control and progression-free survival after 1 and 2 years were 92.9%, 67.8%, and 46.2%, as well as 24.3%, respectively. Thirteen patients (24%) suffered from grade 1 or 2 toxicities. The BED10 showed a significant impact on LC (p < 0.01). Treatments with a BED10 equal to or above the median were associated with a better LC (p < 0.01). CONCLUSION: Robotic SBRT is an efficient and safe treatment modality for AGM. Treatment-associated side effects are sporadic and manageable. Results suggest short-course SBRT to be a preferable and time-saving treatment option for the management of AGMs if an adequate BED10 can be safely applied.

Dual Energy-Derived Metrics for Differentiating Adrenal Adenomas From Nonadenomas on Single-Phase Contrast-Enhanced CT.

BACKGROUND. Adrenal masses are often indeterminate on single-phase postcontrast CT. Dual-energy CT (DECT) with three-material decomposition algorithms may aid characterization. OBJECTIVE. The purpose of this study was to compare the diagnostic performance of metrics derived from portal venous phase DECT, including virtual noncontrast (VNC) attenuation, fat fraction, iodine density, and relative enhancement ratio, for characterizing adrenal masses. METHODS. This retrospective study included 128 patients (82 women, 46 men; mean age, 64.6 ± 12.7 [SD] years) who between January 2016 and December 2019 underwent portal venous phase abdominopelvic DECT that showed a total of 139 adrenal lesions with an available reference standard based on all imaging, clinical, and pathologic records (87 adenomas, 52 nonadenomas [48 metastases, two adrenal cortical carcinomas, one ganglioneuroma, one hematoma]). Two radiologists placed ROIs to determine the following characteristics of the masses: VNC attenuation, fat fraction, iodine density normalized to portal vein, and for masses with VNC greater than 10 HU, relative enhancement ratio (ratio of portal venous phase attenuation to VNC attenuation). Readers' mean measurements were used for ROC analyses, and clinically optimal thresholds were derived as thresholds yielding the highest sensitivity at 100% specificity. RESULTS. Adenomas and nonadenomas were significantly different (all p < .001) in VNC attenuation (mean ± SD, 18.5 ± 12.9 vs 34.1 ± 8.9 HU), fat fraction (mean ± SD, 24.3% ± 8.2% vs 14.2% ± 5.6%), normalized iodine density (mean ± SD, 0.34 ± 0.15 vs 0.17 ± 0.17), and relative enhancement ratio (mean ± SD, 186% ± 96% vs 58% ± 59%). AUCs for all metrics ranged from 0.81 through 0.91. The metric with highest sensitivity for adenoma at the clinically optimal threshold (i.e., 100% specificity) was fat fraction (threshold, ≥ 23.8%; sensitivity, 59% [95% CI, 48-69%]) followed by VNC attenuation (≤ 15.2 HU; sensitivity, 39% [95% CI, 29-50%]), relative enhancement ratio (≥ 214%; sensitivity, 37% [95% CI, 25-50%]), and normalized iodine density (≥ 0.90; sensitivity, 1% (95% CI, 0-60%]). VNC attenuation at the traditional true noncontrast attenuation threshold of 10 HU or lower had sensitivity of 28% (95% CI, 19-38%) and 100% specificity. Presence of fat fraction 23.8% or greater or relative enhancement ratio 214% or greater yielded sensitivity of 68% (95% CI, 57-77%) with 100% specificity. CONCLUSION. For adrenal lesions evaluated with single-phase DECT, fat fraction had higher sensitivity than VNC attenuation at both the clinically optimal threshold and the traditional threshold of 10 HU or lower. CLINICAL IMPACT. By helping to definitively diagnose adenomas, DECT-derived metrics can help avoid downstream imaging for incidental adrenal lesions.