Erickson, Dana

Abstract Endocrinopathies are frequently the initial presentation of histiocytic neoplasms, which are rare hematologic disorders affecting multiple organ systems. Langerhans cell histiocytosis and Erdheim–Chester disease are 2 such disorders known to infiltrate the hypothalamus and/or pituitary gland, leading to arginine vasopressin deficiency (AVP-D) and anterior pituitary dysfunction (APD) in 20% to 30% of cases, often as the first manifestation. Conversely, histiocytic disorders account for a notable proportion (10-15%) of all pituitary stalk lesions. The diagnosis of histiocytoses is often delayed in such cases due to the nonspecific presentation of endocrinopathies and pituitary involvement. Consequently, endocrinologists are at the frontline and uniquely positioned to achieve early diagnosis by recognizing the varied nonendocrine features of these disorders. This article provides an overview of the endocrine manifestations of histiocytic disorders and presents a simplified algorithm to guide the diagnostic workup in cases presenting with “idiopathic” AVP-D or APD. Such cases should be evaluated for histiocytic neoplasms with additional imaging studies and biopsies of suspected disease sites. If no disease site beyond the pituitary is identified, the risks and benefits of a pituitary stalk lesion biopsy must be carefully considered. While treatments of histiocytic neoplasms are highly efficacious, endocrinopathies are considered permanent and require long-term hormone replacement. It remains unclear whether early diagnosis and novel targeted therapies can reverse these endocrine disorders. Therefore, the role of the endocrinologist role is critical in the diagnosis and management of these rare diseases.

Abstract BACKGROUND Pituitary adenomas are often effectively managed with medical therapy, surgery, and radiation therapy. However, up to 15% of pituitary neoplasms exhibit rapid growth, invasive behavior, or, rarely, metastasize despite optimal standard treatments. Temozolomide is associated with a survival benefit for patients with these aggressive pituitary tumors. METHODS We present a case series of 8 patients with an aggressive pituitary tumor (APT) or pituitary carcinoma (PC) treated with temozolomide. RESULTS Eight patients (3 female, median age at diagnosis 44) with APT (n=6) or PC (n=2) were treated. A variety of pituitary tumor types were represented (1 prolactinoma, 5 corticotroph adenomas, 1 gonadotroph adenoma, 1 thyrotropinoma). Prior to temozolomide initiation, patients underwent a median 5 treatments including medical management (n=4), surgery (n=7), radiation therapy (n=7). Temozolomide was started at median 3.5 recurrence. Median treatment duration was 6 cycles (n=6, 150-200 mg/m2 days 1-5, 28-day cycles; n=1, 75 mg/m2, days 1-21, 28-day cycles). Seven patients experienced progression after temozolomide treatment, median progression-free survival (PFS) was 4 months. One patient remains on treatment, progression-free at 5 months. MGMT methylation status was assessed for 3 tumors. Among 2 patients with MGMT promoter methylated tumors, PFS was 4 months for one patient, the other remains on treatment. For one patient with MGMT promoter unmethylated corticotroph adenoma, PFS was 9 months. No ≥ grade 4 toxicities were noted. Most common toxicities were nausea (n=5), thrombocytopenia (n=3), and fatigue (n=2). CONCLUSION In this group of heavily pretreated patients, temozolomide monotherapy was well-tolerated and associated with median PFS of 4 months. Interestingly, PC patients had longer PFS at 9 months and 24 months. Our findings support use of single-agent temozolomide chemotherapy for patients with APT/PC, but further prospective analysis is needed to identify patients more likely to benefit from treatment and optimal timing of chemotherapy initiation.

Abstract Disclosure: B. Graner: None. D.Z. Erickson: None. D. Donegan: None. Introduction: Pituitary lesions are a common incidental finding on brain MRI, the majority of which are cystic. The natural history and management of cystic pituitary lesions have not been clearly established. Purpose: The purpose of this study is to determine the natural history of incidentally identified cystic pituitary lesions, risk factors for growth and the proportion of patients who develop clinically significant symptoms requiring surgical intervention. Methods: Pituitary MRI reports between 01/01/2015 and 12/31/2022 in patients aged 18 years and older were searched for using Dig Our Radiology Information System (DORIS) using the words “cyst” or “cystic.” Additional inclusion criteria included a follow-up pituitary MRI of at least one year duration, clinical evaluation by Endocrinology, and the presence of a cystic pituitary lesion. Patients with non-contrast exams, excessive pituitary hormone secretion, and surgery within 1 year of presentation were excluded. Patient demographics, imaging characteristics of the lesion and clinical outcomes were collected. All pituitary MRI exams were reviewed by a single neuroradiologist. Results: A total of 157 MRIs in 56 patients with a mean age of 48 ±15 years were included, 39 (70%) were female. The mean follow-up was 2.3 ± 1.4 years. The most common indication for MRI was headache (n= 18, 32%). There was no significant difference in mean maximum (max) diameter at last follow-up compared to baseline (7.45 ±4.23 vs 7.04 ±4.35 mm, p=0.06) or mean cyst volume (197.08 ±252.68 vs 201.43 ±326.18 mm3). Nine (16%) of the lesions increased in volume with a mean change in volume of 105 ±133.64 mm3/yr, note 11 (20%) decreased volume and 36 (64%) remained the same size. Using univariate logistic regression, the odds of cyst growth was greater the larger the max diameter (p= 0.03) or volume was at baseline (p= 0.02)/ Female sex (p=0.32), age at diagnosis (p=0.70) or whether the lesion was thought to be a Rathke cleft cyst or a cystic adenoma (p=0.80) were not associated with increased odds of growth. The risk of growth was higher (42 vs 9%, p=0.016) and the volume change per year was greater (67.2 ±134 vs -7 ±28 mm3, p=0.04) in those with a baseline max diameter of >10 mm. Surgery was performed in 4 patients (7%), 3 of which demonstrated lesion growth (baseline size 12-15 mm and growth rates of 59-341mm3/yr). Pathology revealed one Rathke cleft cyst, one cystic adenoma and fibrotic pituitary changes. The fourth surgical patient opted for resection at an outside facility without a demonstrated increase in size (Rathke cleft cyst). Conclusion: The majority of incidentally found cystic pituitary lesions do not increase after an average follow-up 2-3 years. Growth necessitating surgical intervention was only required in 5% of patients over the study period. A pituitary cyst >10 mm at diagnosis was associated with an increased risk of growth and therefore warrants closer follow-up. Presentation: 6/1/2024

Abstract Disclosure: J. Hewlett: None. S. Mohan: None. C.J. Davidge-Pitts: None. J. Abeykoon: None. R. Go: None. D.Z. Erickson: None. Objective: Erdheim-Chester Disease (ECD) is a multisystem histiocytic disorder which can infiltrate the pituitary gland, often leading to endocrine dysfunction. Central Arginine Vasopressin Deficiency (cAVP-D) commonly affects ECD patients, and those harboring BRAFV600E are reported to have an increased risk. Insufficient data exist about the risk associated with other mutations, and if cAVP-D or pituitary imaging improves with targeted therapies (TT). Methods: We conducted a review of a prospectively maintained database of adults with ECD treated at a tertiary center between 1992-2023. Objectives of this study were to identify mutations associated with cAVP-D and assess for improvement in cAVP-D (remission of disease or decrease in dose of desmopressin) or pituitary gland involvement (via MRI imaging) following TT for ECD. Results: Of 148 patients with ECD, the majority were male (98, 66.2%) and the mean age at diagnosis was 56.5 years [range: 19-82]. Median length of follow-up was 24 months (95% CI, 17 to 27). Of 121 (81.8%) patients with molecular testing results, 89 (73.6%) harbored a somatic mutation. 67 of 89 (75.3%) carried BRAF mutations, with BRAFV600E in 61 (91.0%) and missense mutations/fusions in 6 (9.0%). 22 of 89 (24.7%) patients harbored other somatic mutations, with MAP2K1 in 13 (14.6%) being the most common. 35 (23.6%) patients were diagnosed with cAVP-D, and the median onset of polyuria and polydipsia prior to diagnosis of ECD was 51 months (95% CI, -120 to -6). Molecular testing was performed in 28 patients with cAVP-D: 17 (60.7%) harbored BRAF mutation and 3 (10.7%) MAP2K1 mutation. There was no significant association between the presence of cAVP-D and MAP2K1 (p=0.69, 95% CI, -0.08 to 0.21). The association between cAVP-D and BRAF did not reach statistical significance (p=0.07, 95%CI, -0.03 to 0.38). Additionally, there was no association between BRAF and timing of cAVP-D symptoms before ECD diagnosis (p=0.08, 95% CI -163.4 to 10.3). Pituitary MRI was available in 32 patients with cAVP-D (91.4%) showing infundibular involvement in 17 (53.1%) and loss of the posterior bright spot in 5 (15.6%). 28 (80%) patients with cAVP-D received systemic therapy, 18 (64.3%) of whom received TT. One patient with cAVP-D was able to discontinue desmopressin. Improvement of pituitary MRI was noted in 7 (21.9%), among whom 4 received TT, 2 received systemic non-TT, and 1 was lost to follow-up. There was no significant MRI improvement associated with TT (p=0.67, 95% CI -0.30 to 0.42). Conclusion: In this large cohort of patients with ECD, of whom the majority underwent molecular testing, we identified no association between MAP2K1 mutation and cAVP-D, and no impact of TT on the clinical course or MRI findings associated with cAVP-D. BRAF mutation carriers were more likely to have cAVP-D and more likely to have onset of symptoms closer to ECD diagnosis, but the results did not reach statistical significance. Presentation: 6/2/2024

Abstract Disclosure: J. Herndon: None. W.G. Breen: None. N. Laack: None. W.S. Harmsen: None. D.Z. Erickson: None. Background: Treatment of chordomas and parasellar meningiomas includes surgical resection and/or various forms of radiotherapy. Proton beam therapy (PBT) is able to provide higher doses of radiation to the targeted tissues while better sparing surrounding structures, potentially facilitating decreased toxicity. While proton utilization has increased, there is a paucity of data regarding short- and long-term endocrinologic outcomes in these patients. Objective: Determine rate of hypopituitarism in patients with chordomas and parasellar meningiomas undergoing PBT. Methods: A prospectively maintained radiation database including adult patients treated with PBT since 2015 at a tertiary referral center for chordomas and parasellar meningiomas was reviewed. Data collected at baseline included demographic data, tumor diagnosis and pathology, prior history of surgery/radiation, radiation treatment, biochemical hormonal data, and incidence of pituitary insufficiencies (PI). Biochemical pituitary hormonal data and incidence of new PI was recorded at 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, and up to two additional time points up to 10 years post-PBT. Statistical analysis includes descriptive statistics presented as number (%) and median [IQR]. Results: Of 177 patients with sellar/parasellar masses with sufficient endocrine data who underwent PBT, a total of 64 patients (36.2%) were included; 40 (62.5%) with parasellar meningioma and 24 (37.5%) with chordoma. Median age of patients was 49.5 years old [37.7, 63.2], and 44 (68.8%) were female. Median follow-up was 24 months [12, 36]. Prior to PBT, 52 patients (81.3%) were treated surgically, 5 (7.8%) had prior fractionated photon or gamma-knife radiation therapy. At baseline 10 patients (15.6%) exhibited PI in at least one pituitary axis, most commonly secondary hypogonadism (7, 70%). Median PBT total prescribed dose was 54 Gy [50.4, 70.0] in a median of 30 [28, 35] fractions. Cumulative incidence of newly diagnosed PI at follow-up was 4.7% at 6 months, 9.4% at 1 year, 14.1% at 2 years, and 17.2% at 3+ years. No patients with PI at baseline developed new deficiencies. Among the 11 patients (17.2%) who developed new PI, 17 various deficiencies were recorded (range 1-3 per patient), including hypogonadism (8, 47.1%), hypothyroidism (6, 35.3%), and adrenal insufficiency (4, 23.5%). No growth hormone deficiency was clinically diagnosed, however IGF-1 levels decreased from baseline at the follow-up (when available) by a median of -11.8 ng/mL at 6 months (n = 12), -3.0 at 1 year (n = 12), -17.0 at 2 years (n = 7), -30.5 at 3 years (n = 4), -55.0 at 4 years (n = 3), and -37.5 at 5 years (n = 2). Conclusion: Incidence of newly developed PI in chordomas and parasellar meningiomas following PBT for adult patients after median initial follow up of 2 years was low, however extended follow up data are necessary. Presentation: 6/1/2024

Abstract Disclosure: A.Y. Chang: None. D.Z. Erickson: None. W.F. Young: None. K. Grennan: None. J.C. Andrews: None. E. Kapoor: None. Background: While mild androgen excess is frequently encountered in endocrine practices, severe symptoms, rapid onset or markedly abnormal biochemical testing lead to further evaluation for rare ovarian androgen-producing tumors, ovarian hyperthecosis or androgen-secreting adrenal tumors. Combined ovarian and adrenal vein sampling (COAVS) might be necessary to identify the source of androgen hypersecretion and guide treatment. The utility of COAVS has been studied in limited case series, combining case reports and different centers. There is no consensus regarding the testosterone gradient that localizes the androgen source or the added value of COAVS when a pathologic source of androgen excess is suspected. The additional clinical benefit of adrenal vein sampling (AVS) when combined with ovarian vein sampling (OVS) has also not been examined. Objectives: We sought to determine: a) the optimal total testosterone (TT) gradient for identifying unilateral vs bilateral source of hyperandrogenism and b) the utility of AVS in addition to OVS. Methods: We performed a retrospective chart review of all adult women who had COAVS at Mayo Clinic, Rochester from 1996 to 2023. Pathologic sources of androgen excess were defined as ovarian hyperthecosis (OH) as well as ovarian and adrenal tumors. We calculated the ratio of dominant OV or AV divided by the nondominant OV or AV. Results: 22 COAVS procedures from 7 premenopausal and 15 postmenopausal women were included in the study: 12 (55%) women had adrenal abnormalities seen on computed cross sectional imaging and 5 (23%) had unilateral ovarian imaging abnormalities. Of the 22 participants in the case series, successful 4-vessel catheterization was completed in 20 (1 right ovarian vein could not be cannulated, and 1 had bilateral oophorectomy). Nine (41%) women had unilateral and 10 (45%) bilateral ovarian androgen hypersecretion. Eleven (50%) women had pathologic causes for elevated TT (5 ovarian tumors, 6 cases of OH), 5 lacked follow-up pathology and 5 had benign pathology. AVS did not diagnose an adrenal source of androgen hypersecretion. TT concentrations were significantly greater in patients with unilateral compared to those with bilateral ovarian androgen hypersecretion (median 262.5 ng/dL [245- 401.5 IQR] vs 104 ng/dL [82-190], P = 0.01). In addition, TT concentrations were higher in those women with a pathologic source of TT hypersecretion compared to those with benign ovaries (349 ng/dL [251-538] vs 115 ng/dL [93-195], P = 0.03). All cases of unilateral ovarian disease had a dominant OV gradient of TT ≥ 2.1 compared to the nondominant OV. Conclusion: In a series of successful COAVS in women with androgen hypersecretion, an ovarian side-to-side gradient of ≥ 2.1 diagnosed all sources of unilateral ovarian pathology. AVS did not diagnose any pathologic source of adrenal androgen excess in this patient cohort. Presentation: 6/3/2024