Pituitary Irradiation Research Articles

Fatal high-grade skull osteosarcoma 30 years following radiotherapy for Cushing's disease.

SummaryCushing’s disease is a rare disorder characterised by excessive cortisol production as a consequence of a corticotroph pituitary tumour. While the primary treatment is surgical resection, post-operative radiation therapy may be used in cases of ongoing inadequate hormonal control or residual or progressive structural disease. Despite improved outcomes, radiotherapy for pituitary tumours is associated with hypopituitarism, visual deficits and, rarely, secondary malignancies. We describe an unusual case of a 67-year-old female with presumed Cushing’s disease diagnosed at the age of 37, treated with transsphenoidal resection of a pituitary tumour with post-operative external beam radiotherapy (EBRT), ketoconazole for steroidogenesis inhibition, and finally bilateral adrenalectomy for refractory disease. She presented 30 years after her treatment with a witnessed generalised tonic-clonic seizure. Radiological investigations confirmed an extracranial mass infiltrating through the temporal bone and into brain parenchyma. Due to recurrent generalised seizures, the patient was intubated and commenced on dexamethasone and anti-epileptic therapy. Resection of the tumour revealed a high-grade osteoblastic osteosarcoma. Unfortunately, the patient deteriorated in intensive care and suffered a fatal cardiac arrest following a likely aspiration event. We describe the risk factors, prevalence and treatment of radiation-induced osteosarcoma, an exceedingly rare and late complication of pituitary irradiation. To our knowledge, this is the longest reported latency period between pituitary irradiation and the development of an osteosarcoma of the skull.Learning points:Cushing’s disease is treated with transsphenoidal resection as first-line therapy, with radiotherapy used in cases of incomplete resection, disease recurrence or persistent hypercortisolism.The most common long-term adverse outcome of pituitary tumour irradiation is hypopituitarism occurring in 30–60% of patients at 10 years, and less commonly, vision loss and oculomotor nerve palsies, radiation-induced brain tumours and sarcomas.Currently proposed characteristics of radiation-induced osteosarcomas include: the finding of a different histological type to the primary tumour, has developed within or adjacent to the path of the radiation beam, and a latency period of at least 3 years.Treatment of osteosarcoma of the skull include complete surgical excision, followed by systemic chemotherapy and/or radiotherapy.Overall prognosis in radiation-induced sarcoma of bone is poor.Newer techniques such as stereotactic radiosurgery may reduce the incidence of radiation-induced malignancies.

SAT-143 Missed Pituitary Apoplexy in a HIV Patient

Background: Pituitary hemorrhage has a prevalence of up to 25% in macroadenomas. In apoplectic hemorrhage, loss of pituitary function is associated with significant mortality. Sudden hemorrhagic enlargement of a preexisting adenoma compresses surrounding structures; ophthalmoplegia, mydriasis and ptosis occur when cranial nerves in the cavernous sinus are affected. The classic clinical syndrome of headache, visual deficits, altered mental status and hypopituitarism, combined with imaging, confirms the diagnosis of pituitary apoplexy. Clinical Case: A 73 year-old smoker with a history of transsphenoidal surgery 20 years ago for a pituitary adenoma, HIV (CD4 928), hypertension, diabetes, coronary artery disease presented with two days of altered mental status, lethargy and headaches. Patient was febrile to 104.1°F on arrival. Head CT was done prior to a lumbar puncture, which showed a 1.7 x 2.1 x 2.2 cm pituitary mass. CSF analysis was positive for xanthochromia, and revealed 220 RBCs, 275 WBCs, glucose 143 mg/dL, protein 154 mg/dL and an opening pressure of 9 mm H20. Meropenem and vancomycin were started for presumed meningitis. A hypopituitary state was found on labs: prolactin 1.9 ng/mL (4.6–21.4 ng/mL), ACTH 3.2 pg/mL (7.2–63.3 pg/mL), cortisol 3.6 ug/dL, TSH 0.164 uIU/mL (0.27–4.0 uIU/mL), free T4 0.6 ng/dL (0.7–1.5 ng/dL), T3 0.3 ng/mL (0.6–1.6 ng/mL), IGF-1 33 ng/mL (41–179 ng/mL), total testosterone 4 ng/dL (193–740 ng/dL), LH 0.3 mIU/mL and FSH 1.2 mIU/mL. Subsequent MRI showed a 2.2 x 2.4 x 2.9 cm pituitary macroadenoma extending into the suprasellar region with mass effect on the optic chiasm and lateral displacement of the cavernous sinus segment of internal carotid arteries bilaterally. An ophthalmologic exam could not be performed due to altered mentation. Endocrinology recommended cosyntropin testing to assess for adrenal insufficiency. The following day, the patient developed a fixed and dilated right pupil, and was taken to the OR for emergent decompression. IV dexamethasone and levothyroxine were started post-operatively. Conclusion: Differential diagnoses of pituitary apoplexy include bacterial meningitis and subarachnoid hemorrhage with aneurysmal rupture. A nonpupil-sparing third nerve palsy suggests a mass lesion. Given his symptoms and xanthochromia, this patient likely presented with pituitary apoplexy that was overlooked on initial scans. Hemorrhage that is iso-dense to normal brain tissue would not have the typical “pituitary ring sign”, a radiographic feature of peripheral enhancement around a non-enhancing infarcted center. Predisposing factors include hypertension, diabetes mellitus, pituitary dynamic testing, bromocriptine, estrogens or radiotherapy. This patient had multiple comorbidities. A lumbar puncture possibly worsened preexisting pituitary apoplexy, acutely expanding the area of hemorrhage and causing compressive symptoms.

MECHANISMS IN ENDOCRINOLOGY: Autoimmune hypopituitarism: novel mechanistic insights.

Hypopituitarism is caused by various insults to the pituitary, such as hypothalamic and pituitary tumors, inflammation, autoimmunity, vascular injury, genetic abnormalities, irradiation, and trauma. Recently, it has been found that autoimmunity to the pituitary involves many pathological conditions associated with specific or non-specific hormone deficiencies in the gland. This review discusses the recent findings on the underlying mechanism of autoimmune hypopituitarism particularly of lymphocytic hypophysitis, IgG4-related hypophysitis, immune checkpoint inhibitor-induced hypophysitis, anti-PIT-1 hypophysitis, and isolated ACTH deficiency.

Risk Factors for Small Adult Height in Childhood Cancer Survivors.

Between 10% and 20% of childhood cancer survivors (CCS) experience impaired growth, leading to small adult height (SAH). Our study aimed to quantify risk factors for SAH or growth hormone deficiency among CCS. The French CCS Study holds data on 7,670 cancer survivors treated before 2001. We analyzed self-administered questionnaire data from 2,965 CCS with clinical, chemo/radiotherapy data from medical records. SAH was defined as an adult height ≤ 2 standard deviation scores of control values obtained from a French population health study. After exclusion of 189 CCS treated with growth hormone, 9.2% (254 of 2,776) had a SAH. Being young at the time of cancer treatment (relative risk [RR], 0.91 [95% CI, 0.88 to 0.95] by year of age), small height at diagnosis (≤ 2 standard deviation scores; RR, 6.74 [95% CI, 4.61 to 9.86]), pituitary irradiation (5-20 Gy: RR, 4.24 [95% CI, 1.98 to 9.06]; 20-40 Gy: RR, 10.16 [95% CI, 5.18 to 19.94]; and ≥ 40 Gy: RR, 19.48 [95% CI, 8.73 to 43.48]), having received busulfan (RR, 4.53 [95% CI, 2.10 to 9.77]), or > 300 mg/m2 of lomustine (300-600 mg/m2: RR, 4.21 [95% CI, 1.61 to 11.01] and ≥ 600 mg/m2: RR, 9.12 [95% CI, 2.75 to 30.24]) were all independent risk factors for SAH. Irradiation of ≥ 7 vertebrae (≥ 15 Gy on ≥ 90% of their volume) without pituitary irradiation increased the RR of SAH by 4.62 (95% CI, 2.77 to 7.72). If patients had also received pituitary irradiation, this increased the RR by an additional factor of 1.3 to 2.4. CCS are at a high risk of SAH. CCS treated with radiotherapy, busulfan, or lomustine should be closely monitored for growth, puberty onset, and potential pituitary deficiency.

The effects of experimentally irradiated pituitary gland on the growth of rat’s tibia, skull, maxilla and mandible

Background/Aim. The reaction of an organism to radiation depends on the level of irradiation and the sensitivity of the affected tissue cells. The biological effects on the cells and tissues are proportional to the absorbed radiation energy. The aim of our study was to examine the effects of hypofunction of the pituitary gland, previously irradiated with x-rays, on the growth of rat?s craniofacial and stomatognathic system as well as rat?s tibia. Methods. A total dose of x-rays of 27.92 Gy was applied in eight sessions in the period from 8 to 63 days of animal age on their heads and the effects of irradiation-induced hypofunction of the pituitary gland on the growth of rat?s craniofacial and stomatognathic system and tibia were examined. In order to differentiate the effects of the irradiated pituitary gland from the direct effects of x-rays on the head, the experiment was set as a double study. One group of animals had the pituitary gland protected with a lead plate set beneath the projection of the gland, while the second group was irradiated with the same dose, but without the protection. The control group of animals were non-irradiated. Results. Growth measurements of numerous parameters of the craniofacial and stomatognathic system as well as tibia in rats with the entire locally irradiated head showed a statistically significant delay, compared to both the non-irradiated control group and the group with the protected pituitary gland. Conclusion. The damage of the stomatognathic and craniofacial system was greater in animals with irradiated head without pituitary gland protection compared to those with the gland protection whereby the growth of the craniofacial system was most affected. Irraduition-induced pituitary gland hypofunction and irradiation itself showed a stronger effect on the lower jaw growth rate impairment compared to the upper jaw. Similarly, the delay in tibia growth was more pronounced in animals without pituitary gland protection during irradiation of their heads compared to non-protected ones.

Current Status of Diagnosis and Management for Functioning Pituitary Tumors: Part I.

Pituitary adenomas (PA) account for approximately 15% of all intracranial neoplasms. Pituitary adenomas can be of different subtypes based on the cell of origin or associated hormone hypersecretion (non-functioning pituitary adenoma, prolactinoma, somatotropinoma, corticotropinoma, thyrotropinoma, and gonadotropinoma). Functioning PAs are associated with relatively higher morbidity and mortality because of associated hormone hypersecretion syndromes. Diagnosis of functioning PA is established by biochemical confirmation of hormone hypersecretion and demonstration of a pituitary lesion on imaging. Trans-sphenoidal surgical resection of tumor represents the first-line treatment for most tumor types, except for prolactinomas where medical therapy with dopamine agonists is preferred. Radiotherapy (RT) and medical therapy are the other options for the management of PA. It is important to individualize treatment options based on tumor type, patient's clinical condition, expertise of surgeon, affordability and patient preferences. In the first part of this series, we review the presentation and management of adrenocorticotropic hormone secreting, gonadotropin secreting and aggressive PA. Despite several recent advances, the diagnosis and management of Cushing's disease is still a challenge. Modifications in magnetic resonance imaging techniques like volume interpolated 3D spoiled gradient echo sequence have improved the sensitivity to detect microcorticotropinomas. Pituitary RT, preferably conventional RT, is a useful second-line therapy for the management of CD. Besides the conventional drugs, few drugs such as pasireotide and osilodrostat have been approved by US FDA recently, whereas several others are in pipeline which provide hope for a better outcome in CD patients. Temozolomide is a useful drug for the management of aggressive PA.

Modern Radiation Therapy for Pituitary Adenoma: Review of Techniques and Outcomes.

Pituitary adenomas are benign tumors arising in the adenohypophysis and comprise 8%-20% of all reported primary brain tumors in the west. Transsphenoidal surgery with an aim to achieve complete tumor resection is the recommended first-line treatment for nonfunctioning as well as secretory pituitary adenoma. External beam radiation therapy (RT) has been demonstrated to be an effective treatment modality for pituitary adenoma, uncured by surgery and/or medical therapy, providing excellent long-term local control (>90%), but lower and variable rates (50%-80%) of biochemical remission in secretory tumors. The adoption of pituitary RT in the community has been limited due to concerns regarding potential late toxicity and long latency in normalization of hormonal hypersecretion. Over the years, technological advances in RT planning and delivery have resulted in progressive conformation of high doses to the target tissues while sparing adjacent neurovascular structures providing a favorable therapeutic index. The choice of RT technique should be based on size, site, and availability of infrastructure and expertise, with no significant differences between fractionated approaches and stereotactic radiosurgery (SRS). In contemporary clinical practice, the recommended dose of fractionated RT for pituitary adenoma is 45-50.4Gy in 25-28 fractions delivered over 5-6 weeks using modern high-precision techniques. The recommended dose of SRS given in a single fraction is 12-14Gy for nonfunctioning adenomas and 16-20Gy for secretory tumors. Late toxicity of pituitary RT includes hypopituitarism, neurocognitive impairment, neuropsychological dysfunction, optic neuropathy, cerebrovascular accidents, and second malignant neoplasms. Hence, RT in pituitary adenoma should be offered only to patients with residual, recurrent, progressive, or high-risk tumors with careful assessment of the benefit-risk ratio by an experienced multidisciplinary neurooncology team.

Risk Factors for Small Adult Height in Childhood Cancer Survivors

BACKGROUND: Between 10-20% of childhood cancer survivors (CCS) suffer impaired growth leading to small adult height (SAH). Our study aimed to quantify risk factors for SAH or growth hormone (GH) deficiency among CCS. METHODS: The FCCSS holds data on 7670 cancers survivors treated before 2001. We analyzed self-questionnaire data from 2965 CCS with clinical, chemo/radiotherapy data from medical records. SAH was defined as an adult height <2 Standard Deviation Scores (SDS) of control values obtained from a French population health study. RESULTS: After exclusion of the 189 CCS treated with GH, 9.2% (254/2776) had a SAH. Being young at the time of cancer treatment (RR 0.91 [95% CI, 0.88-0.95], by year of age), small height at diagnosis ( 40 Gy RR 19.48 [95%CI, 8.73-43.48]), having received busulfan (RR 4.53 [95%CI, 2.10- 9.77]), or more than 300 mg/m² of lomustine ([300-600]mg/m² RR 4.21 [95%CI, 1.61-11.01], >600mg/m² RR 9.12 [95%CI, 2.75-30.24]) were all independent risk factors for SAH. Irradiation of seven or more vertebrae (>15 Gy on >90% of their volume) without pituitary irradiation increased the RR of SAH by 4.62 [95%CI, 2.77-7.72]. If patients had also received pituitary irradiation, this increased the RR by an additional factor of 1.3 to 2.4. CONCLUSION: CCS are at high risk of SAH. Any CCS who has been treated with radiotherapy, busulfan, or lomustine should be closely monitored for growth, puberty onset, and potential pituitary deficiency. FUNDING STATEMENT: This work was supported by the French Society of Childhood Cancer (SFCE), the PAIR Research Program “START - INCa-ARC-Ligue_11902, the PAIR Research Program “Mr Robot” – INCa-ARCLIGUE_11909, the Electricite de France (EDF), the Pfizer Foundation for childhood and adolescent health, the Ligue Nationale Contre le Cancer (LNCC), the Institut de Recherche en Sante Publique (IRESP), and the French “Agence Nationale Pour la Recherche Scientifique” (Hope-Epi Project). DECLARATION OF INTERESTS: All authors declared to have no conflict of interest with this study. ETHICS APPROVAL STATEMENT: The study has been approved by the French Data Protection Authority (CNIL) and the ethics committee of the National Institute of Medical Research and Health (INSERM).

Evaluation of Treatment of Central Hypothyroidism Versus Primary Hypothyroidism in Relation to Levothyroxine Replacement Dose

Objective: The aim of this study was to evaluate levothyroxine (LT4) replacement daily doses in patients with central hypothyroidism (CeH) and compare them with those adequate for patients with primary hypothyroidism (P-HYPO). Methods: We included 53 patients with CeH and 57 with P-HYPO, matched by sex, age, weight, and body mass index, in the period of 1 year. At the time of inclusion, all presented a stable and adequate dose of LT4 for at least 3 months, considering as adequate the dose associated with normal thyroid-stimulating hormone (TSH) levels and free thyroxine (T4) in P-HYPO patients, and free T4 levels in CeH patients. Results: The absolute daily dose of LT4 differed significantly between the two groups, 103.0 ± 27.1 μg (CeH) and 89.3 ± 32.0 μg (P-HYPO) (P = .017), even after adjustment for age, gender, and free T4 (P = .04). The LT4 dose adjusted to weight was also higher after adjustment for age, gender and free T4 (P = .04), with an average of 1.3 ± 0.4 μg/kg (CeH) and 1.2 ± 0.4 μg/kg (P-HYPO). Sheehan syndrome patients had a lower absolute daily dose of LT4 (P = .001), and patients who underwent pituitary radiotherapy required higher doses (P = .008). There was no difference in the daily dose of LT4 according to other pituitary hormone deficiencies. Conclusion: The results reinforce the relevance of a careful individualization of LT4 replacement in CeH management and the need for new markers for proper LT4 replacement therapy in such cases. Abbreviations: BMI = body mass index; CeH = central hypothyroidism; GH = growth hormone; LT4 = levothyroxine; P-HYPO = primary hypothyroidism; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone.

Hyperprolactinemia diagnosis in elderly men: a cohort of 28 patients over 65 years.

To characterize a cohort of elderly men with prolactinomas and their response to treatment. We have identified 28 elderly men diagnosed after the age of 65 with prolactinomas at seven different endocrine clinics in Israel. A retrospective electronic chart review identified a control group of 76 younger men with macroprolactinomas treated in one of the centers. Mean age at diagnosis was 71.3 ± 5.6 (range 65-86) years, and current age 76.6 ± 7.5 years. Initial complaints leading to diagnosis included sexual dysfunction in 17 males (61%), headaches in two patients (7%), and visual abnormalities in two (7%). Three men presented with osteoporosis. Ten patients (36%) were diagnosed incidentally following brain imaging for unrelated reasons. Seventeen patients (61%) had macroadenoma, while eleven (39%) presented with a microadenoma or no visible adenoma. Mean prolactin (PRL) at presentation was 1594 (median 382; range 50-18,329) ng/ml. Testosterone was low in 21 men. Patients were treated with cabergoline (max dose, 1.1 ± 0.5 mg/week), except for one given bromocriptine; none required pituitary surgery or radiotherapy. Treatment normalized PRL in 24 patients, and in three men PRL suppressed to <2 ULN. Fifteen men normalized testosterone, three improved without normalization, and in three the normal baseline level increased. After a mean follow-up of 5.3 years, 14/15 patients harboring a macroadenoma showed significant adenoma shrinkage. Most patients reported improvement of low libido/erectile dysfunction. In the control group 60 men (79%) achieved PRL normalization. Elderly men with prolactinomas are diagnosed incidentally in 36% of cases. Long-term medical therapy is successful, achieving biochemical remission, adenoma shrinkage, and clinical improvement in almost all patients.

Radiotherapy as a tool for the treatment of Cushing's disease.

Treatment of Cushing's disease (CD) is one of the most challenging tasks in endocrinology. The first-line treatment, transsphenoidal pituitary surgery, is associated with a high failure rate and a high prevalence of recurrence. Re-operation is associated with an even higher rate of a failure and recurrence. There are three main second-line treatments for CD - pituitary radiation therapy (RT), bilateral adrenalectomy and chronic cortisol-lowering medical treatment. All these treatments have their limitations. While bilateral adrenalectomy provides permanent cure of the hypercortisolism in all patients, the unavoidable chronic adrenal insufficiency and the risk of development of Nelson syndrome are of concern. Chronic cortisol-lowering medical treatment is not efficient in all patients and side effects are often a limiting factor. RT is efficient for approximately two-thirds of all patients with CD. However, the high prevalence of pituitary insufficiency is of concern as well as potential optic nerve damage, development of cerebrovascular disease and secondary brain tumours. Thus, when it comes to decide appropriate treatment for patients with CD, who have either failed to achieve remission with pituitary surgery, or patients with recurrence, the pros and cons of all second-line treatment options must be considered.

MON-454 Recovery of the Hypothalamic-Pituitary-Adrenal, Gonadal, and Thyroid Axes Following Trans-Sphenoidal Adenomectomy: A Single Center Experience

Background Hypopituitarism is a potential sequelea of pituitary macroadenoma or trans-sphenoidal adenomectomy (TSA). Recovery of pituitary function can occur post-TSA, and reassessment is required to avoid needless hormonal replacement. The timing and frequency of re-testing is variable across centres and the aim of this study was to determine rate of, and time to recovery of hypothalamic-pituitary adrenal (HPA), gonadal and thyroid axes postTSA. Methods We performed a single-centre retrospective analysis of TSA patients from February 2015 to September 2018. Patients with apoplexy, corticotroph adenomas, redo-surgery, emergency TSA, craniotomy or pituitary radiotherapy were excluded. Thyroid, gonadal and HPA axis adequacy was respectively assessed with TSH/freeT4, FSH/LH/estradiol or testosterone measurement and short synacthen test (SST), performed pre-TSA and at 6-weeks, 3-, 6-, and 9 to 12-months post-TSA. Results Data on 135 patients (mean age 54±17 years; 80M) were analysed. Macroadenomas occurred in 118 (87.4%), microadenoma in 8 (5.9%). Histology confirmed gonadotroph (53%), somatotroph (10.4%), plurihormonal (13.3%), lactotroph (5.2%), meningioma (1.5%), craniopharyngioma (12.6%), thyrotroph (1.5%) and metastatic malignancy (2.2%). 53.7%, 30.2% and 19.1% of patients had pre-op gonadal, thyroid and HPA function deficit respectively. 59% of patients had at least one deficit at baseline. Age was associated with the number of deficits manifested (F=6.026, p<0.001). 6-weeks post-TSA, 31.4%, 20.6% and 32% showed gonadal, thyroid and HPA axis deficit respectively. 35.7% of patients with normal pre-op pituitary function developed at least one new hormonal axis deficit at 6-weeks. Of 19.1% patients with abnormal pre-op HPA function, 30.4 % (7/23) recovered at 6-weeks. Among patients with abnormal HPA function at 6 weeks, 12.2%, 7.3% and 4.9% recovered at 3-, 6-, and 9 to 12-months respectively. 31.6% of patients with abnormal pre-op thyroid and 20% of patients with abnormal pre-op gonadal axes recovered at 6-weeks. Among patients recovering HPA axis function at 6-weeks, the majority also recovered thyroid axis (85.1% vs 14.9%, χ2=4.839, OR 2.643, p=0.03), whereas no association was found between gonadal and HPA axis recovery (54.1% vs 45.9%, p=0.16). Conclusions We demonstrate a significant rate of recovery of pre-operative pituitary deficit following TSA. 6-weeks post-operatively, gonadal failure is the most prevalent deficit. Regaining HPA axis function is a positive predictor for thyroid axis recovery but not gonadal axis recovery. HPA axis normalization can even occur at 9 to 12-months post-TSA, emphasizing the importance of periodic reassessment to avoid unnecessary hydrocortisone replacement in those who could eventually regain function. More longitudinal data are needed to assess the potential for recovery of thyroid and gonadal axes at >6 weeks post-op.

MON-418 Symptomatic Pituitary Metastasis: Two Case Reports with Contrasting Clinical Presentations

Introduction: Pituitary metastases (PM) are a rare occurrence with a poor prognosis. The most common cancers to metastasize to the pituitary are breast and lung. Most PMs are asymptomatic, but when symptoms occur the most commonly reported presentation is central DI. Clinical Cases: Case 1. An 86 year old male presented to the hospital with progressive weakness, fatigue and low appetite. He had a history of widely metastatic papillary thyroid cancer treated with thyroidectomy, repeated doses of RAI and repeated neck dissections. Most recent TG was 27,405 ng/mL (nl 2.8-40.9). An 8AM cortisol was checked and found to be low at 0.8 mcg/dL (nl 10-20). Further hormonal workup showed low ACTH, TSH <0.01uIU/mL (nl 0.3-5), FT4 1.43 ng/dL (nl 0.76-1.46) while on LT4, prolactin 38.94ng/mL (nl 2.1-17.7), low LH and FSH consistent with panhypopituitarism. Pituitary MRI showed an infiltrative process enlarging the pituitary gland, with extension into the stalk and hypothalamus concerning for metastatic disease. He was started on steroid replacement. He underwent systemic tyrosine kinase inhibitor therapy as well as pituitary radiation, but unfortunately, he died 7 months after presenting with central AI. Case 2. A 56 year old male was referred to endocrine clinic for polydipsia, polyuria and nocturia. Initial labs showed normal glucose, Na 145 mmol/L (nl 136-145), serum Osm 299mOsm/kg (nl 276-305), and urine Osm 92mOsm/kg (nl 500-800). Water deprivation test confirmed central DI. Further labs showed intact anterior pituitary function. Pituitary MRI showed an infiltrative process in the pituitary gland, affecting stalk and hypothalamus concerning for metastatic disease. Imaging was obtained and showed masses in the lung, kidney, spine, and mediastinal lymph nodes. The patient had a remote history of colon cancer and underwent biopsy of the lymph and renal masses, both showing metastatic colorectal cancer. He was started on DDAVP and symptoms improved. Three weeks later he presented with severe fatigue, dizziness, and hot flashes. Workup showed panhypopituitarism. Repeat MRI showed interval growth of the pituitary lesion. He underwent pituitary radiation and chemotherapy. He did not tolerate the side effects of systemic therapy and enrolled in hospice care. Conclusions: The most commonly reported symptomatic presentation of PM is central DI, however the reported incidence of anterior pituitary dysfunction is rising and clinicians should be aware. Pituitary metastases should remain on the differential in any case of anterior or posterior pituitary dysfunction, particularly in patients with any history of malignancy.

MON-415 Pituitary Carcinoma With Sequential Hormone Hypersecretion And A Novel Renal Complication Of Hormone Excess

Background: Pituitary carcinoma is a rare diagnosis, occurring in <1% of pituitary tumours. Most are hormonally active and resistant to conventional treatment. We present a rare case of a malignant lactotroph tumour whose extreme and evolving secretory phenotype has induced an unprecedented form of nephropathy. Case: A 55 year old man presented to ophthalmology with painful right third nerve palsy. Subsequent imaging revealed a 24 x 26 mm sellar mass extending into the right cavernous sinus and encroaching upon the optic chiasm. Endocrine evaluation demonstrated prolactin (PRL) of 68,000 mIU/L and accompanying hypogonadism (testosterone 1.3 nmol/L, FSH 1.8 IU/L, LH 1.4 IU/L), hypoadrenalism (peak cortisol 272 nmol/L after 250 mcg synacthen) and hypothyroidism (TSH 2.9 mIU/L, T4 8 pmol/L). IGF1-1 was also at the lower end of the reference range (10 nmol/L). He made an initial good response to cabergoline with PRL falling to 1570 mIU/L, resolution of visual symptoms, tumour shrinkage to 7 x 16 mm and restoration of HPA axis function. Five years later he demonstrated escape from hormone control with PRL rising to 32,000 mIU/L and return of the ophthalmoplegia, despite escalation of cabergoline to 3.5mg weekly. Unexpectedly, he also developed acute ketotic diabetes mellitus secondary to new onset acromegaly (GH >100 ug/L, IGF-1 97 nmol/L). The tumour remnant had expanded into the cavernous sinus on MRI. Biopsy of the lesion showed a tumour with strong PRL staining, micro-vacuolation, sparse GH staining and Ki-67 of 15-20% suggesting an aggressive nature and potentially in keeping with the rare acidophilic stem cell tumour subtype. He underwent stereotactic pituitary radiotherapy and later commenced pegvisomant therapy after a failed octreotide trial. Following this, prolactin levels continued to rise. Unfortunately, subsequent investigations for back pain with bilateral hand paraesthesia (at first considered secondary to acromegaly) revealed metastatic lesions in spine, lung and stomach - the latter confirmed to be of PRL-secreting neuroendocrine origin on biopsy. There was no uptake on octreotide scan. In response to new renal dysfunction (creatinine 463 umol/L with microscopic haematuria and proteinuria), a renal biopsy was also performed and revealed changes compatible with interstitial nephritis with cast nephropathy. The tubular casts stained positive for PRL, and serum PRL at this time reached a peak of 3.7 million mIU/L. Temolozamide has been commenced, and the patient may later be considered for immunotherapy . Conclusion: This is the first documented case of prolactin cast nephropathy and a rare example of a changing tumour secretion pattern, with intractable acute on chronic hyperprolactinaemia and acute acromegaly, in a case of metastatic pituitary carcinoma.

Visual vignette- Nelson’s syndrome: a giant pituitary

Nelson’s syndrome is an infrequent pituitary mass with an incidence of 8–43% in adults and 25–66% in children that develops following total bilateral adrenalectomy (TBA) for the treatment of Cushing’s disease. It is one of the most challenging of all endocrine conditions. The frequent aggressiveness of the underlying ACTH-secreting pituitary adenoma (corticotrophinoma) necessitates regular biochemical and radiological screening. Current evidence favours a lack of prophylactic neoadjuvant pituitary radiotherapy at the time of TBA and a rapid rise of ACTH levels in the year post TBA as factors that may predict the occurrence of Nelson’s syndrome. Though, computerized tomography (CT)/magnetic resonance imaging (MRI) have led to the early diagnosis and improvement in management. Nelson’s related tumours are sometimes detected late, through clinical manifestations of invasion and compression of the surrounding structures. With this perspective in mind, we describe a 22 year old gentleman 10 years after TBA who presented with right sided hemiparesis due to a corticotroph adenoma.

Decreased quality of life (QoL) in hypopituitary patients: involvement of glucocorticoid replacement and radiation therapy

Hypopituitary patients are assumed to have decreased QoL due to GHD. However, in placebo controlled trials, the effects of GH replacement are no different from placebo. Hydrocortisone dose > 20mg/day and pituitary radiation are independently associated with poorer QoL. We assessed QoL in panhypopituitary GH- deficient patients never treated with GH. Study group was divided into: (a) surgery followed by radiation (n = 21) and (b) surgery alone (n = 32). Mean duration of GHD was 71.4 ± 7.8 months and mean daily hydrocortisone dose was 15 ± 0.7mg. Control group had transnasal surgery for benign sinus conditions (n = 54). AGHDA scores were significantly worse in the entire study group compared to controls (8.1 ± 1.0 vs. 5.1 ± 0.9, p = 0.03). In patients with history of radiation therapy AGHDA scores were significantly worse than in controls (9.1 ± 1.5, p = 0.02) and SNOT-22 (Sino-Nasal Outcome Test) scores were also significantly worse (15.8 ± 2.0 vs. 23.2 ± 3.5, p = 0.04). However, AGHDA scores in patients without history of radiation and on "physiological" dose of hydrocortisone were similar to those in controls (5.1 ± 0.9 vs. 7.3 ± 1.3, p = 0.17). Replacement with hydrocortisone doses not exceeding 20mg/day and avoidance of radiation therapy was accompanied by normal QoL in patients not replaced with GH. Thus, we suggest that the decreased QoL in hypopituitary patients may not be due to GH deficiency per se, but rather to high hydrocortisone doses and to aftereffects of cranial radiation.

Beat the giant: case of a giant prolactinoma during pregnancy on cabergoline.

SummaryGiant prolactinomas are a rare entity; during pregnancy, the risk for complications associated with these tumors is higher. Here, we report a case of a young woman who had an invasive, giant prolactinoma post resection with residual disease who became pregnant. This patient was treated with cabergoline to prevent tumor expansion in pregnancy, resulting in the uneventful delivery of a healthy baby boy.Learning points:Giant prolactinoma can cause both diagnostic and therapeutic challenges given their atypical presentation.Accurate diagnosis is paramount to avoid unnecessary surgical intervention or pituitary irradiation.This case demonstrates the effectiveness and safety of CAB therapy during pregnancy.

Endocrine Deficiency As a Function of Radiation Dose to the Hypothalamus and Pituitary in Pediatric and Young Adult Patients With Brain Tumors.

There are sparse data defining the dose response of radiation therapy (RT) to the hypothalamus and pituitary in pediatric and young adult patients with brain tumors. We examined the correlation between RT dose to these structures and development of endocrine dysfunction in this population. Dosimetric and clinical data were collected from children and young adults (< 26 years of age) with brain tumors treated with proton RT on three prospective studies (2003 to 2016). Deficiencies of growth hormone (GH), thyroid hormone, adrenocorticotropic hormone, and gonadotropins were determined clinically and serologically. Incidence of deficiency was estimated using the Kaplan-Meier method. Multivariate models were constructed accounting for radiation dose and age. Of 222 patients in the study, 189 were evaluable by actuarial analysis, with a median follow-up of 4.4 years (range, 0.1 to 13.3 years), with 31 patients (14%) excluded from actuarial analysis for having baseline hormone deficiency and two patients (0.9%) because of lack of follow-up. One hundred thirty patients (68.8%) with medulloblastoma were treated with craniospinal irradiation (CSI) and boost; most of the remaining patients (n = 56) received involved field RT, most commonly for ependymoma (13.8%; n = 26) and low-grade glioma (7.4%; n = 14). The 4-year actuarial rate of any hormone deficiency, growth hormone, thyroid hormone, adrenocorticotropic hormone, and gonadotropin deficiencies were 48.8%, 37.4%, 20.5%, 6.9%, and 4.1%, respectively. Age at start of RT, time interval since treatment, and median dose to the combined hypothalamus and pituitary were correlated with increased incidence of deficiency. Median hypothalamic and pituitary radiation dose, younger age, and longer follow-up time were associated with increased rates of endocrinopathy in children and young adults treated with radiotherapy for brain tumors.

Personality Traits and Physical Complaints in Patients With Acromegaly: A Cross Sectional Multi-Center Study With Analysis of Influencing Factors.

Objective: Acromegalic patients display a distinct neuropsychological profile and suffer from chronic physical complaints. We aimed to investigate in more detail these aspects in acromegalic patients, dependent on influencing factors like disease activity, age, sex, chronic medication, surgery, pituitary radiation, pituitary insufficiency and comorbidities.Design: Cross sectional, multicentric.Methods: 129 patients (M/W 65/64, 58.3 ± 12.7 years, 53/76 with active/controlled disease). Acromegalic patients completed the following inventories: NEO-FFI, IIP-D, and the Giessen Complaints List (GBB-24), after written informed consent. Age, sex, IGF-1 concentrations, comorbidities, treatment modalities and pituitary insufficiency were documented.Results: Acromegalic patients or specific patient-subgroups were more agreeable, neurotic, exploitable/permissive, introverted/socially avoidant, non-assertive/insecure, nurturant and less open to experience, cold/denying, domineering, compared to normal values from the healthy population (controls). Multivariable analysis demonstrated that these overall results were due to the specific patient subgroups as patients on chronic medication, with arthrosis and pituitary insufficiency. Disease activity was only associated with the trait nurturant. Higher scores for introversion were associated with arthrosis. Lower domineering was independent of any disease- or treatment related variable or comorbidity. The GBB inventory showed overall higher scores in patients, with higher scores for exhaustion and general complaints being associated with pituitary insufficiency, coronary heart disease and history of malignancy in the multivariable analysis. Joint complaints were independent of any disease- or treatment- related variable.Conclusions: We define new aspects of a distinct neuropsychological profile in patients with acromegaly, which are largely independent of disease activity. Chronic physical complaints are more pronounced in patients than in controls, with exhaustion and general complaints showing no association with disease activity.

Long-term follow-up of a large prospective cohort of patients with nonfunctioning pituitary adenomas: The outcome of a conservative management policy.

To assess the clinical outcome of a strategy of conservative monitoring of patients with nonfunctioning pituitary adenomas (NFPA) after pituitary surgery and in patients without surgery. Retrospective study of outcomes, using a clinical information system. An unselected, clinical series of patients seen in a single centre between 1989 and 2015. Review of clinical information system data to obtain details and dates of surgery, radiotherapy, pituitary imaging and outcomes. We identified 190 cases of NFPA. Trans-sphenoidal surgery (TSS) had been performed as primary therapy in 132 cases (all macro-adenomas). At a mean 7.6-years follow-up after TSS without immediate pituitary radiotherapy, recurrence occurred in 10.7% of cases with no visible postoperative residual adenoma, 38.8% with intrasellar and 66.7% with extrasellar residuum. Recurrence was defined as growth of residual tumour requiring intervention. On survival analysis, at 10years, recurrence-free survival was 75% in patients with no residual tumour and 40% with intrasellar residuum. Recurrence occurred in 12.5% of 24 patients who had received postop radiotherapy. Patients were monitored conservatively without initial surgery in 65 patients. After a mean of 5-year monitoring, only 20% required intervention during follow-up (18.5% TSS) and 30.8% died of nonpituitary causes during follow-up. This study suggests that a conservative approach may be safe and appropriate in patients with NFPA if followed up with appropriate imaging surveillance, whether postoperative or without primary surgery.