E-Poster Presentation 63rd Endocrine Society of Australia Annual Scientific Meeting 2020

Acromegaly occurs when chronic growth hormone (GH) excess leading to somatic tissue hypertrophy and an adverse metabolic profile.^1,2 The predominant cause (>95%) are pituitary somatotroph adenomas, representing 10-20% of pituitary adenomas.¹ International guidelines recommend transsphenoidal surgical resection (TSS) as first-line management.¹

The novel coronavirus pandemic swept the world in 2020 with more than 24 million confirmed cases and 800,000 deaths.³ Due to the high risk of infection and potential severity of subsequent illness, airbourne precautions are recommended for aerosol-generating procedures, such as the beginning of TSS. After reports of high rates of infection, and multiple deaths among ear, nose and throat surgeons overseas, in March 2020, the Australian Society of Otolaryngology, Head and Neck Surgery issued guidelines for addressing the COVID-19 pandemic.⁴ This included undertaking only emergency and urgent upper airway operations for malignancy, threatened airway and bleeding. In response, all TSS were postponed at our centre, with craniotomy the approach chosen when requiring urgent pituitary surgery. Transcranial surgery (TCS) is currently reserved for large tumours with either dominant or eccentric extra-sellar extension and is believed to carry higher rates of post-operative complications.⁵

Here we present a case with newly diagnosed with acromegaly and visual field defects who avoided TCS through neoadjuvant medical therapy.

Case

A 45-year-old woman presented to her GP with 12-18 months of constant, pressure-sensation headache. On questioning, she had noted contemporaneous development of symptoms including soft tissue swelling, acral enlargement, skin oiliness, new skin tags, easy weight gain, jaw ache and onset of snoring. Oligomenorrhoea present for 18 months was associated with occasional vasomotor symptoms. During this time, the patient had also noticed dipoplia, ptosis of the left eye and frequently running into walls to suggest visual field deficits. Past medical history contained only a spleen-preserving distal pancreatectomy 3 years prior for solid pseudopapillary tumour, a distant smoking history, and previous hazardous, now infrequent alcohol use. Examination yielded typical features of acromegaly. Blood pressure 104/76mmHg, pulse rate 80bpm and regular, with no postural changes. There were no features of other endocrinopathy and cardio-respiratory examination was unremarkable. Visual acuity was normal, however there was a partial left ptosis, both bi- and monocular diplopia (worse in the left eye), no relative afferent papillary defect, normal ocular movements and no nystagmus. Visual perimetry results are included (figure 1) and are concerning for optic chiasm compression. Biochemistry is shown in table 1, in the setting of a markedly elevated insulin-like growth factor 1 (IGF-1), high random GH and clinical features consistent with acromegaly, a confirmatory oral glucose tolerance test was deemed unnecessary.  Mild hyperprolactinaemia was present secondary to stalk effect from the 24x24x17mm macroadenoma with significant suprasellar extension, displacing and compressing the optic chiasm with extension into the cavernous sinus bilaterally (figure 2). The patient had been booked for emergent transcranial debulking to alleviate chiasmal compression. Her tumour would otherwise be amenable for TSS if not for the coronavirus embargo. After multi-disciplinary discussion and consent of the patient, she was commenced on intramuscular octreotide LAR 30mg monthly with 14 days of subcutaneous octreotide 100mcg TDS. We planned to repeat visual field testing after 2 weeks and proceed to surgery if no improvement. At 2 weeks, perimetry had improved (figure 1) and repeat MRI showed a 25% reduction in tumour volume (now 22x21x16mm) with improved effacement of the optic chiasm. Her symptoms had mostly resolved. After 4 months of treatment, visual fields had normalised, the tumour had not further involuted (figures 1 and 2), and IGF-1 remained elevated at 92nmol/L.

The diplopia was attributed by the neuro-ophthalmologist to unrelated corneal scarring with protective ptosis. She is now awaiting TSS which has since recommenced.

Discussion

The incidence of acromegaly is between 0.2-1.1 per 100,000 population.² The insidious onset of clinical features causes a median diagnostic delay of 4.5-5 years.² As a result, many patients present with macroadenomas with mass effect, the most concerning feature being visual field loss.² Additionally, it is associated with excess mortality double that of the general population, predominantly driven by cardiovascular disease.¹ The goals of treatment are a random GH level <1ug/L (shown to return mortality rates to that of the general population), age-adjusted normalisation of IGF-1, and management of comorbidities and complications of the disease.¹ TSS is recommended as first line management.¹ Pre-operative medical therapy is recommended in those patients with comorbidities which will heighten peri-operative risk, and are likely to improve with biochemical control of acromegaly.¹

The first successful pituitary adenomectomy in 1905 was via a transfrontal approach.⁵ Surgical techniques were refined in the following century, now TSS predominates. Less than 10% of resections occur transcranially (pterional).⁵ It is thought that TCS is associated with higher rates of complications, however the data is limited to heterogeneous retrospective series of mixed adenoma types. Resolution of visual field defects is either better, no different, or less frequent in TCS compared to TSS.^5,6 Outcomes of anterior pituitary function may favour TCS for resolution of pre-operative deficits and are mixed with regards to new dysfunction.^5,6 Rates of permanent post-operative diabetes insipidus (DI) are consistently higher in TCS than TSS.^5-7 From the available data, the proportion of risk attribute to TCS (over TSS) cannot be separated from that secondary to the nature of tumours which require this approach. The degree of tumour deformation of the third ventricle/hypothalamus was a predictor of permanent DI, suggesting the latter may engender more of the risk.⁷  Surgical remission of acromegaly is more than twice as likely in TSS than TCS, this is to be expected with lower rates of invasive adenomas in the TSS arms.⁶ When considering cure in invasive lesions, TSS is still superior.⁶

Hypothalamic somatostatin inhibits GH secretion via binding to SST receptors (5 subtypes).⁸ These G-protein couple receptors activate broad downstream signalling cascades reducing GH secretion, cell growth and inducing apoptosis.⁸ SST2 (95%) and SST5 (85%) are the abundant subtypes on somatotroph adenomas.⁸ First generation somatostatin analogues (SSA; octreotide, lanreotide) preferentially bind SST2 and are effective at achieving biochemical control in 17-55% of patients in the adjuvant setting.^1,8 In a meta-analysis considering tumour shrinkage induced by primary SSA therapy, 36.6% of patients achieved significant reduction in tumour size (variable criterion) and the weighted mean reduction in size was 49.8% in those that responded, 19.4% for all patients.⁹ A number of small studies using short-acting octreotide have shown tumour reduction occurs rapidly, between 18-30% within the first 2-4 weeks.^9,10 Further involution appears to plateau after 3 months.^9,10 This has been associated with improvement and even resolution of visual field defects in the first 2-4 weeks of treatment.⁹

As with previously described cases, our patient had an impressive reduction in tumour volume and improvement in visual field defects within two weeks of commencing treatment, her perimetry subsequently normalised with stability of tumour size at four months. This allowed her to avoid TCS and the potential increased risk of post-operative endocrine complications.

Take Home Messages:

• In acromegaly, pre-operative SSA therapy can rapidly induced tumour shrinkage and alleviate chiasm compression in 2-4 weeks. Most cases use subcutaneous octreotide ~300mcg/day.
• In pituitary adenomas, TCS may lead to higher rates of post-operative endocrine dysfunction and lower rates of cure (compared to TSS) but the evidence is conflicting, and the risk may be more attributable to tumour size/invasiveness.