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

Introduction

Silent pituitary adenomas are now being classified according to adenohypophyseal hormones and transcription factors in the latest 2017 WHO Classification of pituitary tumors^1-2. Previously identified silent subtype 3 adenomas can be redefined as aggressive monomorphous plurihormonal adenomas of Pit-1 lineage, which are often non-functioning but may be associated with hyperthyroidism, acromegaly or galactorrhoea and amenorrhoea.

Case

A 19-year old man attended our Young Adult Endocrine clinic in February 2020 for a follow-up review of his pituitary macroadenoma. The patient was diagnosed with a non-functioning pituitary macroadenoma in August 2017 after presenting to Queensland Children’s Hospital with worsening diplopia for 5 weeks. Radiologically, it was a homogeneous sellar mass (29x33x26mm) extending into the suprasellar region with bilateral cavernous sinus involvement (Figure1). Biochemically, he was found to have secondary adrenal and testosterone deficiency. However, his free T3 was marginally elevated with unsuppressed thyroid-stimulating hormone (TSH) and his thyroid ultrasound was unremarkable.

Initially, he was started on hydrocortisone and he underwent elective trans-sphenoidal 50% debulking surgery, which was uneventful. The histopathology report was consistent with atypical pituitary adenoma with proliferative activity (Ki-67 proliferation fraction 5% and up to three mitoses per 10 high power fields) and focal immunoreactivity for growth hormone. Despite that, his pre-surgery insulin-like growth factor 1(IGF-1) and growth hormone were within the range at 20 nmol/L (16-66 nmol/L) and 0.53 ug/L (0.05-3 ug/L) respectively. He was followed up regularly at Children’s Hospital and replaced with hydrocortisone and intramuscular testosterone therapy. The rest of the anterior pituitary hormones were within the range.

In late 2018, he was referred to the Young Adult Endocrine team at Mater Hospital. Unfortunately, from mid-2018 to mid-2019, his repeat MRI revealed a gradual increase in the size of adenoma up to 22x25x28 mm extending to the right sphenoidal sinuses and positive mass effect on posterior pituitary and infundibulum. His free T3 was mildly elevated at the time of tumor regrowth. Subsequently, the patient had volumetric modulated arc therapy (VMAT) based salvage radiotherapy (50.4 Gray units in 28 fractions) in December 2019.

Throughout the reviews up to August 2020, the patient did not report any symptoms suggestive of uncontrolled endocrinopathy. The examination was similarly unremarkable. Moreover, he does not have any family history or clinical and biochemical evidence suggestive of multiple endocrine neoplasia (MEN). His last 2 MRI pituitary in March and June 2020 demonstrated an interval decrease in size reflecting a favorable response to radiotherapy.

Surprisingly, his free thyroid hormones were gradually rising with inappropriately normal TSH as depicted in Table 1 attached. His thyroid function tests were repeated in three different labs with different analytical platforms but they result in a similar pattern ruling out heterophile antibodies interferences.  The rest of his recent anterior pituitary hormones can be reviewed in Table 2.

After review by the neuropathologist, immunohistochemistry for TSH was repeated on the 2017 biopsy material, which again demonstrated no discernible staining. However, the tumor showed strong diffuse staining for the transcription factor Pit-1 but was negative for GATA2 and estrogen receptor, confirming a poorly differentiated Pit-1 lineage pituitary adenoma. Although often silent, these adenomas can present with hormone excess, most commonly hyperthyroidism, and is probably the cause of the patient’s central hyperthyroidism.

Thyrotropin-releasing hormone stimulation test resulted in blunted TSH response consistent with TSH producing pituitary macroadenoma (Table 3). This is further supported by evidence of elevated serum glycoprotein alpha-subunit at 2.12 IU/L (reference range 0.0-0.7).

The case was discussed in the monthly multidisciplinary pituitary meeting as clear guidelines are not widely available for this challenging and complex case. We would initiate the treatment with somatostatin analog subcutaneous injection to restore euthyroidism. The literature review also mentions that somatostatin analog treatment is a viable option as silent thyrotropinomas express somatostatin receptor (SSTR) ⁴. In addition, he may likely require repeat surgery as the definitive treatment depending on his tumour growth and escape of thyroid function tests over time because there are a few cases reported with the resolution of hormonal excess post repeat surgery⁵.

Learning points

• Immunoreactivity of various anterior pituitary hormones, pituitary lineage transcription factors, the ultrastructural features, and histological features can define pituitary adenomas. Moreover, they are helpful in the prediction of the disease course and response to adjunctive therapies.
• The standardized report for diagnosis of pituitary tumors, taking account of the invasion, the immunohistochemical (IHC) profile, and the proliferative markers have been recently proposed by the European Pituitary Pathology Group (EPPG)³.
• 9% of silent pituitary adenomas are Pit-1 (GH/Prolactin/TSH) lineage positive⁴.
• Pit-1 lineage adenomas possess aggressive characteristics with hormonal excess histologically and biochemically, though they can be clinically silent or borderline.
• They can be associated with multiple endocrine neoplasia type 1 syndrome in younger patients particularly if hyperprolactinemia is present⁵.
• Mitotic count, Ki-67 proliferative index, and tumor suppressor gene p53 act as general histologic prognostic markers in pituitary neuroendocrine tumors⁶.
• Multidisciplinary team effort is essential for a precise diagnosis, effective treatment with appropriate follow-up, and the best outcomes.
• Further studies and research are required in the areas of novel prognostic markers, emerging imaging, therapeutic guidelines, and drugs for managing challenging cases of complex and aggressive pituitary macroadenomas.

Table1: Thyroid hormone changes throughout the follow-up

Table2: Recent pituitary hormones profile of the patient

Table3: Thyrotropin-releasing hormone (TRH) stimulation test

Figure1: T2 Coronal view comparison of pituitary macroadenoma Pre (left) and post-surgery (right)

Figure 2: Pit 1 staining 

Figure3: HE staining with mitosis center

Figure 4: GH staining      

Figure 5: TSH Staining with mitosis center