Pituitary tumours destined to become PC almost always begin as macroadenomas. However, size at presentation does not correlate with potential for malignant behaviour as giant lactotroph tumours can be highly sensitive to dopamine agonist treatment. Commonly there is a history of relatively indolent behaviour with emergence of aggressive disease years later preceding the identification of metastases. There is considerable variability in the latency to development of metastatic disease from months to more than 20 years from diagnosis with a mean of 7 years. Clinically aggressive tumour behaviour may be evident at presentation with fulminant progression.
Mass effect symptoms, such as visual impairment, headache, and cranial nerve palsies, tend to dominate the clinical presentation of PC. Unusual neurological signs, such as ataxia or motor weakness, should raise concern about the possibility of PC. Diabetes insipidus (DI) is rarely encountered in PC, and in general the presence of DI should alert to an alternative diagnosis, such as metastasis to the sellar arising from a non- pituitary primary.
Systemic metastases occur most commonly (47%), are more frequent among lactotroph compared with corticotroph tumours and most often involve the liver, lung, and bone, with rare sites of meta static disease including the orbit, heart, pancreas, kidney, ovary, myometrium, and pelvic lymph nodes. Systemic dissemination occurs through haematogenous spread via the cavernous sinuses and/ or jugular veins. Metastases to cervical lymph nodes are also seen and thought to result from invasion of lymphatics of the skull base and soft tissues. Craniospinal metastases also occur frequently (40%), spread occurring through cerebrospinal fluid dis semination. Both craniospinal and systemic metastases are seen in 15% of patients.
The primary diagnostic modality is structural imaging with magnetic resonance imaging (MRI) or computed tomography (CT) with attention to site- specific symptoms such as neck or back pain that may indicate a site of metastatic disease. Functional imaging modalities may be useful in detecting otherwise occult metastases. Ga68 Dotatate and F18 FDG- PET/ CT may identify different sites of metastatic disease when used concurrently, with potential therapeutic and prognostic implications. According to 2017 WHO criteria, the following need to be met in order to diagnose a PC: (1) the primary lesion must be a histologically proven adenohypophyseal tumour; (2) an alternative primary lesion must be excluded; (3) discontinuous spread must be present in the craniospinal axis; and (4) the pathological features of metastases should be similar to those of the primary pituitary tumour.
Thus, while imaging may suggest PC, a surgical biopsy may be re quired to confirm the diagnosis. However, fine needle aspiration biopsy of metastases within cervical lymph nodes, liver and lung have been successfully performed.
Only a minority of aggressive pituitary tumours (APT) ultimately manifest metastases. However, recognition of an APT is vital to identify tumours with malignant potential. Furthermore, the morbidity and mortality of APT are increased even in patients without metastases. An APT demonstrates invasion and dis plays an unusually rapid growth rate, or continued growth despite multimodal treatment (surgery, radiotherapy, standard medical therapy). Serial MRI imaging is required to determine tumour growth rates, with accurate reporting of tumour dimensions and ideally tumour volume measurements. In a large study of 153 pituitary tumours (functioning and non- functioning), the mean tumour volume doubling time (TVDT) was 1147 +/ – 870 (SD) days (range 60– 3478). Tumours with a more rapid growth rate (below 1 SD TVDT) had a TVDT under 1 year. Younger patients with non- functioning pituitary adenomas (NFPA) and females with functioning tumours have been found to have faster growth rates. The rapid growth of a corticotroph pituitary tumour following bilateral adrenalectomy (Nelson’s syndrome) is also cause for concern and has been found in 67% of corticotroph PC. Metastatic disease should be suspected when there are discordant biochemical and radiological findings, for example rising prolactin (PRL), adrenocorticotropin hormone (ACTH) or growth hormone (GH) levels in the setting of low volume sella- based disease.
Functioning PC typically exhibit very high hormone levels, however there is significant overlap with levels found in pituitary adenomas (PA). One hallmark that may indicate malignant trans formation of a PA is the emergence of resistance to medical treatment. This is particularly seen with prolactinomas, where resistance to dopamine agonist (DA) therapy may be a feature present early in the disease course but can also be acquired during treatment. Transformation of a PA from silent to functioning may also herald malignant progression, well described for silent corticotroph adenomas but also reported in silent somatotroph tumours and in one case of an initially hormone- immunonegative tumour that subsequently transformed into a thyroid stimulating hormone (TSH) and PRL- secreting PC with brain metastases. Conversely, tumour de- differentiation is thought to account for cases where reduced hormone secretion has been observed.
