How to Classify and Define Pituitary Tumors: Recent Advances and Current Controversies

Pituitary tumors are very complex and heterogeneous and have a very wide range of proliferative and aggressive behaviors, and how to define and classify these tumors remains controversial. This review summarizes the epidemiology and progress in the classification and definition of pituitary tumors, as well as controversial issues. Based on the results of radiologic and autopsy studies, the prevalence of pituitary tumors has recently increased significantly. However, the majority of pituitary tumors are incidentally discovered and asymptomatic, and such tumors are called pituitary incidentalomas. Most of these incidentalomas do not induce symptoms, remain stable in size, and do not need treatment. The recent revised classification strategies mainly depend on immunohistochemistry (IHC) to detect pituitary hormones and pituitary transcription factors; therefore, the accuracy of diagnosing pituitary tumors has improved. Although new classification strategies and definitions for pituitary tumors have been presented, there are still some controversies. The term pituitary neuroendocrine tumor (PitNET) was proposed by the International Pituitary Pathology Club, and this terminology can encompass the unpredictable malignant behavior seen in the subset of aggressive pituitary adenomas (PAs). However, some endocrinologists who oppose this change in terminology have argued that the use of tumor in the terminology is misleading, as it gives PAs a harmful connotation when the majority are not aggressive. Such terminology may add new ambiguity to the origin of PAs and unnecessary anxiety and frustration for the majority of patients with benign PAs. The classification of aggressive PAs mainly relies on subjective judgment of clinical behavior and lacks objective biomarkers and unified diagnostic criteria. However, the term “refractory” could more accurately represent the characteristics of these tumors, including their clinical behaviors, radiological features, and pathologic characteristics. Moreover, the diagnostic criteria for refractory PAs are stricter, more objective, and more accurate than those for aggressive PAs. Early identification of patients with these tumors through recognition and increased awareness of the definition of refractory PAs will encourage the early use of aggressive therapeutic strategies.

Two Cases of Double Adenomas in a Surgical Series over 16 Years in a Single Centre

Background: Double pituitary adenomas (DA) are two morphologically and immunohystochemically different tumours in the same gland. They are rare, generally small adenomas and divided in: separated, when clearly recognizable before or during surgery, and contiguous, when diagnosed only in the following histopathological examination. Acromegaly and Cushing’s disease are the main prevalent clinical presentation. Objective: We described two cases of DA in a surgical series over 16 years in a single center. Methods: In September 2018 we diagnosed a DA in a man with acromegaly (case 1). In order to assess the presence of other cases of DA, we performed a retrospective analysis of the endonasal endoscopically operated sellar adenomas from January 2004 to December 2019. Results : 468 pituitary adenomas were found. A DA with a Pit-1 positive small macroadenoma (GH-TSH- PRL positive) and an ACTH microadenoma clinically silent in an acromegalic woman was retrospectively found (case 2). Conclusion : Our analysis confirms that DA are rare (0.4 % of the pituitary adenomas) and often associated with acromegaly. Their pre-operatively diagnosis is difficult but clinician’s awareness of DA can improve the diagnosis. The use of pituitary transcription factors could be useful in detecting DA.

Sex-specific changes in postnatal GH and PRL secretion in somatotrope LEPR-null mice

The developing pituitary is a rapidly changing environment that is constantly meeting the physiological demands of the growing organism. During early postnatal development, the anterior pituitary is refining patterns of anterior hormone secretion in response to numerous genetic factors. Our laboratory previously developed a somatotrope leptin receptor (LEPR) deletion mouse model that had decreased lean body mass, disrupted metabolism, decreased GH stores and was GH deficient as an adult. To understand how deletion of LEPR in somatotropes altered GH, we turned our attention to postnatal development. The current study examines GH, PRL, TSH, ACTH, LH and FSH secretion during postnatal days 4, 5, 8, 10 and 15 and compares age and sex differences. The LEPR mutants have dysregulation of GH (P < 0.03) and a reduced developmental prolactin peak in males (P < 0.04) and females (P < 0.002). There were no differences in weight between groups, and the postnatal leptin surge appeared to be normal. Percentages of immunolabeled GH cells were reduced in mutants compared with controls in all age groups by 35–61% in males and 41–44% in females. In addition, we measured pituitary expression of pituitary transcription factors, POU1F1 and PROP1. POU1F1 was reduced in mutant females at PND 10 (P < 0.009) and PND 15 (P < 0.02) but increased in males at PND 10 (P < 0.01). PROP1 was unchanged in female mutants but showed developmental increases at PND 5 (P < 0.02) and PND 15 (P < 0.01). These studies show that the dysfunction caused by LEPR deletion in somatotropes begins as early as neonatal development and involves developing GH and prolactin cells (somatolactotropes).