We propose to refine the definition of SCAs as a tumor subtype comprising clinical and cellular characteristics of both corticotroph and gonadotroph adenoma cells and suggests naming this entity a SCGA (). Previous studies reported the incidence of SCAs to be up to 19% of adenomas classified preoperatively as nonfunctioning adenomas [6
] and ~20% of all corticotroph adenomas [5
]. While SCAs immunostained for ACTH, similar to functional corticotroph adenomas, the clinical course was more typical of nonfunctioning adenomas. SCAs presented as nonfunctioning adenomas due to local mass effects and pituitary hormone deficiencies [11
]. There was a female SCA preponderance in some reports compared to nonfunctioning adenomas [7
], but not others [8
]. Up to 60% of SCAs manifested with preoperative hypopituitarism, similar to rates observed in nonfunctioning adenomas [8
]. However, cavernous sinus invasion as visualized by MRI was more prevalent in SCAs than in nonfunctioning adenomas [8
]. SCAs consistently demonstrated a more aggressive postoperative course compared to nonfunctioning adenomas. New onset post-operative hypopituitarism had been reported in about one-third of SCAs [8
] with reports of postoperative adrenal insufficiency in SCAs [5
]. While SCA recurrence rates of up to 57% had been documented [8
], these rates did not differ from those observed with nonfunctioning adenomas [6
] nor had SCAs been shown to recur earlier [11
] though one series demonstrated that SCAs frequently had multiple recurrences [6
Fig. 6 Proposed model for development of silent corticogonadotroph adenoma (SCGA). Expression of both corticotroph and gonadotroph transcription factors is observed in SCGAs. Functional corticotroph adenomas, most of which are microadenomas, express ACTH, Tpit, (more ...)
Our study is one of the largest cohort analyses directly comparing SCAs to nonfunctioning adenomas and includes comprehensive preoperative and postoperative clinical outcomes. We demonstrate that SCAs have a 63% recurrence rate while 38% of nonfunctioning adenomas recurred. In addition, we show that SCAs recur 5 years sooner than nonfunctioning adenomas, in contrast to prior reports [11
] and demonstrate that de novo recurrences are seen more frequently in patients with SCAs. A further observed difference between SCAs and nonfunctioning adenomas is development of new postoperative pituitary deficits in 54% of patients with SCAs compared to 17% of nonfunctioning adenomas, especially in the thyroid and adrenal axes. Furthermore, given that we do not find that new postoperative hypopituitarism in SCAs correlated with invasive characteristics nor with the presence of residual tumor or with recurrences, it is likely that the higher rate of postoperative hypopituitarism is reflective of a unique SCA biology or cytogenesis.
As SCAs follow a unique clinical course, they ostensibly express distinctive differentiated cellular proteins. On immunostaining, SCAs expressed ACTH to a similar degree as functional corticotroph adenomas [18
]. However, examination of Tpit in SCAs have yielded conflicting reports with one study showing Tpit positive immunohistochemistry staining in three of four SCAs [25
] while another demonstrated lower Tpit mRNA levels in SCAs than in functional corticotroph adenomas [33
]. NeuroD1, a factor contributing to differentiation of corticotroph adenomas and α-GSU positive cells, was also expressed in SCAs [32
]. In addition to corticotroph markers and consistent with our findings here, a single SCA showed expression of gonadotroph markers, namely DAX-1 and SF-1 [34
]. Indeed, LH, FSH, and α-GSU were all expressed in SCAs and also in functional corticotroph adenomas (), often with cellular colocalization.
Summary of reports of ACTH/SF-1/LH expression
The current study provides a characterization of integrated corticotroph and gonadotroph features of SCAs using immunohistochemistry and EM. SCAs incorporate corticotroph markers of NeuroD1 and ACTH and gonadotroph markers of DAX-1, α-GSU, and SF-1. On the other hand, SCAs are distinct from corticotroph and gonadotroph adenomas as evidenced by the lack of nuclear Tpit expression while maintaining the presence of cytoplasmic and nuclear SF-1, respectively. The reason for cytoplasmic localization of SF-1 is, however, unclear. Other nuclear proteins in pituitary tumors exhibit abnormal intracellular localization and change of function, for example, Brg1, a nuclear protein found to accumulate in the cytoplasm of corticotroph adenoma cells, alters pituitary tumor sensitivity to glucocorticoids [40
SCAs had been characterized by ultrastructural morphology showing two morphologic variants of SCAs. Type 1 adenomas were similar to functional corticotroph adenomas in that they were densely granulated basophilic tumors with abundant cytokeratin filaments. Subtype 2 adenomas were chromophobic and lacked cytoplasmic intermediate filaments [41
]. In addition to corticotroph features, SCAs were shown to incorporate gonadotroph elements as evidenced by the presence of honeycomb Golgi [13
] and increased mitochondrial density [13
]. Similar findings were reported in functional corticotroph adenomas [43
]. In this study, two SCAs tested were categorized as SCA subtype II while the remainder incorporate elements of both corticotroph and gonadotroph adenomas. In particular, oncocytic transformation seen in the three SCAs tested is typical of gonadotroph adenomas, whereas the granule pleomorphism and enlarged lysosomes/enigmatic bodies we observed in all the SCAs resemble corticotroph adenomas.
Several confounding factors may bias our results including unavailability of comprehensive clinical data on each patient. However, longer follow-up times in the NFAs (median of 8 years) compared to the SCAs (median of 3 years) further strengthens the observation of a higher number of recurrences occurring at an earlier timepoint as well as higher rates of post-operative hypopituitarism in SCAs. The immunohistochemistry technique employed may not be sufficiently sensitive to detect very low levels of Tpit expression. Although quantitative PCR would have been useful to confirm the immunohistochemistry staining, sufficient tumor tissue was not available after pathologic examination. Furthermore, micro-deposits of normal pituitary tissue contaminating these very small tumor specimens would also confound sensitive quantitative PCR measurements. Variability of immunostaining expression may be reflective of low antibody sensitivity and penetration as well as tumor heterogeneity. However, we used slides derived from the same block of tumor tissue to reduce section heterogeneity and utilized the same dilution of antibody for each batch. In addition, for the immunohistochemistry studies, we used only gonadotroph adenomas and excluded oncocytomas and null cell adenomas, for though these latter two adenomas may express low levels of gonadotroph subunits, they are not consistently positive for all gonadotroph transcription factors [46
In summary, our results support prior findings that SCAs are benign but aggressively growing biochemically silent pituitary adenomas that combine clinical and pathological features of corticotroph and gonadotroph cells further suggesting a common corticotroph and gonadotroph pituitary progenitor cell origin. This is also supported by reports of a change of corticotroph committed cells to that of gonadotrophs in Tpit
knockout mice through a possible trans-repression of Tpit and SF-1 [47
Understanding that SCGAs comprise both cellular and clinical features of both corticotrophs and gonadotrophs has clinical implications for patients undergoing long-term SCGA follow-up. The diagnosis of this tumor subtype emphasizes the need for increased postoperative surveillance of SCGAs for earlier detection of recurrences and hypopituitarism through rigorous pituitary reserve testing thereby reducing morbidity and improving quality of life in these patients.