Clinical and Pathological Aspects of Silent Pituitary Adenomas

Abstract

Context: Silent pituitary adenomas are anterior pituitary tumors with hormone synthesis but without signs or symptoms of hormone hypersecretion. They have been increasingly recognized and represent challenging diagnostic issues.

Evidence acquisition: A comprehensive literature search was performed using MEDLINE and EMBASE databases from January 2000 to March 2018 with the following key words: (i) pituitary adenoma/tumor and nonfunctioning; or (ii) pituitary adenoma/tumor and silent. All titles and abstracts of the retrieved articles were reviewed, and recent advances in the field of silent pituitary adenomas were summarized.

Evidence synthesis: The clinical and biochemical picture of pituitary adenomas reflects a continuum between functional and silent adenomas. Although some adenomas are truly silent, others will show some evidence of biochemical hypersecretion or could have subtle clinical signs and, therefore, can be referred to as clinically silent or "whispering" adenomas. Silent tumors seem to be more aggressive than their secreting counterparts, with a greater recurrence rate. Transcription factors for pituitary cell lineages have been introduced into the 2017 World Health Organization guidelines: steroidogenic factor 1 staining for gonadotroph lineage; PIT1 (pituitary-specific positive transcription factor 1) for growth hormone, prolactin, and TSH lineage, and TPIT for the corticotroph lineage. Prospective studies applying these criteria will establish the value of the new classification.

Conclusions: A concise review of the clinical and pathological aspects of silent pituitary adenomas was conducted in view of the new World Health Organization classification of pituitary adenomas. New classifications, novel prognostics markers, and emerging imaging and therapeutic approaches need to be evaluated to better serve this unique group of patients.

Figure 1.

During pituitary development, specific transcription factors are fundamental to the complex process of adenohypophyseal cell differentiation. The three main pathways of cell differentiation and the immunoprofile of each cell lineage are illustrated. GATA2, GATA binding protein-2; PROP1, PROP paired-like homeobox 1 (also called prophet of PIT1); PIT1, POU class 1 homeobox 1 (PUO1F1) or pituitary-specific positive transcription factor 1; TPIT, T-box transcription factor 19 (TBX19).

Figure 2.

Silent pituitary adenoma is a diagnosis that can be determined by combining the clinical data (clinically nonfunctioning adenoma) and histopathological data (immunostaining for hormones and transcription factors).

Figure 3.

Continuous spectrum between silent and functioning adenomas.

Figure 4.

True null cell adenomas are composed of uniform, mildly atypical cells with chromophobic cytoplasm. (A) An example showing sinusoidal, papillary, and pseudopapillary architecture similar to the more common gonadotroph adenomas (hematoxylin and eosin stain, ×10). (B) A case of oncocytoma consisting of large cells with acidophilic, granular cytoplasm (hematoxylin and eosin stain, ×20). (C and D) Prevalence of the different SPAs subtypes according to IHC for anterior pituitary hormones: silent gonadotroph adenomas were the most frequent, followed by null cell (according to the World Health Organization 2004 classification), corticotroph, and GH/prolactin/TSH lineage adenomas. The new classification using IHC for anterior pituitary hormones and transcription factor profiling substantially reduced the number of null cell adenomas. Derived from data from Nishioka H, Inoshita N, Mete O, et al. The complementary role of transcription factors in the accurate diagnosis of clinically nonfunctioning pituitary adenomas. Endocr Pathol 2015; 26:349-355.

Figure 5.

Pituitary MRI scans of a silent corticotroph adenoma. (A) T1-weighted MRI sequence and (B) T2-weighted MRI sequence allowing identification of multiple microcysts. [Figure kindly provided by Prof. Bonneville, Lyon, France (130)]. Extension to parasellar structures, invasion of the sellar floor and cystic and hemorrhagic changes can be features of silent corticotroph adenomas. This example of a cystic silent ACTH adenoma type 2 adenoma had invaded both clivus and clinoids and extended superiorly to the third ventricle. (C) Axial contrast-enhanced CT scan). (D) Histologically, the lesion had papillary architecture (hematoxylin and eosin stain, ×20). (Inset) A few neoplastic cells expressed ACTH (immunoperoxidase stain, ×20). (A and B) Derived from data from Bonneville F. Silent corticotroph pituitary adenoma. In: Bonneville JF, Bonneville F, Cattin F, Naggi S, eds. MRI of the Pituitary Gland. Springer; 2016.

Figure 6.

Silent corticotroph adenoma: noninvasive macroadenoma. (A) Axial contrast-enhanced T1-weighted sequence. (B) Histologic slide showing sheets and acini with uniform, medium-size cells with basophilic cytoplasm (hematoxylin and eosin stain, ×20). (C) Expression of ACTH is diffuse (immunoperoxidase stain, ×10). (D) Neoplastic cells show nuclear expression of the transcription factor TPIT (immunoperoxidase stain, ×10). (E) No expression of PC1/3 was present in the tumor cells (immunoperoxidase stain, ×10).

Figure 7.

Proposed mechanism for “silencing” of corticotroph adenomas. Reduced PC1/3 activity decreases tumor cell production of ACTH despite increased levels of POMC. Compared with hormone-negative adenomas, POMC gene expression is increased in pituitary tumor samples from patients with Cushing disease (CD) and patients with SCAs; however, transcripts for PC1/3 are present at 30-fold greater levels in those with Cushing disease than in those with SCAs. Derived from data from Jahangiri A, Wagner JR, Pekmezci M, et al. A comprehensive long-term retrospective analysis of silent corticotrophic adenomas vs hormone-negative adenomas. Neurosurgery 2013;73:8-18.

Figure 8.

A case of a plurihormonal PIT1 adenoma showing the typical diffuse, solid architecture of this tumor type. (A) It was composed of epithelioid cells with eosinophilic cytoplasm, an enlarged nucleus, and prominent nucleolus (hematoxylin and eosin stain, ×40). (B) Some cells expressed PRL (immunoperoxidase stain, ×40). (C) A few tumor cells were positive for TSH β-subunit (immunoperoxidase stain, ×40). (D) Nuclear expression of the transcription factor PIT1 was ubiquitous (immunoperoxidase stain, ×20).