Clinically nonfunctioning pituitary adenoma (CNFPA)

Clinically nonfunctioning pituitary adenoma (CNFPA) is currently the preferred term for designing all the pituitary adenomas which are not hormonally active (in other words, not associated with clinical syndromes such as amenorrhea-galactorrhea in the context of Lactotroph adenomas, acromegaly, Cushing's disease or hyperthyroidism secondary to TSH secreting pituitary adenoma).

see also Clinically nonfunctioning pituitary macroadenoma.

see Clinically Nonfunctioning pituitary adenoma epidemiology.

The natural course of NFMA is largely unknown, because the majority of patients with NFMA are operated. A study described the combined data of both non-functioning microadenomas and macroadenomas, not permitting a conclusion with respect to the natural course of NFMA per se. Those studies, with a follow-up period ranging from 22 to 73 months, show an increase in the tumor size ranging from 25 to 50% of all patients with NFMA. The natural course of NFMA presenting for other reasons than the presence of an incidentaloma is unclear.

In the series of Dekker et al. with non-operated NFMA patients report an increase in tumor size in 50% of all patients during long-term follow-up, accompanied by visual field defects in 50% of these cases. In patients with an increase in tumor size and visual field defects, surgical treatment resolved the visuals field defects. No independent predictors for tumor growth were found by logistic regression. Based on these data, they propose a conservative approach in selected patients with NFMA without visual field defects. In these patients, this is a safe alternative for transsphenoidal surgery, without the risk of irreversibly compromising visual field defects 1).

Clinically nonfunctioning pituitary adenoma classification.

Long noncoding RNAs (lncRNAs) have received increased research interest owing to their participation via distinct mechanisms in the biological processes of clinically nonfunctioning pituitary adenomas. However, changes in the expression of lncRNAs in gonadotropin secreting pituitary adenoma, which is the most common nonfunctional pituitary adenomas, have not yet been reported. In this study, we performed a genome-wide analysis of lncRNAs and mRNAs obtained from gonadotrophin adenoma patients' samples and normal pituitary tissues using RNA-seq. The differentially expressed lncRNAs and mRNAs were identified using fold-change filtering. We identified 839 lncRNAs and 1015 mRNAs as differentially expressed. Gene Ontology analysis indicated that the biological functions of differentially expressed mRNAs were related to transcription regulator activity and basic metabolic processes. Ingenuity Pathway Analysis was performed to identify 64 canonical pathways that were significantly enriched in the tumor samples. Furthermore, to investigate the potential regulatory roles of the differentially expressed lncRNAs on the mRNAs, we constructed general co-expression networks for 100 coding and 577 non-coding genes that showed significantly correlated expression patterns in tumor cohort. In particular, we built a special sub-network of co-expression involving 186 lncRNAs interacting with 15 key coding genes of the mTOR pathway, which might promote the pathogenesis of gonadotrophin tumor. This is the first study to explore the patterns of genome-wide lncRNAs expression and co-expression with mRNAs, which might contribute to the molecular pathogenesis of gonadotrophin adenoma 2).

Clinically nonfunctioning pituitary adenoma clinical features.

Knosp Grade

They mainly invade the sphenoid, cavernous sinus or dura mater.

Detection of a sellar mass by MRI. Biochemical testing can identify the adenoma cell type in those that are clinically silent.

Mean PRL in nonfunctioning pituitary adenomas was 39 ng/ml, with a majority of patients with stalk effect having PRL < 200 ng/ ml 3).

Immunohistochemical evaluation has revealed that most of these lesions are of gonadotroph differentiation, as they usually immunostain for the beta subunit of LH and/or FSH, as well as for the common alpha subunit of these glycoproteic hormones; a small proportion of these patients have tumors that immunostain for ACTH, GH, and TSH, the so-called “silent corticotroph, somatotroph, and thyrotroph adenomas,” respectively 4) 5).

Among pituitary disorders having mass effect of the pituitary gland, nonfunctioning pituitary macroadenoma and lymphocytic hypophysitis are difficult to differentiate without histological examination.

Based on a large series of histologically confirmed cases, serum PRL > 2000 mU/l is almost never encountered in nonfunctioning pituitary macroadenomas. Values above this limit in the presence of a macroadenoma should not be surrounded by diagnostic uncertainty (after acromegaly or Cushing's disease have been excluded); a prolactinoma is the most likely diagnosis 6).

see Clinically nonfunctioning pituitary adenoma treatment.

see Clinically Nonfunctioning Pituitary Adenoma Outcome.

MRI of the Pituitary Gland By Jean-François Bonneville, Fabrice Bonneville, Françoise Cattin, Sonia Nagi

This clinically oriented book will familiarize the reader with all aspects of the diagnosis of tumors and other disorders of the pituitary gland by means of magnetic resonance imaging (MRI). The coverage includes acromegaly, Cushing’s disease, Rathke cleft cysts, prolactinomas, incidentalomas, Clinically nonfunctioning pituitary adenomas, other lesions of the sellar region, hypophysitis, and central diabetes insipidus. Normal radiologic anatomy and the numerous normal variants are described, and guidance is also provided on difficulties, artifacts, and other pitfalls. The book combines concise text and high-quality images with a question and answer format geared toward the needs of the practitioner. MRI is today considered the cornerstone in the diagnosis of diseases of the hypophyseal-hypothalamic region but the relatively small size of the pituitary gland, its deep location, the many normal anatomic variants, and the often tiny size of lesions can hinder precise evaluation of the anatomic structures and particularly the pituitary gland itself. Radiologists and endocrinologists will find MRI of the Pituitary Gland to be full of helpful information on this essential examination, and the book will also be of interest to internists and neurosurgeons.

see Clinically nonfunctioning pituitary adenoma case series.


Fang et al. describe a very rare case of nonfunctional pituitary adenoma (NFPA) that exhibited corticotrophic activity after resection and radiotherapy. The possible mechanisms of the transformation from NFPA to Cushing disease (CD) are discussed.A 43-year-old man presented with impaired vision, bilateral frontal headaches, and hyposexuality. He had no symptoms suggestive of hypercortisolism, and 8 am plasma cortisol concentration was 67.88 ng/mL. Brain imaging revealed a 15 × 15 × 21-mm sellar mass suggestive of a macroadenoma. The tumor was resected by transsphenoidal surgery and identified by immunohistochemical analysis as a chromophobic adenoma that did not stain for pituitary hormones. The patient was treated with prednisone and levothyroxine replacement therapy. After a third recurrence, the patient presented with clinical features and physical signs of Cushing syndrome. Plasma adrenocorticotropic hormone (ACTH) and cortisol concentrations were elevated, and there was a loss of circadian rhythms. Inferior petrosal sinus sampling after desmopressin showed the central-peripheral ACTH ratio was greater than 3:1. A repeat transsphenoidal resection was undertaken. Immunohistochemistry revealed ACTH positivity. Three months following surgery, imaging showed little residual tumor, but plasma ACTH remained elevated. He was referred for postoperative Gamma Knife radiotherapy.The immunological activity and biological features of the hormones secreted from a pituitary adenoma vary with time. Because long-term outcomes are unpredictable, postoperative follow-up is essential to detect postoperative transformation from NFPA to CD 7).

Nonfunctional Pituitary Macroadenoma with Vision Loss and Endocrinopathy

Dekkers OM, Hammer S, de Keizer RJ, Roelfsema F, Schutte PJ, Smit JW, Romijn JA, Pereira AM. The natural course of non-functioning pituitary macroadenomas. Eur J Endocrinol. 2007 Feb;156(2):217-24. PubMed PMID: 17287411.
Li J, Li C, Wang J, Song G, Zhao Z, Wang H, Wang W, Li H, Li Z, Miao Y, Li G, Zhang Y. Genome-wide analysis of differentially expressed lncRNAs and mRNAs in primary gonadotrophin adenomas by RNA-seq. Oncotarget. 2016 Dec 15. doi: 10.18632/oncotarget.13948. [Epub ahead of print] PubMed PMID: 27992366.
Fleseriu M, Bodach ME, Tumialan LM, et al. Congress of Neurological Surgeons Systematic Review and Evidence-Based Guideline for Pretreatment Endocrine Evaluation of Patients With Nonfunctioning Pituitary Adenomas. Neurosurgery. 2016; 79:E527–E529
M. Al-Shraim and S. L. Asa, “The 2004 World Health Organization classification of pituitary tumors: what is new?” Acta Neuropathologica, vol. 111, no. 1, pp. 1–7, 2006.
S. L. Asa and S. Ezzat, “The cytogenesis and pathogenesis of pituitary adenomas,” Endocrine Reviews, vol. 19, no. 6, pp. 798–827, 1998
Karavitaki N, Thanabalasingham G, Shore HC, Trifanescu R, Ansorge O, Meston N, Turner HE, Wass JA. Do the limits of serum prolactin in disconnection hyperprolactinaemia need re-definition? A study of 226 patients with histologically verified non-functioning pituitary macroadenoma. Clin Endocrinol (Oxf). 2006 Oct;65(4):524-9. PubMed PMID: 16984247.
Fang H, Tian R, Wu H, Xu J, Fan H, Zhou J, Zhong L. Cushing Disease After Treatment of Nonfunctional Pituitary Adenoma: A Case Report and Literature Review. Medicine (Baltimore). 2015 Dec;94(51):e2134. doi: 10.1097/MD.0000000000002134. PubMed PMID: 26705201.
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