Somatotroph adenomas: histological subtypes and predicted response to treatment

Abstract

Pituitary adenomas are now described as pituitary neuroendocrine tumors (PitNets) [1]. A large proportion, approximately 22–54%, is clinically defined as nonfunctioning pituitary adenomas and will present with signs and symptoms of mass effect, rather than excessive hormone secretion. ‘Silent pituitary adenomas’ are tumors that express one or more of the anterior pituitary hormones or their transcription factors, which can be visualized by immunohistochemical analysis. Although, they do not secrete hormones at a clinically relevant level. Silent pituitary adenomas can be further sub categorized into totally silent or clinically silent tumors [2]. A null cell adenoma that is restricted to a primary anterior pituitary tumor, is hormone negative (determined by immunohistochemistry) and does not express any of the pituitary transcription factors. The clinical picture of pituitary adenomas reflects a continuum between functional adenomas and ‘totally silent’ adenomas. The functional status of the tumor can change throughout the disease course [3]. Somatotropic tumors are growth hormone (GH) producing tumors. These account for approximately 20% of surgically treated pituitary tumors and more than 95% of cases of acromegaly. Very rare cases of acromegaly are due to an excess of the GH-releasing hormone (GHRH). This may be associated with neuroendocrine tumors of lung, pancreas, medullary thyroid cancer, pheochromocytomas and hypothalamic gangliocytomas. Ectopic production of GH has been reported from rare cases of pancreatic neuroendocrine tumor or lymphoma [4,5]. Many familial syndromes have been reported to predispose to acromegaly or gigantism. These include multiple MEN1 and MEN4, familial isolated pituitary adenoma and Carney complex. A sporadic germline mosaic disorder McCune-Albright disease can also result in GH excess [6]. A rare genetic syndrome, X-linked acrogigantism has been described in early-onset childhood gigantism [7]. In familial cases, onset is in young age with florid presentation due to high GH levels. The response to medical treatment is poor [7]. Silent somatotroph adenomas lack clinical and biological signs of acromegaly but are GH-immunoreactive tumors. They represent approximately 2–4% of all pituitary adenomas in surgical series. Patients with truly silent somatotroph adenomas have normal preoperative GH and IGF-1 levels; some cases can be clinically silent but demonstrate a lack of GH suppression and elevated IGF-1 levels (whispering adenomas) [8]. Growth hormone excess can be due to pure somatotroph adenomas and these can be densely granulated (DGSA) or sparsely granulated (SGSA). DGSA are present in 30–50% of acromegaly cases. The cells are eosinophilic and are strongly as well as diffusely positive for GH and α-subunits. They resemble normal somatotrophes. DGSA is usually present in older patients and are slow-growing lesions. Patients have typical features of acromegaly and high levels of GH and IGF-1 and imaging demonstrates characteristic bone changes of acromegaly and is associated with low intensity tumors on T2-weighted MRI scans. The disease shows an excellent response to somatostatin analogs (SSAs). SGSA accounts for 15–35% of patients with acromegaly. The cells are lightly eosinophilic or chromophobic. The tumors identified usually demonstrate focal or weak GH expression and no α-subunit expression. SGSAs have