Pituitary Acromegaly: Not One Disease

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S L Asa et al. Acromegaly: not one disease 24:3 C1–C4 Commentary

Pituitary acromegaly: not one disease

Sylvia L Asa1, Walter Kucharczyk2 and Shereen Ezzat3

1Department of Pathology, The Endocrine Oncology Site Group, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada 2 Department of Medical Imaging, The Endocrine Oncology Site Group, Princess Margaret Cancer Correspondence Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada should be addressed 3 Department of Medicine, The Endocrine Oncology Site Group, Princess Margaret Cancer Centre, to S L Asa University Health Network, University of Toronto, Toronto, Ontario, Canada Email [email protected]

Abstract

Acromegaly has traditionally been regarded as a monomorphous disorder resulting Key Words from a benign pituitary adenoma. Increasing evidence, however, is highlighting that this ff acromegaly disorder is associated with a spectrum of morphologically distinct pituitary tumors with ff pathology variable clinical, biochemical and radiologic features and differing therapeutic outcomes ff radiology that are attributed to different genetic and epigenetic changes. These data underscore ff biomarkers the need for developing a more refined clinicopathological risk stratification system and ff pituitary tumors implementing personalized targeted therapeutic approaches.

Endocrine-Related Cancer (2017) 24, C1–C4 Endocrine-Related Cancer Endocrine-Related

We read with interest the recent article ‘T2-weighted MRI this principle to our patient management for several signal predicts hormone and tumor responses to somatostatin years (Asa & Mete 2016, Bakir et al. 2016) and discuss it analogs in acromegaly’, published in the November 2016 frequently in our multidisciplinary pituitary tumor case issue of Endocrine-Related Cancer (Potorac et al. 2016). The conferences. We have also found that densely granulated authors concluded that ‘The T2-weighted signal intensity corticotroph and lactotroph tumors tend to exhibit low of GH-secreting adenomas at diagnosis correlates with signal on T2-weighted MR imaging (Bakir et al. 2016). hormone reduction and tumor shrinkage in response to This work emphasizes that pituitary tumors associated primary SSA treatment in acromegaly’. with various clinical entities do not represent a single This report confirms the previous work of Hagiwara disorder but rather a group of morphologically and and coworkers (Hagiwara et al. 2003) who reported that functionally distinct entities (Asa 2011). Although most with respect to pituitary somatotroph tumors, low signal clinicians are now aware that rare cases of acromegaly are on T2-weighted MR imaging is almost exclusive to the due to pituitary hyperplasia that represents a response to densely granulated variant, and our data indicating that excess secretion of growth hormone-releasing hormone hormone and tumor response to somatostatin analogs (GHRH), usually by an extracranial neuroendocrine tumor correlate with densely granulated tumor morphology (Sano et al. 1988), many seem to be unaware that primary in acromegaly (Ezzat et al. 1995, Bhayana et al. 2005). pituitary endocrine neoplasms that cause acromegaly Others have confirmed the predictive value of tumor represent a spectrum of lesions. Some may be hereditary histologic subtyping with respect to somatostatin and when they present in childhood, the manifestations responsiveness (Fougner et al. 2012, Heck et al. 2012, of gigantism are distinct (Hannah-Shmouni et al. 2016). Kato et al. 2012, Brzana et al. 2013, Larkin et al. 2013, The vast majority, however, are sporadic and develop Kiseljak-Vassiliades et al. 2015a). We have been applying in adults.

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10.1530/ERC-16-0496 Commentary S L Asa et al. Acromegaly: not one disease 24:3 C2

Pituitary GH-secreting lesions are divided by harbor the activating GNAS mutations that constitutively histopathological classifications into multiple variants. upregulate cyclic adenosine monophosphate (cAMP) Somatotroph neoplasms may be composed of densely or signaling (Spada et al. 1990, Asa et al. 2007, Mayr et al. sparsely granulated somatotrophs based on keratin patterns 2013). In contrast these mutations are usually not found (Asa 2011); the importance of accurate interpretation of in sparsely granulated somatotroph tumors with rare keratin staining patterns was emphasized by Obari and exceptions (Larkin et al. 2013). The molecular alterations coworkers who showed clearly that mixed or intermediate in these more aggressive tumors remain unclear, but seem staining patterns reflect a densely granulated tumor and to involve GH receptor and STAT signaling (Asa et al. only neoplasms with a pure pattern of ‘fibrous body’ 2007, Tateno et al. 2011) that result in the manifestation keratin staining should be classified as sparsely granulated of cytoskeletal dysfunction seen as keratin aggregation somatotroph tumors (Obari et al. 2008). Although into fibrous bodies (Asa & Ezzat 1998, 2002, 2009). sparsely granulated tumors are usually monohormonal, Patients with AIP germline mutations tend to harbor densely granulated somatotroph tumors often produce sparsely granulated tumors (Daly et al. 2010) and sparsely alpha-subunit (Asa 2011). Less frequent plurihormonal granulated somatotroph tumors are overrepresented neoplasms may be composed of mammosomatotrophs among sporadic somatotroph neoplasms with low AIP that synthesize and secrete prolactin as well as GH and expression (Denes et al. 2015), suggesting that loss of alpha-subunit and may occasionally co-secrete TSH also AIP may play a role in their development. Although (Asa 2011); these are usually densely granulated and the pathogenesis of poorly differentiated tumors of resemble densely granulated somatotroph tumors. Rarely, Pit-1 lineage is not known, some of these patients were acromegaly may be caused by poorly differentiated tumors members of MEN1 kindreds (Mete et al. 2016). of Pit-1 lineage (Mete et al. 2016). Given the differences in pathogenesis that give There are differences in the clinical presentations rise to distinct clinical, biochemical, radiological of these various neoplasms, and they exhibit different and morphological features of the various tumors behaviors (Asa 2011). In general, densely granulated associated with acromegaly, it is no surprise that their somatotroph and mammosomatotroph tumors tend to be responses to targeted therapies are different. Tumors associated with high levels of GH and IGF-1 and florid that are dependent on cAMP signaling would logically symptomatology (Trouillas et al. 1996, Fougner et al. be responsive to the inhibition of this pathway that is 2012, Heck et al. 2012, Kato et al. 2012, Brzana et al. mediated by somatostatin analogs, especially those that Endocrine-Related Cancer Endocrine-Related 2013, Larkin et al. 2013, Kiseljak-Vassiliades et al. 2015a); target the somatostatin receptor type 2 (SSTR2). Those perhaps because of this hypersecretory status, they are receptors are highly expressed in most somatotroph occasionally diagnosed as intrasellar tumors that can tumors, but recent studies have suggested that SSTR2 be surgically resected and cured (Asa 2011). In contrast, may be downregulated in the sparsely granulated tumors sparsely granulated somatotroph tumors tend to be (Kato et al. 2012, Brzana et al. 2013, Casar-Borota et al. associated with less obvious clinical symptomatology and 2013, Mayr et al. 2013, Kiseljak-Vassiliades et al. 2015b, more subtle biochemical alterations; they are usually large Iacovazzo et al. 2016). and invasive at diagnosis (Obari et al. 2008, Brzana et al. It should be noted that the same distinctions are 2013, Larkin et al. 2013, Kiseljak-Vassiliades et al. 2015b). even more pronounced in Cushing disease where densely Clinically, mammosomatotroph tumors are associated granulated tumors tend to be small and associated with with hypersecretion of prolactin and/or TSH; interestingly, florid clinical and biochemical features, whereas sparsely patients with pure somatotroph tumors are significantly granulated tumors are often more subtle, and although more likely to present with diabetes mellitus or impaired not silent, have been described as ‘whispering’ (Asa glucose tolerance than those with plurihormonal tumors 2011). Mutations in the ubiquitin-specific peptidase (Cheng et al. 2013). Poorly differentiated tumors of Pit-1 USP8 (Ma et al. 2015, Reincke et al. 2015, Hayashi et al. lineage represent an extreme variant that is more likely 2016) have been identified in small tumors that were to be diagnosed when large and more highly invasive almost certainly densely granulated; these mutations (Mete et al. 2016). Although molecular alterations are rare may predict response to the somatostatin analog in pituitary tumors (Asa & Ezzat 1998, 2002, 2009), the pasireotide (Hayashi et al. 2016). Therefore, our ability densely granulated somatotroph and mammosomatotroph to detect densely granulated tumors in Cushing disease, tumors represent a subset in which there may be a which we have experienced, may also prove to have characteristic genetic alteration; a subset of these tumors therapeutic significance.

In the era of precision medicine, it is critical that Asa SL & Mete O 2016 The pituitary gland. In Endocrine Pathology, endocrine oncology maintain its position as a leader in pp 315–397. Eds O Mete & SL Asa. Cambridge, UK: Cambridge University Press. understanding the importance of tumor classifications Asa SL, DiGiovanni R, Jiang J, Ward ML, Loesch K, Yamada S, Sano 1, based on pathology and the value of biomarkers that Yoshimoto K, Frank SJ & Ezzat S 2007 A growth hormone receptor predict appropriate therapeutic responsiveness. In other mutation impairs growth hormone autofeedback signaling in pituitary tumors. Cancer Research 67 7505–7511. (doi:10.1158/0008- tumors, it has become a standard of care to ensure 5472.CAN-07-0219) accurate subclassification before determining therapeutic Bakir B, Chan M, Cruz JP, Kartal MGD, Gulenchyn KY, Kucharczyk W, approaches. One would never consider treating a breast Salmaslioglu A & Yu E 2016 Radiological imaging. In Endocrine Pathology, pp 109–214. Eds O Mete & SL Asa. Cambridge, UK: cancer patient for ‘infiltrating ductal carcinoma’ or a Cambridge University Press. lung cancer patient for ‘adenocarcinoma’ as we used Bhayana S, Booth GL, Asa SL, Kovacs K & Ezzat S 2005 The implication to 20 years ago; instead, we classify every tumor based of somatotroph adenoma phenotype to somatostatin analog responsiveness in acromegaly. Journal of Clinical Endocrinology and on the biomarkers that define pathogenesis and predict Metabolism 90 6290–6295. (doi:10.1210/jc.2005-0998) therapeutic efficacy. Similarly in the pituitary, we Brzana J, Yedinak CG, Gultekin SH, Delashaw JB & Fleseriu M 2013 often see a diagnosis of ‘pituitary adenoma’ or perhaps Growth hormone granulation pattern and somatostatin receptor subtype 2A correlate with postoperative somatostatin receptor ligand ‘pituitary adenoma producing GH’. However, in patients response in acromegaly: a large single center experience. Pituitary 16 with acromegaly, the most important immunostain that 490–498. (doi:10.1007/s11102-012-0445-1) pathologists should evaluate is the keratin stain that at Casar-Borota O, Heck A, Schulz S, Nesland JM, Ramm-Pettersen J, Lekva T, Alafuzoff I & Bollerslev J 2013 Expression of SSTR2a, but least allows the distinction of the two most important not of SSTRs 1, 3, or 5 in somatotroph adenomas assessed by subclasses of GH-producing tumors. If this approach monoclonal antibodies was reduced by octreotide and correlated identifies abundant and distinct fibrous bodies, instead of with the acute and long-term effects of octreotide. 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Received in final form 23 January 2017 Accepted 25 January 2017 Accepted Preprint published online 25 January 2017