Path. Res. Pract. 183, 623-625 (1988)

Pituitary Hyperplasia

E. HorvathSt. Michael's Hospital, Department of Pathology, University of Toronto, Toronto,Ontario, Canada

SUMMARY

The morphologic study ofa large number ofhuman pituitary tissues provided conclusiveevidence that hyperplasia ofvarious adenohypophysial cell types exists. These rare lesionsmay serve as the underlying cause of pituitary hypersecretory syndromes. The non-neo­plastic proliferation of adenohypophysial cell types may be secondary to orthotopic orectopic oversecretion ofhypothalamic regulatory peptides, such as GRH, CRH, TRH andGnRH, disturbances ofdopaminergic regulation or iatrogenic factors. Histologically, ade­nohypophysial hyperplasia may be diffuse or nodular. The former type does not result inmajor alterations in pituitary architecture and may be impossible to recognize in smallsurgical specimens. The latter type is associated with enlargement of pituitary acini.Examination of the reticulin network, using silver staining techniques, represents usefultools in the differential diagnosis. The possible emergence of adenoma on the grounds ofhyperplasia is discussed.

Pituitary hyperplasia

The subject of hyperplasia is probably the most contro­versial area of pituitary pathology. The morphologicaldetails of hyperplasia have not been studied untilrecendy4,8 and the existence of the lesion as a separateentity still did not gain universal acceptance. The investi­gation of hyperplasia in surgically-removed pituitaryspecimens is gready hindered by several factors, such asthe regional distribution of some cell types, the often frag­mented nature and poor quality of surgical specimens and,last but not least, the lack of generally accepted mor­phologic criteria.

Pituitary hyperplasia is rare and despite our efforts tostudy every case in great detail, several aspects are unresol­ved. In our view, pituitary hyperplasia, i.e. the numericalincrease in one or more cell types, does exist and it may

© 1988 by Gustav Fischer Verlag, Stuttgart

occur in two morphologically different forms as diffuse ornodular hyperplasia. The two forms may coexist.

The term diffuse hyperplasia signifies the numericalincrease of hormone-producing cells without major altera­tions in cell morphology and pituitary architecture. Itappears that diffuse hyperplasia is the normal, acuteresponse to physiologic stimulation, such as pregnancy,lactation, declining circulating levels of gonadal steroids,etc. This morphologic type is difficult or impossible torecognize in fragmented surgical material.

In case of intense, sustained stimulation, nodular hyper­plasia, i.e. the marked enlargement of pituitary acini,chiefly populated by the hyperplastic cell type, develops.This lesion is associated with marked distortion of pituit­ary architecture as shown by reticulin techniques. Theultrastructure of hyperplastic cells may be distinctly differ­ent from that of the normal counterpart.

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624 . E. Horvath

Growth hormone (GH) cell hyperplasia. In the over­whelming majority of cases with acromegaly, the underly­ing pathology is an autonomous solitary adenoma produc­ing GH. It is well established, however, that excess growthhormone-releasing hormone (GRH), produced ectopicallyby various endocrine neoplasms (especially those arising inpancreatic islets, bronchi, thymus, thyroid parafollicularcells and adrenal medulla), may lead to chronic stimula­tion and, thus, hyperplasia of GH cells, as well as acrome­galyl,lO. The lesion shows elements of both diffuse andnodular forms. It is of interest that some lesions are mono­hormonal, whereas others contain both GH and prolactin.By electron microscopy (EM), the cells are similar todensely granulated GH cells with large, hypertrophicGolgi complex.

Prolactin (PRL) cell hyperplasia. The diffuse formoccurs and may reach extensive proportions in the lasttrimester of pregnancy and during lactation. To a muchlesser degree, the alteration may also be seen in disturb­ances of dopaminergic regulation due to destruction of thehypothalamus and/or infundibulum by various tumors ornon-neoplastic processes.

PRL cell hyperplasia is hardly ever the sole cause ofpituitary disease. A diffuse accumulation of large,hyperactive PRL cells can rarely be associated with PRL­producing and ACTH-producing adenomas. The extent ofthe change cannot be established often in surgical material.Thyrotroph hyperplasia, in cases of untreated or insuffi­ciently treated primary hypothyroidism, may also beaccompanied by hyperprolactinemia, the cause of whichlies in the overactivity of PRL cells with or without theirnumerical increase. In one case, nodular PRL cell hyper­plasia was noted7

•

Corticotroph cell hyperplasia and its role in the causa­tion of pituitary dependent Cushing's disease is a much­debated subject. In the majority of cases, a solitary auton­omous adenoma (usually microadenoma) appears to bethe underlying lesion. In a minority of cases, the surgicallyremoved tissue contains only corticotroph hyperplasia or acombination of hyperplastic and neoplastic changesS

, 6, 8.

The prevalence of this condition is still uncertain, for thedetailed histologic study of the entire gland may be neces­sary to establish the diagnosis of hyperplasia.

As a cause of Cushing's disease, pure diffuse cortico­troph hyperplasia appears to be extremely rare9

• The usualfinding is the combination of diffuse accumulation andnodular hyperplasia of corticotrophs. The scattered cellsin diffuse hyperplasia are large showing varying degrees ofCrooke's change. The enlarged acini of the nodular lesioncontain uniform corticotrophs, which appear somewhatsmaller than normal and show mild or no Crooke'schange.

Unusually massive, diffuse and multinodular hyper­plasia was also seen in a case of ectopic corticotropin­releasing hormone (CRH) production2

•

Thyrotroph hyperplasia occurs in the setting of sus­tained, profound primary hypothyroidism and may be

extensive enough to cause sellar enlargement. The milder,diffuse hyperplasia was seen only in pituitaries removed atautopsy from hypothyroid subjects. The thyrotrophs inthese glands are fairly large, densely granulated, reactingintensely with antihuman ~-TSH. Massive thyrotrophhyperplasia may mimic neoplastic lesion leading to surgi­cal exploration of the sella3

• In such cases, we haveobserved only nodular hyperplasia consisting of large,often sparsely granulated, "thyroid deficiency cells". As ithas already been alluded to, ~his lesion may be associatedwith the overactivity and even hyperplasia of PRL cells7

•

Gonadotroph hyperplasia is extremely rare and it doesnot seem to cause a clinical syndrome. The condition islargely unexplored at the present time.

Comment

Our studies confirm the existence of hyperplasia involv­ing potentially any pituitary cell type. The condition, how­ever, does not represent a single well-defined entity, butrather a spectrum of changes ranging from the slight, dif­fuse accumulation of the affected cell type(s) to massive,multinodular, space-occupying lesions associated withgradual alterations in cell morphology and pituitaryarchitecture. The rarity of pituitary hyperplasia notwith­standing, we have seen nodular GH cello, corticotroph-,and thyrotroph lesions in which focal dissolution of nor­mal pituitary architecture was noted, suggesting adenomaformation.

References

1 Asa SL, Kovacs K, Thorner MO, Leong DA, Rivier J, Vale W(1985) Immunohistological localization of growth hormone­releasing factor in human tumors. J Clin Endocrinol Metab 60:423-427

2 Carey RM, Varma SK, Drake CR Jr, Thorner MO, KovacsK, Rivier J, Vale W (1984) Ectopic secretion of corticotropin­releasing factor as a cause of Cushing's syndrome: a clinical,morphologic, and biochemical study. N Engl J Med 311: 13-20

3 Khalil A, Kovacs K, Sima AAF, Burrow GN, Horvath E(1984) Pituitary thyrotroph hyperplasia mimicking prolactin-se­creting adenoma. J Endocrinol Invest 7: 399-404

4 Kovacs K, Horvath E (1986) Tumors of the pituitary gland.In: Atlas of Tumor Pathology. Fascicle XXI, 2nd series. pp1-264, Armed Forces Institute of Pathology, Washington, D.C.

S Lloyd RV, Chandler WF, McKeever PE, Schteingart DE(1986) The spectrum of ACTH-producing pituitary lesions. AmJSurg PathollO: 618-626

6 McKeever PE, Koppelman MCS, Metcalf D, Quindlen E,Kornblith PL, Strott CA, Howard R, Smith BH (1982) RefractoryCushing's disease caused by multinodular ACTH cell hyper­plasia. J Neuropathol Exper Neurol 41: 490-499

7 Pioro EP, Scheithauer BW, Laws ERJr, Randall RV, KovacsK, Horvath E (1988) Combined thyrotroph and lactotroph

hyperplasia simulating prolactin-secreting pituitary "adenoma"in longstanding primary hypothyroidism. Surg Neurol 29:218-226

8 Saeger W, Liidecke DK (1983) Pituitary hyperplasia. Defini­tion, light and electron microscopical structures and significancein surgical specimens. Virchows Arch Pathol Anat 399: 277-287

Received January 30, 1988 . Accepted March 9, 1988

Pituitary Hyperplasia . 625

9 Schnall AM, Kovacs K, Brodkey JS, Pearson OH (1980)Pituitary Cushing's disease without adenoma. Acta Endocrinol(Kbh) 94: 297-303

10 Thorner MO, Perryman RL, Cronin MJ, Rogol AD, Draz­nin M, Johanson A, Vale W, Horvath E, Kovacs K (1982)Somatotroph hyperplasia. J Clin Invest 70: 965-977

Key words: Adenohypophysis - Diffuse hyperplasia - Nodular hyperplasia - Pituitary hyperplasia - Pituitary hyper­secretory syndrome

Eva Horvath, Ph. D., Department of Pathology, St Michael's Hospital, 30 Bond Street, Toronto, Ont., M5B 1W8, Canada