, Volume 18, Issue 3, pp 251–254 | Cite as

Double adenomas of the pituitary: an imaging, pathological, and clinical diagnostic challenge

  • George Kontogeorgos
  • Eleni Thodou
Review Article


Double and multiple adenomas of the pituitary are composed of two or more distinct tumors located in the same gland. They represent uncommon lesions measuring less than 1 cm, reported as having a low incidence in autopsies and occurring even more infrequently in surgical series. The histological diagnosis of double adenomas in surgical material is often extremely difficult, and confirmation requires immunohistochemistry and, occasionally, electron microscopy. Fragmented tissue material submitted for histology after transsphenoidal resection complicates the diagnosis. Difficulties in demonstrating double or multiple adenomas by imaging techniques contribute to diagnostic failure. Magnetic resonance imaging (MRI) techniques may disclose two separate adenomas located in the same pituitary gland. Intraoperative MRI and imaging ultrasonography, together with positron emission computed tomography, more accurately identify sites of residual tumors. These techniques might also detect postoperatively a residual tumor belonging to the second component of double adenoma. Double adenomas may also create extreme clinical diagnostic challenges. It is almost impossible to suspect functioning double adenomas with combined hormone secretion, each one secreting a different hormone, and distinguish them from an isolated plurihormonal adenoma, simultaneously secreting more than one hormone. Double adenomas may underlie surgical failure when one adenoma is removed while the other is left behind. Despite the low frequency of double adenomas, identification and resection of both of them is of major importance for the achievement of biochemical cure.


Double adenomas Multiple adenomas Histology Hormones Imaging techniques Immunohistochemistry Pituitary 

Double adenomas of the pituitary, which are composed of two clearly distinct tumors located in the same gland, occur infrequently. Multiple adenomas, which consist of more than two tumors [1, 2], may coexist with other sellar neoplasms or tumor-like lesions [3, 4]. To the best of our knowledge, a single case of pituitary adenoma coexisting with ectopic adenoma located in the pituitary stalk has been reported [5]. In most instances, double adenomas are simultaneously diagnosed, while asynchronous development is rare [1, 2, 6]. As a rule, double adenomas are microadenomas measuring less than 1 cm. The first series of multiple adenomas reported 44 tumors in an autopsy material (16 double and 4 triple), while the first surgical series of double adenomas included another 11 tumors [1, 2]. According to a recent review, 63 patients with 129 adenomas, including 60 double and three triple were reported [7]. For the first time, a short chapter dedicated to double adenomas of the pituitary was included in the recent edition of the World Health Organization (WHO) classification of tumors of endocrine organs [8].

The incidence of double adenomas is very low, ranging from 0.4 to 1.3% in surgical material and 0.9 to 0.9% in autopsy series [1, 2, 9, 10]. Their lower frequency in surgical series is attributed to several reasons. Recognition in routine hematoxylin-eosin histological sections is often difficult or impossible, unless they are composed of two different cell types. Transsphenoidally removed adenomas submitted in small fragments for histology make diagnosis extremely complex. It is impossible to separate double adenomas with the same immunoprofile on histology grounds [2]. In addition, due to selective adenoma resection, the residual adenohypophysial parenchyma remains unexplored. Lastly, aspiration during transsphenoidal surgery results in partial loss of the adenoma tissue. While multiple adenomas are incidentally found in autopsies, their detection in surgical material is exceptional [1, 7, 11], since, as a rule, they are of small size and hormonally nonfunctional [1]. Given that, in autopsies, the whole pituitary gland is available for evaluation, the geographic distribution of multiple adenomas permits easy identification, even of tumors composed of the same cell type. In addition, clear demarcation of the adenoma, compression of the adjacent adenohypophysial parenchyma, and condensation of the surrounding reticulin fiber network allow precise identification of even tiny adenomas. Nevertheless, the higher incidence of multiple adenomas in autopsy material suggests that many of these lesions remain undiagnosed, particularly when they are clinically nonfunctioning.

The etiology of double and multiple adenomas remains uncertain. They might originate from the incidental occurrence of two monoclonal components belonging to two different cytogenetic lineages. Alternatively, they may represent two different lesions deriving from clonal expansion of uncommitted stem cells that have undergone multidirectional differentiation [2, 12]. Immunohistochemistry for transcription factors (Pit-1, Tpit, and SF-1) confirms the divergent lineages of cytodifferentiation in double adenomas [12]. However, according to the recent WHO classification of endocrine tumors, application of transcription factors can be complementary and is not recommended for routine diagnosis [13]. Double adenomas are in their substantial majority sporadic neoplasms, occasionally associated with multiple endocrine neoplasia type-1 [14, 15].

Difficulties in demonstrating super numerical adenomas by imaging techniques may result in diagnostic failure. CT scan and MRI can identify microadenomas of 2–3 mm with a sensitivity of 60 and 85%, respectively [16]. High-resolution MRI techniques may disclose two separate adenomas in the same pituitary gland [9, 14, 17, 18]. It is more difficult to detect a residual pituitary adenoma after transsphenoidal surgery. Postoperative imaging using conventional MRI may only occasionally distinguish residual tumor from normal anterior pituitary parenchyma [19]. Intraoperative MRI (iMRI), combined with synchronous direct inspection of the sellar or suprasellar areas during the surgical procedure, facilitates detection and removal of residual tumor. However, this method is less sensitive when the tumor remnants are smaller than 3 mm [20]. Furthermore, intraoperative pituitary imaging ultrasonography (iUS) may identify and allow targeted resection of small hyperechoic pituitary tumors, even in MRI-negative cases, as is typical in Cushing’s disease [21]. Lastly, functional imaging using 11C-methionine positron emission tomography, co-registered with 3D gradient echo MRI (Met-PET/MRI), can recognize sites of residual hormone active adenoma in acromegaly patients operated on via transsphenoidal surgery [22]. All these novel techniques might also detect the second component belonging to a double adenoma left behind in the initial operation.

The histological diagnosis of double adenomas in surgical material is often challenging and can be complex. Even in cases where their presence is suspected by hematoxylin-eosin routine sections, confirmation requires immunohistochemistry and, infrequently, electron microscopy [2]. Diagnosis is certain when adenomas are composed of two clearly distinct cell types, evident by immunohistochemistry for pituitary hormones (Fig. 1). It is impossible to distinguish double adenomas with an identical immunoprofile unless they are detected preoperatively, either by MRI or during the intraoperative inspection, in which case the neurosurgeon removes each one selectively and submits them separately for histology [9, 16].
Fig. 1

Consecutive sections of double adenoma located in the same tissue fragment with distinct histology and immunoreactivity. The upper part corresponds to acidophilic, densely granulated somatotroph adenoma, while the lower part to chromophobic lactotroph adenoma (a hematoxylin-eosin stain, b GH immunostain, c PRL immunostain; × 2.5)

Functioning double adenomas of the pituitary are associated with endocrine symptoms due to hormonal excess by one or both of them [2, 23]. There is no general agreement regarding the relevance of functioning somatotroph and corticotroph adenomas among double adenomas in surgical material [7, 8]. Several studies have reported a higher frequency in acromegaly patients, followed by those presented with Cushing’s disease [2, 8, 24]. A recent review of the literature, based on a cohort of 63 patients harboring double adenomas, reported a slight numerical difference between acromegaly and Cushing’s patients. Twenty-four of them were diagnosed in patients presenting with Cushing’s disease and 22 in subjects with acromegaly [7]. The discrepancy with earlier studies is attributed to the inclusion of a publication by experts in Cushing’s disease. In this study, the authors focused on assessing the incidence of multiple pituitary adenomas only in patients harboring Cushing’s disease [9]. A more recent review analyzed truly separate double or multiple pituitary adenomas identified preoperatively by MRI and confirmed by histology and immunohistochemistry. Among these 17 cases published between 1975 and 2016, the authors report a higher frequency of growth hormone (GH)-secreting adenomas, followed by corticotropin hormone (ACTH)-secreting adenomas. In addition, the patients’ age ranged from 22 to 67 years, with a higher preponderance in females [25]. The overall reported incidence in patients with double adenomas associated with Cushing’s is 1.6–3.3% [9, 14, 26]. Corticotroph adenomas found in double lesions may coexist with corticotroph cell hyperplasia, rarely proceeding to adenoma transformation [27, 28]. Corticotroph adenomas, among double tumors in surgical material, may also present as silent [1, 7, 9, 25]. Functioning adenomas producing other hormones often coexist with nonfunctioning tumors [1, 2, 7, 29]. The latter, among double adenomas, are diagnosed either on the basis of mass effect symptoms or incidentally [2]. In autopsies, silent lactotroph adenomas are the most frequent among multiple adenomas, followed by silent corticotroph, silent somatotroph, and gonadotroph adenomas [1, 7]. The latter showing focal immunopositive for luteinized or/and follicle-stimulating hormone or/and α-glycoprotein hormone subunit were previously diagnosed as null cell tumors or oncocytomas [1, 30].

Coexistence of double adenomas in the same pituitary gland also creates extreme clinical diagnostic difficulties. Surgical resection of the nonfunctioning adenoma rather than the functioning one in double adenomas leads to a poor clinical outcome [2, 23]. It is almost impossible to suspect functioning double adenomas independently producing distinct pituitary hormones [2, 23, 27]. In such a case, double adenomas may underlie surgical failure when one adenoma is removed while the other is left behind. Hyperprolactinemia in acromegaly patients further complicates the diagnosis raising the question whether it is a result of pituitary stalk compression or it is due to separate secretion of GH and PRL by two independent somatotroph and lactotroph adenomas respectively. A typical example illustrating this issue has been published describing a patient with acromegaly and galactorrhea-amenorrhea caused by two separate adenomas, one producing GH and the other PRL [23]. Other reports exemplify patients with Cushing’s disease harboring double adenomas, in whom the neurosurgeon removed only the GH- or a PRL-secreting tumor, while resection of the residual functioning corticotroph adenoma was performed in a second operation [9, 27]. Therefore, continuing endocrine symptoms after pituitary surgery are highly suspicious for the implication of double adenomas.

In summary, identification of double adenomas is of utmost importance to make a correct diagnosis and to correlate the patient’s clinical presentation with the type of hormone product, thus avoiding a second surgery. Imaging techniques should always be carefully applied in order to achieve identification of the presence of double adenomas, meticulous surgical pituitary exploration being particularly important in patients with Cushing’s disease or acromegaly. However, a definitive diagnosis of double adenomas should be assessed exclusively upon pathological evaluation. It must be stressed that, despite the low frequency of double adenomas, it is of major clinical importance to identify and remove both tumors in one step so as to achieve biochemical cure.


Compliance with ethical standards

Conflict of interest

All authors declare that they have no conflict of interest.


  1. 1.
    Kontogeorgos G, Kovacs K, Horvath E, Scheithauer BW (1991) Multiple adenomas of the human pituitary. A retrospective autopsy study with clinical implications. J Neurosurg 74(2):243–247. CrossRefPubMedGoogle Scholar
  2. 2.
    Kontogeorgos G, Scheithauer BW, Horvath E, Kovacs K, Lloyd RV, Smyth HS, Rologis D (1992) Double adenomas of the pituitary: a clinicopathological study of 11 tumors. Neurosurgery 31(5):840–849, discussion 849. CrossRefPubMedGoogle Scholar
  3. 3.
    Yoshida A, Sen C, Asa SL, Rosenblum MK (2008) Composite pituitary adenoma and craniopharyngioma?: an unusual sellar neoplasm with divergent differentiation. Am J Surg Pathol 32(11):1736–1741. CrossRefPubMedGoogle Scholar
  4. 4.
    Koutourousiou M, Kontogeorgos G, Wesseling P, Grotenhuis AJ, Seretis A (2010) Collision sellar lesions: experience with eight cases and review of the literature. Pituitary 13(1):8–17. CrossRefPubMedGoogle Scholar
  5. 5.
    Mendola M, Dolci A, Piscopello L, Tomei G, Bauer D, Corbetta S, Ambrosi B (2014) Rare case of Cushing’s disease due to double ACTH-producing adenomas, one located in the pituitary gland and one into the stalk. Hormones 13(4):574–578. CrossRefPubMedGoogle Scholar
  6. 6.
    Thodou E, Kontogeorgos G, Horvath E, Kovacs K, Smyth HS, Ezzat S (1995) Asynchronous pituitary adenomas with differing morphology. Arch Pathol Lab Med 119(8):748–750PubMedGoogle Scholar
  7. 7.
    Budan RM, Georgescu CE (2016) Multiple pituitary adenomas: a systematic review. Front Endocrinol (Lausanne) 1(7):1–8. CrossRefGoogle Scholar
  8. 8.
    Kontogeorgos G, Kovacs K, Lloyd RV, Righi A (2017) Plurihormonal and double adenomas. In: Lloyd RV, Osamura RY, Klöppel G, Rosai J (eds) WHO classification of tumours of endocrine organs, 4th end. IACR, Lyon pp 39–40Google Scholar
  9. 9.
    Ratliff JK, Oldfield EH (2000) Multiple pituitary adenomas in Cushing’s disease. J Neurosurg 93(5):753–761. CrossRefPubMedGoogle Scholar
  10. 10.
    Gorczyca W, Hardy J (1988) Microadenomas of the human pituitary and their vascularization. Neurosurgery 22(1 Pt 1):1–6. CrossRefPubMedGoogle Scholar
  11. 11.
    Pantelia E, Kontogeorgos G, Piaditis G, Rologis D (1998) Triple pituitary adenoma in Cushing’s disease: case report. Acta Neurochir 140(2):190–193CrossRefPubMedGoogle Scholar
  12. 12.
    Jastania RA, Alsaad KO, Al-Shraim M, Kovacs K, Asa SL (2005) Double adenomas of the pituitary: transcription factors Pit-1, T-pit, and SF-1 identify cytogenesis and differentiation. Endocr Pathol 16(3):187–194CrossRefPubMedGoogle Scholar
  13. 13.
    Osamura RY, Grossman A, Korbonits M, Kovacs K, Lopes BMS, Masturo A, Troullas J (2017) Pituitary adenoma. In: Lloyd RV, Osamura RY, Klöppel G, Rosai J (eds) WHO classification of tumours of endocrine organs, 4th end. IACR, Lyon pp 14-18Google Scholar
  14. 14.
    Kannuki S, Matsumoto K, Sano T, Shintani Y, Bando H, Saito S (1996) Double pituitary adenoma–two case reports. Neurol Med Chir (Tokyo) 36:818–821. CrossRefGoogle Scholar
  15. 15.
    Kim K, Yamada S, Usui M, Sano T (2004) Preoperative identification of clearly separated double pituitary adenomas. Clin Endocrinol (Oxf) 61(1):26–30. CrossRefGoogle Scholar
  16. 16.
    Johnsen DE, Woodruff WW, Allen IS, Cera PJ, Funkhouser GR, Coleman LL (1991) MR imaging of the sellar and juxtasellar regions. Radiographics 11(5):727–758. CrossRefPubMedGoogle Scholar
  17. 17.
    Pu J, Wang Z, Zhou H, Zhong A, Jin K, Ruan L, Yang G (2016) Oncol Lett 12(1):585–590. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Miyagi N, Doi R, Kuramoto T, Sakata K, Tahara S, Sugita Y, Morioka M (2018) Double pituitary adenomas associated with persistent trigeminal artery: a rare case report and the review of literature. Neurosurg Rev 41(1):341–345. CrossRefPubMedGoogle Scholar
  19. 19.
    Kremer P, Forsting M, Ranaei G, Wüster C, Hamer J, Sartor K, Kunze S (2002) Magnetic resonance imaging after transsphenoidal surgery of clinically non-functional pituitary macroadenomas and its impact on detecting residual adenoma. Acta Neurochir 144(5):433–443. CrossRefPubMedGoogle Scholar
  20. 20.
    Paterno V, Fahlbusch R (2014) High-filed iMRI in transsphenoidal pituitary adenoma surgery with special respect to typical localization of residual tumor. Acta Neurochir 156(3):463–474. CrossRefPubMedGoogle Scholar
  21. 21.
    Knappe UJ, Engelbach M, Konz K, Lakomek HJ, Saeger W, Schonmayr R, Mann WA (2011) Ultrasound-assisted microsurgery for Cushing’s disease. Exp Clin Endocrinol Diabetes 119(4):191–200. CrossRefPubMedGoogle Scholar
  22. 22.
    Koulouri O, Kandasamy N, Hoole AC et al (2016) Eur J Endocrinol 175(5):485–498. CrossRefPubMedGoogle Scholar
  23. 23.
    Tolis G, Bertrand G, Carpenter S, McKenzie JM (1978) Acromegaly and galactorrhea-amenorrhea with two pituitary adenomas secreting growth hormone or prolactin. A case report. Ann Intern Med 89(3):345–348. CrossRefPubMedGoogle Scholar
  24. 24.
    Sano T, Horiguchi H, Xu B, Li C, Hino A, Sakaki M, Kannuki S, Yamada S (1999) Double pituitary adenomas: six surgical cases. Pituitary 1:243–250CrossRefPubMedGoogle Scholar
  25. 25.
    Ogando-Rivas E, Alalade AF, Boatey J, Schwartz TH (2017) Pituitary 20(6):702–708. CrossRefPubMedGoogle Scholar
  26. 26.
    McKelvie PA, McNeill P (2002) Double pituitary adenomas: a series of three patients. Pathology 34:57–60CrossRefPubMedGoogle Scholar
  27. 27.
    Meij BP, Lopes MB, Vance ML, Thorner MO, Laws ER Jr (2000) Double pituitary lesions in three patients with Cushing’s disease. Pituitary 3(3):159–168CrossRefPubMedGoogle Scholar
  28. 28.
    Mazarakis N, Kontogeorgos G, Kovacs K, Horvath E, Borboli N, Piaditis G (2001) Pituitary 4(4):215–221CrossRefPubMedGoogle Scholar
  29. 29.
    Buurman H, Saeger W (2006) Subclinical adenomas in postmortem pituitaries: classification and correlations to clinical data. Europ J Endocrinol 154(5):753–758. CrossRefGoogle Scholar
  30. 30.
    Kontogeorgos G, Thodou E (2016) The gonadotroph origin of null cell adenomas. Hormones 15(2):243–247.

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© Hellenic Endocrine Society 2019

Authors and Affiliations

  1. 1.Department of PathophysiologyUniversity of AthensAthensGreece
  2. 2.Department of PathologyUniversity of ThessalyLarissaGreece

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