Diagnosis and Discussion - Case 1125

Final Diagnosis

Double Pituitary Adenoma with Synchronous Mammosomatotroph and Corticotroph Differentiation.

Discussion

Pituitary adenomas or pituitary neuroendocrine tumors (PitNETs) are neuroendocrine tumors of the anterior pituitary gland that are composed of neoplastic cells that can produce pituitary hormones. PitNETs are the third most common intracranial tumor, after meningiomas and gliomas and are mostly benign [1], although they may show invasive growth into neighboring structures, and very rarely present as aggressive metastasizing tumors [2]. The neoplasm is typically composed of cells with uniform round nuclei, delicate chromatin, inconspicuous nucleoli, and moderate cytoplasm that can be variable basophilic, eosinophilic or chromophobic, based on tinctorial differences on H&E-stained material. Mitotic activity is usually uncommon, and the Ki-67 proliferation indices are usually low. 

PitNETs are predominantly identified in the sellar region but may show suprasellar extension. Rare ectopic pituitary adenomas are seen and are believed to arise from the embryonal remnant of the pituitary migration [3]. PitNETs occur mainly in the 4th to 7th decade and show a spectrum of clinical features, ranging from incidental findings to presenting with hormonal excess syndromes or mass effects [4]. PitNETs occur equally in both sexes, with an overall predominance of ACTH secreting tumors in female patients, and non-functioning and lactotroph tumors more often resected in male patients. [4, 5 and 6]

The 2021 5th edition of the WHO classification of tumors of the central nervous system describes three main cell lineages as defined by expression of the following transcription factors: PIT1, SF1 and TPIT [4]. SF1 (steroidogenic factor 1) expression is seen in gonadotroph adenomas while TPIT (T box family member TBX19) expression is seen in corticotroph adenomas [4]. PIT1 (pituitary specific POU class homeodomain transcription factor) staining is observed in a broader spectrum of adenomas including, but not limited to somatotroph, mammosomatotroph, lactotroph and thyrotrophs adenoma [4]. Any of these tumors can be clinically non-functioning [4]. Tumors that do not express transcription factor are classified as null cell tumors [4].

As seen in the case presented, mammosomatotroph adenomas express PIT1, estrogen receptor (ER), prolactin and growth hormone (GH), and are distinguished from mixed somatotroph-lactotroph adenomas by the presence of coexpression of prolactin and GH in the same cells in the former entity as opposed to 2 distinct cell populations, one expressing GH and the other expressing prolactin, in the latter entity. Patients with mammosomatotroph adenomas often present clinically with acromegaly and hyperprolactinemia [4]. Corticotroph adenomas are TPIT positive adenomas that may secrete adrenocorticotropic hormone (ACTH) and are classified into 3 subtypes: 1) Densely granulated corticotroph tumor which are often small in size and are often associated with florid Cushing syndrome; 2) Sparsely granulated corticotroph tumor which are often larger in size and can be silent or show subtle manifestations of Cushing disease; and 3) Crooke cell tumor which are often large in size and associated with Cushing disease [4].

Very rarely, PitNETs can demonstrate multiple distinct cell lineages, as seen in the current case. These lesions are termed double or triple pituitary adenomas, and the synchronous clinical manifestation is extremely rare [2, 4, 7 and 8]. These tumors show different cell lineage and express several combinations of hormones with corresponding transcription factors (e.g., GH/ PIT1 and ACTH/TPIT) [4]. The clinical presentation of these multiple synchronous PitNETs is variable, with reports of acromegaly being the most common manifestation [7].

While the majority of PitNETs occur sporadically, a subset of PitNETs are associated with familial tumor syndromes, such as multiple endocrine neoplasia type 1 (MEN1), McCune-Albright syndrome, Carney complex, and familial isolated pituitary adenoma syndrome [11].   At the molecular level, activating GNAS mutations which can lead to the upregulation of the cAMP/PKA pathway is one of the most common somatic mutations seen in somatotroph adenomas [9]. Somatic mutation in the USP8 and USP48 genes have been observed in corticotroph adenomas [10].

The prognosis of PitNETs is believed to be associated with tumor recurrence [4]. Tumors with elevated proliferation activity are thought to be more aggressive and likely to recur [12], and five subtypes (sparsely granulated somatotroph adenomas, silent corticotroph adenomas, Crooke cell adenomas, poorly differentiated PIT1 lineage adenoma, and lactotroph adenoma in men) are currently recognized as being more prone to exhibit aggressive clinical behavior, as defined by resistance to treatment and/or early recurrence: [4].

References

  1. Vamvoukaki, R., Chrysoulaki, M., Betsi, G., & Xekouki, P. (2023). Pituitary Tumorigenesis-Implications for Management. Medicina (Kaunas, Lithuania), 59(4), 812. https://doi.org/10.3390/medicina59040812
  2. Hagel, C., Schüller, U., Flitsch, J., Knappe, U. J., Kellner, U., Bergmann, M., Buslei, R., Buchfelder, M., Rüdiger, T., Herms, J., & Saeger, W. (2021). Double adenomas of the pituitary reveal distinct lineage markers, copy number alterations, and epigenetic profiles. Pituitary, 24(6), 904–913. https://doi.org/10.1007/s11102-021-01164-1
  3. Agely, A., Okromelidze, L., Vilanilam, G. K., Chaichana, K. L., Middlebrooks, E. H., & Gupta, V. (2019). Ectopic pituitary adenomas: common presentations of a rare entity. Pituitary, 22(4), 339–343. https://doi.org/10.1007/s11102-019-00954-y
  4. Lopes MBS, Mete O, Osamura RY, et al. Pituitary adenoma / pituitary neuroendocrine tumour. In: WHO Classification of Tumours Editorial Board. Central Nervous System tumours. Lyon (France): International Agency for Research on Cancer; 2021. (WHO classification of tumours series, 5th ed.; vol. 6). Available from: https://tumourclassification.iarc.who.int/chaptercontent/45/191
  5. Fernandez, A., Karavitaki, N., & Wass, J. A. (2010). Prevalence of pituitary adenomas: a community-based, cross-sectional study in Banbury (Oxfordshire, UK). Clinical endocrinology, 72(3), 377–382. https://doi.org/10.1111/j.1365-2265.2009.03667.x
  6. Mete, O., Cintosun, A., Pressman, I., & Asa, S. L. (2018). Epidemiology and biomarker profile of pituitary adenohypophysial tumors. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, 31(6), 900–909. https://doi.org/10.1038/s41379-018-0016-8
  7. Mete, O., Alshaikh, O. M., Cintosun, A., Ezzat, S., & Asa, S. L. (2018). Synchronous Multiple Pituitary Neuroendocrine Tumors of Different Cell Lineages. Endocrine pathology, 29(4), 332–338. https://doi.org/10.1007/s12022-018-9545-4
  8. Collazo-Gutiérrez, N., de Jesús, O., Villamil-Jarauta, M., Alvarado, M., González, L., Ramírez, M., & Carlo-Chevere, V. J. (2019). Double Pituitary Adenomas with Synchronous Somatotroph and Corticotroph Clinical Presentation of Acromegaly and Cushing's Disease. World neurosurgery, 132, 161–164. https://doi.org/10.1016/j.wneu.2019.08.224
  9. Romanet, P., Galluso, J., Kamenicky, P., Hage, M., Theodoropoulou, M., Roche, C., Graillon, T., Etchevers, H. C., De Murat, D., Mougel, G., Figarella-Branger, D., Dufour, H., Cuny, T., Assié, G., & Barlier, A. (2021). Somatotroph Tumors and the Epigenetic Status of the GNAS Locus. International journal of molecular sciences, 22(14), 7570. https://doi.org/10.3390/ijms22147570
  10. Sbiera, S., Perez-Rivas, L. G., Taranets, L., Weigand, I., Flitsch, J., Graf, E., Monoranu, C. M., Saeger, W., Hagel, C., Honegger, J., Assie, G., Hermus, A. R., Stalla, G. K., Herterich, S., Ronchi, C. L., Deutschbein, T., Reincke, M., Strom, T. M., Popov, N., Theodoropoulou, M., … Fassnacht, M. (2019). Driver mutations in USP8 wild-type Cushing's disease. Neuro-oncology, 21(10), 1273–1283. https://doi.org/10.1093/neuonc/noz109
  11. Vasilev, V., Daly, A. F., Zacharieva, S., & Beckers, A. (2020). Clinical and Molecular Update on Genetic Causes of Pituitary Adenomas. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme, 52(8), 553–561. https://doi.org/10.1055/a-1143-5930
  12. McCormack, A., Dekkers, O. M., Petersenn, S., Popovic, V., Trouillas, J., Raverot, G., Burman, P., & ESE survey collaborators (2018). Treatment of aggressive pituitary tumours and carcinomas: results of a European Society of Endocrinology (ESE) survey 2016. European journal of endocrinology, 178(3), 265–276. https://doi.org/10.1530/EJE-17-0933