Brain Pathology Case of the Month - March 2012


Atypical pituitary adenoma with prominent lymphocytes infiltration and germinal centers.


Pituitary neoplasms are the third most common intracranial tumor after meningioma and gliomas. Typically pituitary adenoma are composed of cells with uniform round nuclei, delicate stippled chromatin, inconspicuous nucleoli and moderate amount of cytoplasm. The mitoses are uncommon and the Ki-67 (MIB-1) labeling indices are usually less than 3%. Based on the 2004 edition of the WHO classification of tumors of endocrine organs, some pituitary tumors with features of atypical morphology, elevation of mitotic figures and a Ki-67 labeling index greater than 3%, as well as extensive diffuse nuclear staining of p53, are considered "atypical adenoma" (3). In this case, large pleomorphic tumor cells with prominent nucleoli were observed, as well as elevated Ki-67 labeling index to 15%. The diagnosis of pituitary carcinoma requires identification of distant metastasis. Mitotic figures, proliferating cell nuclear antigen (PCNA), Ki-67/MIB-1, and anti-apoptotic Bcl-2 have demonstrated no consistent correlation with tumor behavior (1). The DNA topoisomerase II alpha, a marker for cellular proliferation, as well as Galectin-3 (a marker for cellular differentiation and angiogenesis) have also been studied, but so far none correlated with the behavior of atypical adenomas (5, 6).

Lymphocytic infiltration is a rare finding in pituitary adenomas. Hassan M. et al. found that lymphocytic infiltration is rare in pituitary adenoma (2.9% in 1400 cases reviewed) and the frequency is not statistically different in major categories of secreting adenomas. It is noteworthy that in their report, no germinal center was ever found when cells were clustered and the lymphocytes were almost exclusively T cells (4). In the present case, the lymphocytes infiltration was either perivascular or in interstitial areas with frequent germinal center formation. The immunostaining for CD20 highlights nodular aggregation of B-cells that correspond to the germinal centers, while the CD3 highlights the T cells in the interfollicular area.

Tumors occurring in the pituitary stalk with prominent lymphocytic infiltration include pituitary adenomas, germinomas, and lymphocytic hypophysitis. Germinomas are composed of uniform large germ cells with prominent nucleoli and usually a dense lymphocytic infiltrate. The germinoma tumor cells often stain positive for either Placental alkaline phosphate (PLAP) or c-kit, or both. Serum and CSF assays for -fetoprotein and placental alkaline phosphatase are also helpful in preoperative diagnosis of a germ cell tumor. Lymphocytic hypophysitis is characterized by infiltration of the anterior pituitary gland by lymphocytes and plasma cells with destruction of the gland and eventual fibrosis. Germinal centers are occasionally identified. This condition is almost exclusively encountered in postpartum women (2). In summary, we have reported an atypical pituitary adenoma with prominent lymphocytic infiltration and germinal centers. The significance of lymphocytic infiltration in pituitary adenoma remains to be established.


  1. Amar AP, Hinton DR, Krieger MD, Weiss MH (1999) Invasive pituitary adenomas: significance of proliferation parameters. Pituitary 2:117-212
  2. Bellastella A, Bizzarro A, Coronella C, Bellastella G, Sinisi AA, De Bellis A (2003) Lymphocytic hypophysitis: a rare or underestimated disease? Eur J Endocrinol 149: 363-76.
  3. DeLellis RA, Lloyd RV, Heitz PU, Eng C (eds) (2004) World Health Organization classification of tumors: Tumors of endocrine organs. IARC, Lyons.
  4. Heshmati HM, Kujas M, Casanova S, Wollan PC, Racadot J, Van Effenterre R, Derome PJ, Turpin G (1998) Prevalence of lymphocytic infiltrates in 1400 pituitary adenomas. Endocr J. 45:357-61.
  5. Riss D, Jin L, Qian X, Bayliss J, Scheithauer BW, Young WF Jr, Vidal S, Kovacs K, Raz A, Lloyd RV (2003) Differential expression of galectin-3 in pituitary tumors. Cancer Res 63:2251-2255.
  6. Vidal S, Kovacs K, Horvath E, Rotondo F, Kuroki T, Lloyd RV, Scheithauer BW (2002) Topoisomerase II alpha expression in pituitary adenomas and carcinomas: relationship to tumor behavior. Mod Pathol 15:1205-12.

Contributed by Fang-Yi Lee, MD, Mei-Chin Wen, MD, John-Wang, MD, PhD

International Society of Neuropathology