Splenomegaly and white and red pulp expansion in p66Shc^−/− mice. (A) Representative image of spleen from age-matched control (+/+) or p66Shc^−/− (−/−) mice (left) and histogram showing the weight mean values (± SD; control, gray; p66Shc^−/−, black; right). Note the significant increase in size of the mutant spleen in p66Shc-deficient mice (n = 19; **P < .01). (B,C) Histologic analysis of spleen tissue from 12-month-old control (+/+) or p66Shc^−/− (−/−) mice. (B) Hematoxylin and eosin (H&E; top, 100×) and Giemsa (bottom, 50 ×) staining of spleen sections from 12-month-old control (+/+) or p66Shc^−/− (−/−) mice showing normal architecture in wild-type mice versus white pulp hyperplasia with florid germinal centers (GCs) in p66Shc^−/− mice (n ≥ 3). Average number of follicles per full longitudinal section (mean ± SD): 40.75 (± 14) in p66Shc^−/− mice versus 19.75 (± 4.4) in control mice; average number of germinal centers: 12.25 (± 3.3) in p66Shc^−/− mice versus 3.25 (± 1.1) in control mice (n = 4). Germinal centers were only sporadically observed in lymph node sections, without any significant difference between p66Shc^−/− and control mice (not shown). (C) Histologic analysis of splenic red pulp in 12-month-old control (+/+) or p66Shc^−/− (−/−) mice. The red pulp is characterized, in p66Shc^−/− mice, by largely increased extramedullary hematopoiesis (note the megakaryocytes and the islands of erythropoiesis; H&E, 100×, n ≥ 3).