PT-DLBCL develops in an immune privileged site, the testis, which lies within the blood-testes barrier. Immune privileged sites are sanctuaries where abnormal antigens that occur in them, such as those that are expressed on cancer cells, do not evoke the development-suppressing and growth-suppressing actions of the immune surveillance system. Since PT-DLBCL often spreads from its origin in one testicle to other immune privileged sites such as the central nervous system and the contralateral testicle, the disease's development and/or progressive seems to depend on evading immune attack. Additionally, the neoplastic B-cells in this disease acquire abnormalities in their expression of certain genes that further allow them to escape immune responses. They have loss of function mutations in the beta-2 macroglobulin gene, B2M (~17% of cases); inactivating mutations in the NLR family CARD domain containing 5 gene, NLRC5 (10% of cases); and gains in the number of copies of DNA stretches in the long arms of chromosome 18 at position 13.1 and chromosome 12 at position 13,42 which lead to the overexpression of leukocyte immunoglobulin-like receptor subfamily A member 3 gene, LILRA3. These and possibly other unidentified gene abnormalities cause the complete lose of the expression of MHC class I and MHC class II proteins in >65% of all PT-DLBCL cases. MHC class I and II proteins are required for immune cells to identify and attack them. The neoplastic B cells in PT-DLBCL also show gains and amplifications of CD274 and PDCD1LG2, which are the genes for the pro-death ligands, PDL1 and PDL2, respectfully. Overexpression of these ligand proteins inhibits the immune responses of various cell types. The neoplastic cells in PT-DLBCL have deletions in one or both copies of the CDKN2A gene which can lead to genome instability, i.e. a high rate of acquisition of other genetic abnormalities. These cells also have acquired mutations in: 1) the MYD88 gene (~83% of cases), PIM1 and/or PIM2 genes (~73% of cases), CARD11 gene (~16% of cases), TNFAIP3 gene (3-15% of cases), and NFKBIZ gene (~40% of cases), any one of which can lead to overaction of the NF-κB signaling pathway and thereby prolong cell survival; 2) the CD79B gene (~50% of cases) which can lead to overactivation of B-cell receptor signaling pathways and thereby stimulation of cellular proliferation and survival. 3) the genes for AKT1, AKT2, and PIK3CB, any one of which can lead to overactivation of the PI3K/AKT/mTOR signaling pathway and thereby excessive cellular proliferation and survival; 4) the MYC gene (~15% of cases) which can lead to increased cellular proliferation; and 5) the BCL2 gene (~10% of cases) which leads to prolonged cell survival. These data suggest that in PT-DLBCL B-cells sequestered in an immune privileged testicular environment acquire a series of genetic abnormalities that promote their genetic instability (i.e. development of more genetic abnormalities), further escape the immune system, and dysregulate key signaling pathways that stimulate their proliferation, survival, and other pro-malignant behaviors. Some of these genetic abnormalities and dysregulated signaling pathways are potential<unk> ts for treating the disease.
Primary testicular diffuse large B-cell lymphoma
Testicular sarcoidosis
Transitional cell carcinoma of the ovary
Renal medullary fibroma
Renal anaplastic sarcoma
Metanephric adenoma
Multilocular cystic renal cell carcinoma
Renal cell carcinoma with t