Primary testicular diffuse large B-cell lymphoma
Primary testicular diffuse large B-cell lymphoma, also termed testicular diffuse large B-cell lymphoma and diffuse large B-cell lymphoma of the testes, is a variant of the diffuse large B-cell lymphomas. DLBCL are a large and diverse group of B-cell malignancies with the great majority being typed as diffuse large B-cell lymphoma, not otherwise specified. PT-DLBCL is a variant of DLBCL, NOS that involves one or, in uncommon cases, both testicles. Other variants and subtypes of DLBCL may involve the testes by spreading to them from their primary sites of origin in other tissues. PT-DLBCL differs from these other DLBCL in that it begins in the testes and then may spread to other sites.
The B-cells in PT-DLBCL are malignant lymphocytes that normally function in the humoral immunity component of the adaptive immune system by secreting antibodies that, for example, bind to and neutralize invasive pathogens. In ~75% of PT-DLBCL cases these malignant B-cells are termed "activated B-cells" to distinguish them from "germinal center B-cells". While DLBCL may involve either type of B-cell, the various forms and subtypes of the DLBCL that involve activated B-cells are more aggressive and may require different therapies than those involving germinal center B-cells.
Lymphomas that begin in the testes, i.e. primary testicular lymphomas, are rare forms of lymphoma that represent 1-2% of all non-Hodgkins lymphomas and 5% of all testicular malignancies. PT-DLBCL is by far the most common form of PTL, accounting for >85% all PTL cases. Other forms of PTL include testicular mantle cell lymphoma, extranodal marginal zone B cell lymphoma, extranodal NK/T-cell lymphoma, nasal type, peripheral T-cell lymphoma, activin receptor-like kinase-1–negative anaplastic large cell lymphoma, and pediatric-type follicular lymphoma. Some European investigators have combined PT-DLBCL and most of the latter lymphomas into a lymphoma group termed "non-Hodgkin's primitive lymphoma of the testes".
All forms of PTL except the pediatric-type follicular lymphoma are highly aggressive malignancies PT-DLBCL is no exception to this rule: it begins in a testis, often spreads to the contralateral testis as well as to the central nervous system and other sites, and commonly recurs following its treatment. In consequence, the disease has had a 5-year cause-specific survival of only ~60%. Addition of the immunotherapeutic drug, rituximab, to standard chemotherapy protocols has somewhat improved the treatment of most cases of this disease. In addition, clinical trials are testing new drugs for preventing relapses in, as well as treating, PT-DLBCL.
Presentation
PT-DLBCL is by far the most common form of testicular cancer in men >60 years of age. It usually develops in this age group and presents as a painless testicular mass or swelling in one testis or, in ~6% of cases, both testes: PT-DLBCL is the most common testicular cancer to present with disease in both testicles. About 30-40% of afflicted individuals present concurrently with hydrocele testis, i.e. an enlarged testis due to the accumulation of clear fluid. The tumors commonly increase in size at a rapid pace, may advance locally to involve the epididymis, spermatic cord, scrotal skin, and/or regional lymph nodes, and may cause sharp scrotal pain. About 10% to 33% of individuals have B symptoms such as fever, night sweats, and weight loss. Initial laboratory studies show increases in serum lactate dehydrogenase levels in a third of cases. Some 80% of individuals present with either localized Ann Arbor stage I or locally advanced Ann Arbor stage II disease. The remaining ~20% of cases have disseminated Ann Arbor stage III or IV disease that has spread to the abdominal lymph nodes, Waldeyr's ring of lymphoid tissue that surrounds the nasopharynx and oropharynx, contralateral testis, skin, lung, and, most seriously, the parenchyma of and/or the leptomembranes surrounding either the brain or spinal cord.Pathophysiology
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 ; inactivating mutations in the NLR family CARD domain containing 5 gene, NLRC5 ; 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, PIM1 and/or PIM2 genes, CARD11 gene, TNFAIP3 gene, and NFKBIZ gene the CD79B gene 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 ' the BCL2'' gene 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, 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 targets for treating the disease.