Primary cutaneous diffuse large B-cell lymphoma, leg type

Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) (also termed PCDLBCL, leg type or primary cutaneous DLBCL, leg type) is a

Most lymphomas begin in a lymph node, mucosa-associated lymphoid tissue, the spleen, or another lymphoid tissue within the lymphatic system and then may spread to the skin. In these cases the skin is a secondarily site of involvement. PCDLBC, LT is a primary cutaneous lymphoma, i.e. it begins in the skin and then may spread to lymphoid and/or non-lymphoid tissues in virtually any other site.^[6] A suspect PCDLBCL, LT that is not limited to the skin at the time of diagnosis should be regarded as some other variant or subtype of the diffuse large B-cell lymphomas.^[7]

PCDLBC, LT represents 5–10% of all primary cutaneous lymphomas.

Afflicted individuals (median age 76 years; range 49–92 years; more common in females[3]) typically present with one or more rapidly growing red to bluish-red, firm tumors located on the leg(s) at some site(s) below the knees.^[5] Occasionally the lesions are ulcerated.^[3] About 10% of cases do not have lesions on the legs but rather present with one or more skin lesions outside of the legs; ~20% of individuals present with cutaneous lesion(s) but on further or later investigation are found to have disease in non-cutaneous sites such as the lymph nodes, visceral organs,^[1] bone marrow, and/or, rarely, central nervous system.^[5] Some individuals, particularly those with widespread disease, complain of having the B symptoms of fever, night sweats, and/or weight loss.^[1] DLBCL cases that have cutaneous lesions in association with widespread disease may be advanced PCDLBCL, LT but without evidence that the disease began in the skin are diagnosed as having and treated for some other variant or subtype of the diffuse large B-cell lymphomas that has spread to the skin.^[7]

Pathophysiology

The neoplastic cells in DLBCL are derived primarily from either

• Overexpression of the
  protooncogene's product, Myc, encodes a transcription factor which regulates the expression of genes whose products stimulate cell proliferation and metastasis (i.e. spread to other tissues).^[10]
• Overexpression of the BCL2 gene (33% of cases) whose product, BcL2, inhibits apoptosis (i.e. programmed cell death) to thereby increase cell survival. "Double expresser lymphomas", i.e. those lymphomas with neoplastic cells that overexpress both Myc and Bcl2, are associated with a poor prognosis in PCDLBCL, LT.^[3]
• NF-kappa B signaling pathway. Both effects block apoptosis and thereby prolong cell survival.^[3]
• Mutations in the CD79B and CARD11 genes (rare cases) also lead to activation of the NF-kappa B signaling pathway.^[8]
• Overexpression of
  PD-L2 genes (frequent cases) due to their translocation (both genes are located on the long arm of chromosome 9 at position 24.1) or to overactivation of the JAK-STAT signaling pathway caused by mutations in the MYC gene, overexpression of MIr35A microRNA, or increased expression of cytokines (e.g. IL-10 or Interferon gamma) in the tumor environment.^[3] The products of these two genes, programmed death-ligand 1 and programmed cell death 1 ligand 2, respectively, inhibit the anti-tumor responses of cells in the immune system and thereby help the neoplastic cells to avoid immune surveillance.^[11]
• Mutations in the PIM1 gene occur occasionally. The product of this protooncogene, proto-oncogene serine/threonine-protein kinase Pim-1, is indirectly involved in, and can promote, the proliferation and survival of cells.^[6]
• tumor suppressor genes, CDKN2B and CDKN2A (11 and 44% of cases, respectively) stops the genes from expressing their products, cyclin-dependent kinase 4 inhibitor B and cyclin-dependent kinase inhibitor 2A, respectively. Both products act indirectly to limit the proliferation and survival of the neoplastic cells in PCDLBCL, LT^[5] Silencing the CDKN2A gene is associated with a poor prognosis in PCDLBCL, LT^[4] and appears to be involved in the development of various types of cancer.^[12]
• Various chromosome imbalances (i.e. abnormal numbers of chromosomes or parts of chromosomes) such as increases in chromosome 3, the long arm of chromosome 2 or 11, or the short arm of chromosome 7 and decreases in chromosomes 13, 14, or 19 or the short arm of chromosome 17 or the long arm of chromosome 6 occur in PCDLBCL, LT and are likely to cause gene abnormalities that help promote this disease's malignancy.[5]