Primary Cutaneous Diffuse Large B-cell Lymphoma

Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) (also termed PCDLBCL, leg type or primary cutaneous DLBCL, leg type) is a cutaneous lymphoma skin disease that occurs mostly in elderly females. In this disease, B cells (a type of lymphocyte) become malignant, accumulate in the dermis (i.e. the layer under the epidermis) and subcutaneous tissue below the dermis to form red and violaceous skin nodules and tumors. These lesions typically occur on the lower extremities but in uncommon cases may develop on the skin at virtually any other site. In ~10% of cases, the disease presents with one or more skin lesions none of which are on the lower extremities; the disease in these cases is sometimes regarded as a variant of PCDLBL, LT termed primary cutaneous diffuse large B-cell lymphoma, other (PCDLBC-O). PCDLBCL, LT is a subtype of the diffuse large B-cell lymphomas (DLBCL) and has been thought of as a cutaneous counterpart to them. Like most variants and subtypes of the DLBCL, PCDLBCL, LT is an aggressive malignancy. It has a 5-year overall survival rate of 40–55%, although the PCDLBCL-O variant has a better prognosis than cases in which the legs are involved.

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. 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.

PCDLBC, LT represents 5–10% of all primary cutaneous lymphomas. It is to be distinguished from two other primary cutaneous lymphomas that involve B-cells, primary cutaneous follicle center lymphoma (PCFCL) and primary cutaneous marginal zone lymphoma (PCMZL), as well as from a B-cell lymphoma that at diagnosis may appear to be limited to the skin but often is a systemic disease affecting numerous organs and tissues viz., intravascular large B-cell lymphoma (IVLBCL). These three B-cell lymphomas differ from PCDLBCL, LT in numerous ways but most importantly in their aggressiveness. IVLEBC is, like PCDLBCL, LT, an aggressive disease with a guarded prognosis, but unlike the former disease, is often widely disseminated at presentation. PCFCL and PCMZL, in contrast, are indolent lymphomas with a relatively good prognosis. Distinguishing between these four cutaneous B-cell lymphomas at the time of diagnosis is critical for their appropriate treatment.

Presentation

Afflicted individuals (median age 76 years; range 49–92 years; more common in females) 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. Occasionally the lesions are ulcerated. 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, bone marrow, and/or, rarely, central nervous system. Some individuals, particularly those with widespread disease, complain of having the B symptoms of fever, night sweats, and/or weight loss. 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.

Pathophysiology

The neoplastic cells in DLBCL are derived primarily from either germinal center B cells (i.e. GBC) or activated B cells (i.e. ABC) with ABC-based DLBCL usually being a more aggressive disease than GBC-based DLBCL. The neoplastic cells in PCDLBCL, LT are ABC, bear gene abnormalities similar to those found in ABC-based DLBCL, and as a likely result of this produce an aggressive disease. The potentially pathogenic gene abnormalities in the neoplastic cells of PCDLBCL, LT include:
* Overexpression of the '' MYC'' gene caused by its mutation and/or translocation occurs in ~50% of cases. This 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).
* 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.
* Loss of function mutations in the '' TNFAIP3'' gene (40% of cases) whose product, tumor necrosis factor, alpha-induced protein 3, acts indirectly to inhibit TNF-mediated apoptosis and to activate the NF-kappa B signaling pathway. Both effects block apoptosis and thereby prolong cell survival.
* Mutations in the '' CD79B'' and '' CARD11'' genes (rare cases) also lead to activation of the NF-kappa B signaling pathway.
* Overexpression of '' PD-L1'' and ''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. 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.
* 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.
* Hypermethylated of the promoters for two 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 Silencing

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