Central Nervous System Manifestations of Cutaneous Lymphomas

Primary cutaneous lymphomas (PCL) are an uncommon malignancy of the lymphocytes, primarily presenting with dermatologic lesions. Central nervous system(CNS) metastatic manifestations, are even rarer. This review focus mainly on three aspects namely early suspicion of CNS involvement, selection of cases for CNS chemo-prophylaxis and lastly, the rare occurrence from skin straight to brain without other organ involvement.

Primary extranodal large B-cell lymphomas are very heterogeneous. Recent molecular data have thrown some light on such divergent clinical behaviour. The peculiar, stage-independent risk of CNS spread in testicular, breast, uterine, and possibly Primary Cutaneous Diffuse Large B Cell Lymphoma Leg type (PCDBLCL-LT), may be related to prevalent MCD (MYD88/CD79B-mutated) genomic subtype in these lymphomas. It remains to be seen how this genotype might facilitate invasion of the CNS parenchyma, and whether therapies targeting the B-cell receptor or NF-κB signalling pathways could lower the risk. Some sites of extranodal involvement, almost always indicate disseminated disease with a high propensity to invade the bone marrow and leptomeningeal compartments, particularly in double-hit lymphoma. Conversely, unifocal bone, craniofacial, thyroid, or gastric DLBCL show a relatively favourable prognosis with standard immunochemotherapy. Their risk of CNS recurrence might be largely driven by potential local invasion due to anatomic proximity when epidural, orbital, or skull involvement is present, thus requiring a case-by-case approach to prophylaxis. Future studies can help clarify the relationship between extranodal DLBCLs and their indolent MALT counterparts, and whether the favorable behavior of some ABC-like lymphomas (Activated B-cell-like (ABC) diffuse large B-cell lymphomas (e.g. in the stomach or craniofacial sites) might be explained by less aggressive genotypes (e.g. BCL6/NOTCH2 subtype). MALT lymphoma is a type of non-Hodgkin lymphoma (NHL) that starts in the mucosa lining some body organs and cavities. It is a type of NHL called marginal zone lymphoma. PCL can be defined as non-Hodgkin lymphomas that initially present in the skin without any extra cutaneous manifestations at the time of diagnosis. The skin is the second most common site of occurrence of non-Hodgkin lymphomas, second only to the lymphatic system. PCL can be broadly divided into two types-T cell lymphomas and B cell lymphomas.Major subtypes of T cell lymphomas include mycosis fungoides (MF) and its variants, Sezary syndrome, CD30 + lymphoproliferative disorders, and other more rare entities like subcutaneous panniculitis- like T-cell lymphoma, extranodal NK/T cell lymphoma nasal type, primary cutaneous peripheral T-cell lymphoma not otherwise specified, and adult T-cell leukemia/lymphoma. Cutaneous B-cell lymphomas comprise approximately 25% of all cutaneous lymphomas. There are three main morphologic groups: primary cutaneous marginal zone lymphoma, cutaneous follicle-centre lymphoma, and diffuse large B-cell lymphoma, leg type(DLBCL). Other subtypes include - DLBCL other type (non-leg), and intravascular large B-cell lymphoma. Immunohistochemically cutaneous marginal zone lymphoma is classically bcl-2 positive and bcl-6 negative. This condition has an excellent prognosis, with five-year disease related survival noted to be > 95%. Primary cutaneous follicle-centre lymphoma is a lymphoma of cells of the follicle centre, usually including a combination of centrocytes and centroblasts. Immunohistochemically, the neoplastic follicle cells express bcl-6, and expression of bcl-2 is typically absent or faint. Prognosis is again excellent, with five-year disease related survival noted to be over 95%. Primary cutaneous diffuse large B-cell lymphoma, leg type is a neoplastic disorder of centroblasts and immunoblasts, which typically presents as a red to violaceous nodules or tumours on the lower extremities. Phenotypically, bcl-2 and bcl-6 are often expressed, as is MUM-1. Extracutaneous disease is common, with these tumours having a relatively high propensity to disseminate. Prognosis is variable with disease related 5-year survival being 40-50% in patients with multiple lesions at time of diagnosis, to 100% in those patients that present with a single lesion. Other, rare large B-cell lymphomas can also present in the skin. Intravascular large B-cell lymphoma is a subtype in which neoplastic B-cells have accumulated within blood vessels and often affect many organ systems (including brain), however rarely skin lesions only can occur. CNS involvement is uncommon in both types of cutaneous lymphomas and overall prognosis is not good. Brain masses and meningeal infiltration are the usual patterns though imaging may be negative with demonstration of lymphoma cells only in the CSF by flow cytometry. At times, no other organ involvement may be noted, albeit very rarely. Selection of patients who might benefit with CNS prophylactic agents is of utmost importance. On the whole, most cases of high grade cutaneous DLBCLs need to have CNS chemo-prophylaxis.