hemangiomas and angiolipomas. treatment and prognosis historically, individuals with the cutaneous variant survive significantly longer than that those with the classical variant (3 year overall survival 56% versus 22%). early intervention in the cutaneous variant would appear to be highly desirable. virtually all reports on the treatment of the cutaneous variant were made before rituximab was used to treat ivl. historically, patients with localized disease obtained prolonged remission with conventional chop therapy. however, individuals with single cutaneous lesions were long‐term survivors: when treated with just radiation therapy or surgical removal, these single-lesion patients had prolonged remissions both at initial diagnosis and after relapse. in contrast, patients with multiple lesions had a far worse outcome after treatment with chop: they had an objective response in 86% of cases but nonetheless the majority relapsed within a year of treatment with and only a few being successfully managed with salvage chemotherapy. rituximab may improve the latter situation. presentation the hemophagocytic syndrome-associated variant of ivbcl is a very rare variant of ivbcl. its previous name, intravascular large b-cell lymphoma, asian variant, was recently changed to its current name by the world health organization, 2016. unlike the classical and cutaneous variants, the hemophagocytic syndrome-associated variant presents with the hemophagocytic syndrome. this syndrome is characterized by bone marrow involvement, reduced numbers of circulating blood platelets as well as the reduced levels of other circulating blood cells, and enlarged liver and spleen. less often, it is also associated with overt hemophagocytosis (i.e. the engulfment by non-malignant histiocytes of red blood cells, white blood cells, platelets, and their precursor cells that is most commonly found in the bone marrow and other tissues. the syndrome often reflects excessive secretion of inflammatory cytokines and severe systemic inflammation similar to that seen in the cytokine storm syndrome. in general, individuals present with a rapidly progressive disease (median time from onset to diagnosis~4 weeks, range 2–12 weeks). patients are often extremely ill and experience multiple organ failures. diagnosis the diagnosis of the intravascular large b-cell lymphoma, hemophagocytic syndrome-associated variant depends on the individual presenting with clinical and laboratory findings compatible with the hemphagocytic syndrome (see previous section) and on the histology of biopsied tissues of the bone marrow, spleen, liver, brain, or other organ that clinical and/or laboratory findings suggest are involved in the disease. its histology is described in the diagnosis section of the classical variant but also includes the presence of hemophagocytosis, i.e. the engulfment of red blood cells and/or other mature and immature blood cells. hemophagocytosis can also be found in sites removed from the intravascular lesions such as the cerebrospinal fluid in patients with central nervous system involvement. treatment and prognosis prior to the use of rituximab, individuals with this variant generally followed a rapidly (i.e. weeks to months) fatal course even when treated with the chop regimen. however, addition of rituximab to the chop regimen appears to have improved the treatment of this disease. intravenous methotrexate may be a useful addition to the rituximab-chop regiment in individuals with central nervous system involvement. intravascular nk/t cell lymphomas pathophysiology three studies have examine gene mutations and gene expression abnormalities in ivnk/tl. a retrospective study of 25 patients identified numerous gene abnormalities including tumor-specific splicing alterations in oncogenes and tumor suppressor genes such as hras, mdm2, and vegfa as well as premature termination mutations or copy number losses in a total of 15 splicing-regulator genes such as sf3b5 and tnpo3. a study of two patients with ivnkl identified mutations in genes that produce histone proteins (hist1h2be, hist1h2bn and h3f3a), the histone deacetylase gene, hdac5, two genes that produce helicase proteins (wrn and ddx3x), two genes that make dna methylation-related enzymes (tet2 and dnmt1) and a gene in the swi/snf family of chromatin remodeling genes, arid1a. in a third study of a single patient, copy number analysis identified driver gene alterations in arid1b, hace1, and smad4 genes and gain of the sox2 gene. while further studies are needed before conclusions can be made, one or more of these gene abnormalities may contribute to the development and/or progression of ivnk/tl. the malignant nk and t cells that accumulate within the vascular of individuals with ivnk/tl are usually infected with the epstein–barr virus (ebv). this suggests that most ivnk/tl cases are examples of the epstein-barr virus-associated lymphoproliferative diseases and, like these diseases, are ebv-driven. about 95% of the world's population is infected with ebv. during the initial infection, the virus may cause infectious mononucleosis, only minor non-specific symptoms, or no symptoms. regardless of this, the virus enters a latency phase and the infected individual becomes a lifetime asymptomatic carrier of ebv. weeks, months, years, or decades thereafter, a small percentage of these carriers develop an ebv-associated lymphoproliferative disease, including in extremely rare cases ivnk/tl. ebv is well known to infect nk- and t-cells, to express some of its genes that promote the survival and proliferation of the cells it infects, and thereby to cause various and far more common nk- and t-cell lymphomas. it seems likely that the virus acts similarly to cause ivnk/tl. ivnk/tl may differ from the other types of nk- and t-cell lymphomas which ebv produces because its nk- and t-cells and nearby endothelial cells have defects in the expression of proteins required for the nk/t-cells to pass through the endothelium and into the surrounding tissues (see above section on the pathopysiology ivbcl). presentation individuals (age range 23–81 years) with ivnk/tl typically have a rapidly progressive disease. they commonly present with skin lesions, less commonly symptoms due to central nervous system involvement, and in a minority of cases symptoms due to the involvement of the bone marrow, liver, kidneys, ovaries, and/or cervix. they often show signs of an disseminated disease such as fever, weight loss, night sweats, arthralgias, jaundice, decreased numbers of circulating red blood cells, white blood cells, and/or platelets, bone marrow involvement as determined by biopsy, and signs/symptoms of multiple organ involvement. diagnosis the diagnosis of ivnk/tl depends upon obtaining histology findings in the skin and/or other involved tissue that resembles that seen in ivbcl except that the malignant lymphocytes are not b-cells but rather: 1) nk-cells as evidenced by their expression of nk-cell selective marker proteins (e.g. cd3e, cd2, cd30, cd43, cd56, and/or cd79), expression of granule-bound enzymes (e.g. granzyme b), and expression of ebv proteins (e.g. epstein–barr virus latent membrane protein 1 and ebv-produced small rnas); but not the expression of b-cell (e.g. cd20, cd79a, and pax5) or cytotoxic t cell marker proteins; and 2) cytotoxic t-cell lymphoma as evidenced by the neoplastic cells' expression of t-cell co-receptor proteins (e.g. cd3, cd4, and/or cd8) as well as ebv marker proteins and/or small rnas but usually not b-cell or nk-cell marker proteins. treatment and prognosis patients with ivnk/tl have been treated with various chemotherapy regimens, particularly chop or, less commonly, hypercvad. rare patients have been treated with chemotherapy followed by hematopoietic stem cell transplantation or chemotherapy plus a proteasome inhibitor, bortezomib. in general, patients have responded poorly to treatment, have short (i.e. up to 12 months) survival times regardless of the chemotherapy regimen used. rituximab does not target nk- or t-cells and therefore is not used to treat ivnk/tl.