INTRODUCTION — Intravascular large cell lymphoma (ILCL) is a rare subtype of large cell lymphoma that is characterized by the proliferation of lymphoma cells within the lumina of small blood vessels, particularly capillaries and post-capillary venules, without an obvious extravascular tumor mass or readily observable circulating lymphoma cells in the peripheral blood.
This type of lymphoma has also been described as intravascular lymphomatosis, angiotropic large cell lymphoma, and malignant angioendotheliomatosis. The clinical presentation is varied and often includes symptoms related to organ dysfunction caused by occlusion of blood vessels. Particularly in the past, the diagnosis was usually only recognized at autopsy. In recent years, the heightened awareness of ILCL has resulted in more patients being diagnosed during life, thereby allowing for treatment.
Most information on ILCL comes from case reports and small case series of patients. In addition, an expert panel of pathologists and clinicians, convened under the sponsorship of the International Extranodal Lymphoma Study Group, has proposed practical guidelines [1].
The clinical presentation, diagnosis, and treatment of ILCL will be discussed here. Other types of large cell lymphoma are presented separately. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma" and "Initial treatment of advanced stage diffuse large B cell lymphoma".)
SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The coronavirus disease 2019 (COVID-19) pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. These issues and recommendations for cancer care during the COVID-19 pandemic are discussed separately.
●(See "COVID-19: Considerations in patients with cancer".)
EPIDEMIOLOGY — ILCL is a rare subtype of large cell lymphoma; the true incidence is unknown. Median age at diagnosis is in the sixth to seventh decades; there is no sex predilection [2-4].
CLINICAL PRESENTATION — Patients can present with a bewildering array of symptoms caused by the occlusion of small vessels.
Symptoms — Constitutional B symptoms (ie, fever, night sweats, and weight loss) are seen in the majority of patients (55 to 85 percent) [2-4]. The clinical presentation appears to differ by country of origin, although individual presentations vary tremendously and virtually any organ can be involved:
●In Western countries, patients present most commonly with symptoms related to involvement of the central nervous system (39 to 76 percent) and skin (17 to 39 percent) [2,5]. Fever, skin lesions, and prominent, rapidly progressive neurologic signs (eg, dementia, progressive cerebral vascular accident, peripheral neuropathy) are frequent [2,5-7]. Less commonly involved tissues include the bone marrow (32 percent), spleen (26 percent), and liver (26 percent) [2].
●In Asia, neurological symptoms (27 percent) and cutaneous lesions (15 percent) are less common than in Western countries [8]. Patients frequently present with involvement of the bone marrow (75 percent), spleen (67 percent), and liver (55 percent) [3,9-11]. Hemophagocytic syndrome, a condition stemming from systemic macrophage activation that is associated with B symptoms and the hemophagocytosis of red cells, white blood cells, and/or platelets, can be seen [9]. (See "Treatment and prognosis of hemophagocytic lymphohistiocytosis".)
There is a cutaneous variant of ILCL that presents with symptoms limited to the skin [2]. This variant is seen more frequently in Western countries (24 percent) and is rare in Asia (3 percent) [1]. Patients are mostly younger females with good performance status [2]. Skin lesions are most commonly nodules, plaques, or macules of red to grayish-blue color on the leg (35 percent), thigh (41 percent), and trunk (31 percent) [12]. Telangiectasia, edema, and pain are often seen concomitantly, making it difficult to differentiate cutaneous ILCL from inflammatory skin diseases such as thrombophlebitis or erythema nodosum. To date, no criteria enable clinical distinction between ILCL restricted to the skin and skin lesions concurrent with ILCL in other organs.
Laboratory studies — Patients often present with the following laboratory abnormalities [1,2,5]:
●Elevated serum lactate dehydrogenase (LDH), beta-2 microglobulin, elevated sedimentation rate, C-reactive protein
●Anemia
●Altered hepatic, renal, or thyroid function
●Serum monoclonal protein
Patients from Western countries and Asian countries differ in their rates of thrombocytopenia (29 versus 76 percent) and hypoalbuminemia (18 versus 84 percent).
Anti-proteinase-3-anti-neutrophil cytoplasmic antibodies (ANCA) have been reported in patients with ILCL (which may be related to endothelial damage); this finding may delay the diagnosis [13-15].
PATHOLOGY — Involved tissues demonstrate neoplastic lymphoid cells lodged in the capillaries and post-capillary venules (picture 1). Malignant cells also may be found, albeit rarely, in cerebrospinal fluid or peripheral blood; bone marrow involvement varies with geographic location [16]. Like other subtypes of large cell lymphoma, the morphology varies; most often the lymphoid cells are large in size, have vesicular nuclei and prominent nucleoli (picture 2). Frequent mitotic figures are seen. Ki-67 staining demonstrates high proliferative activity. Immunophenotyping usually identifies the cells to be mature B cells; such cases can be considered an intravascular variant of diffuse large B cell lymphoma. Rare cases of ILCL are of T cell or NK cell origin [17,18]. A subset of the cases associated with hemophagocytic syndrome is positive for Epstein-Barr virus infection. An intravascular gamma-delta T cell lymphoma has been described [19]. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'Pathology' and "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'Diagnosis'.)
In the skin, intravascular neoplastic lymphoid cells may be accompanied by reactive perivascular infiltrates of small lymphocytes and plasma cells (picture 3) [12]. Vessels containing lymphoma cells may be very few in number and can be located anywhere in the skin and subcutaneous tissue.
Relatively little is known about the genetics of ILCL. Case studies have identified diverse translocations involving oncogenes implicated in other B cell lymphomas, including BCL2, BCL6, and CCND1 (cyclin D1) [20-22]. A series of seven cases with abnormal karyotypes revealed complex chromosomal aberrations in all cases, including recurrent abnormalities involving chromosome 6q13, chromosome 8p11.2, and chromosome 19q13 [23]. Targeted exon sequencing of a series of 25 B cell tumors detected mutations in genes that encode B cell receptor signaling pathway components, particularly MYD88 (44 percent) and CD79B (26 percent) [24]; this finding is consistent with an origin from a non-germinal center B cell. Analysis of the genetics of 21 additional cases of B cell ILCL based on sequencing of cell-free DNA from peripheral blood confirmed the presence of frequent mutations in MYD88 (57 percent) and CD79B (67 percent) and also identified 38 percent with mutations involving the genes encoding PD-L1 or PD-L2, suggesting that immune evasion may have a pathogenic role in ILCL [25].
DIAGNOSIS — The diagnosis of ILCL is made by identifying large lymphoma cells within small to medium blood vessels [1].
When the diagnosis of ILCL is suspected, biopsies of involved skin, senile hemangiomata (if present), or random biopsies of apparently normal skin may be diagnostic [26-36]. Incisional biopsies are preferable to punch biopsies [37]. Deep skin biopsies must be performed because involved blood vessels are mostly in the subcutaneous fat [12]. The yield from random skin biopsies is controversial, but some experts advocate that random skin biopsies should include at least three specimens (eg, from both thighs and abdomen) [33,38-40]. In cases of suspected brain involvement of intravascular lymphoma, skin biopsies should be performed before brain biopsies [41].
Other sites may be biopsied if skin biopsies are non-diagnostic, especially if there is evidence of organ dysfunction. Case reports describe diagnostic specimens from liver, lung, and brain [1,26,30,42]. Although commonly involved in other subtypes of lymphoma, bone marrow, lymph nodes, peripheral blood, and cerebrospinal fluid are often uninvolved in ILCL [43]. Involvement of these sites can be subtle, and stains for lymphoid markers (eg, CD20) may detect rare tumor cells within small vessels that are missed by morphology alone. As discussed above, bone marrow involvement is more frequent in the so-called Asian variant of ILCL. (See 'Symptoms' above.)
Immunophenotyping of intravascular lymphoid cells is required to distinguish intravascular large B cell lymphoma (ILBL) from T cell or NK cell ILCL. The rare NK/T cell phenotype (positive for CD2, cytoplasmic CD3, CD56 and cytotoxic proteins such as granzyme B, and negative for CD20, surface CD3, CD4, CD8, and CD5) reveals lymphoma cells that are positive for Epstein-Barr virus antigens; such cases usually follow an aggressive course [44,45]. Ki-67 proliferation index was reported to be an independent risk factor for duration of survival [46]. Double expressor status (ie, C-MYC plus BCL2) may also be a prognostic indicator, with higher mortality compared with non-double expressors [47].
DIFFERENTIAL DIAGNOSIS — On occasion, clusters of activated lymphocytes may be observed within the post-capillary venules of tissues involved in inflammatory or immune reactions, particularly the lymph nodes. On purely morphologic grounds, these may be difficult to distinguish from focal involvement by ILCL. As noted above, however, most patients with ILCL have systemic constitutional symptoms, laboratory abnormalities, and evidence of organ dysfunction, all of which are typically associated with extensive intravascular disease in extranodal organs, allowing for the diagnosis to be established on clinicopathologic grounds.
Intralymphatic histiocytosis is a reactive condition of macrophages associated with rheumatoid arthritis that may present with clinical lesions similar to those of ILCL and with intravascular proliferations of large cells. Intralymphatic histiocytosis can be differentiated from ILCL by immunophenotyping, which will demonstrate expression of macrophage-specific markers (eg, CD68) and absence of lymphoid markers [48].
Recently, a benign atypical intravascular CD30+ T cell proliferation was described, in which CD30+ polyclonal T cells (Epstein-Barr virus negative) are found within lymphatics in close vicinity to ulceration or an inflammatory skin disease [49].
PRETREATMENT EVALUATION — The pretreatment evaluation both determines the extent of the disease and provides information about the individual's comorbidities that are likely to have impact on treatment options. In general, the pretreatment evaluation is the same as that performed for patients with diffuse large B cell lymphoma. This is presented in detail separately. Of note, patients with intravascular large B cell lymphoma have a high rate of central nervous system involvement. As such, we typically evaluate the central nervous system with a lumbar puncture and magnetic resonance imaging (MRI) of the brain. (See "Initial treatment of advanced stage diffuse large B cell lymphoma", section on 'Pretreatment evaluation'.)
TREATMENT — The treatment of patients with ILCL includes both systemic therapy and therapy directed at the central nervous system.
Systemic therapy — Due to the presence of lymphoma cells within the blood vessels, all cases of ILCL are considered disseminated and are therefore treated as advanced disease. Only case reports and retrospective analyses have been reported on the treatment of ILCL. Most patients diagnosed with intravascular large B cell lymphoma (ILBL) are treated with regimens used for the treatment of diffuse large B cell lymphoma. Specifically, a combination of cyclophosphamide, doxorubicin, vincristine, and prednisone with the recombinant anti-CD20 antibody rituximab (R-CHOP) is the most commonly employed treatment (table 1). (See "Initial treatment of advanced stage diffuse large B cell lymphoma".)
Anthracycline-based chemotherapy (eg, CHOP, CHOP-R) can achieve response rates in >60 percent and estimated three-year overall survival >30 percent; long-term survival appears to be possible [1,2,4,5,28,50-53].
Support for the use of rituximab plus anthracycline-based chemotherapy comes from case reports and retrospective studies [1,2,4,28,50-53]. The largest retrospective analysis of treatment included 106 patients with newly diagnosed ILBL treated either with chemotherapy alone (57 patients) or chemotherapy plus rituximab (49 patients) [4]. Approximately 83 percent of the patients received CHOP or CHOP-like chemotherapy with or without rituximab. There was no difference in the rate of treatment-related deaths. At a median follow-up of 18 months, patients treated with chemotherapy plus rituximab had significantly higher rates of:
●Complete response (82 versus 51 percent)
●Two-year progression-free survival (56 versus 27 percent)
●Two-year overall survival (66 versus 46 percent)
CNS directed therapy — Central nervous system (CNS) involvement is seen in 30 to 40 percent of patients with ILBL at diagnosis and occurs in another 25 percent of patients during follow-up [8]. Systemic therapy with R-CHOP does not sufficiently penetrate the CNS, therefore patients with ILBL also require therapies directed towards the CNS, either as prophylaxis for or treatment of CNS involvement. As mentioned above, the pretreatment evaluation includes a lumbar puncture and magnetic resonance imaging (MRI) of the brain. CNS-directed therapy is determined based on the results of these tests:
●For patients without tumor cells in the cerebrospinal fluid (CSF) and normal imaging by MRI, we administer CNS prophylaxis. (See "Secondary central nervous system lymphoma: Treatment and prognosis".)
●For patients with secondary involvement of the brain or spinal cord at the time of diagnosis, we administer specific treatment targeting these areas. Such treatment varies based on the exact disease site, but can include intrathecal chemotherapy, systemic high dose methotrexate, and/or radiation to the sites of involvement. The treatment of CNS involvement is presented in detail separately. (See "Secondary central nervous system lymphoma: Clinical features and diagnosis".)
Patients with neurologic compromise from spinal cord compression require urgent therapy. The timing of chemotherapy and radiation therapy is controversial; however, many patients are treated with radiation therapy prior to receiving systemic therapy. The benefit of intrathecal therapy, particularly in the presence of a normal spinal fluid evaluation, is unclear. (See "Treatment and prognosis of neoplastic epidural spinal cord compression".)
EVALUATION OF RESPONSE — One month following the completion of planned therapy (or sooner if the outcome is unfavorable), the response to treatment should be documented by history, physical examination, and laboratory studies (complete blood count, lactate dehydrogenase, and biochemical profile). Positron emission tomography/computed tomography (PET/CT) should be obtained six to eight weeks after completion of chemotherapy and 12 weeks after the completion of radiation therapy [54-56]. PET/CT imaging obtained earlier than this is likely to demonstrate increased uptake due to an inflammatory reaction to treatment.
Given its unusual initial presentation and location of disease, the response criteria used for other types of non-Hodgkin lymphoma may not apply. Instead, prospective studies have used the following criteria for response [4]:
●Complete response – Disappearance of all clinical symptoms and radiographic or laboratory abnormalities, including bone marrow involvement, observed at diagnosis and the absence of any new abnormalities.
●Progressive disease – Appearance of new abnormalities associated with the disease or evident deterioration of the initial abnormalities associated with the disease.
●Stable disease – Failure to achieve a complete response and lack of progressive disease.
Relapsed disease occurs when there is progression of the disease after an initial complete response.
PATIENT FOLLOW-UP — Although follow-up data are scarce, relapses may be more common in those with central nervous system involvement and less common in those with cutaneous involvement [1]. When the disease is restricted to the skin, the prognosis seems to be favorable [12].
Following the completion of therapy, restaging, and documentation of complete remission, patients are seen at periodic intervals to monitor for treatment complications and assess for possible relapse. The frequency and extent of these visits depends on the comfort of both the patient and physician. There have been no prospective, randomized trials comparing various schedules of follow-up. When planning the post-treatment surveillance strategy, care should be taken to limit the number of CT scans, particularly in younger individuals, given concerns about radiation exposure and the risk for second malignancies. (See "Radiation-related risks of imaging".)
Our approach to patient surveillance is to schedule patient visits every three months during the first year, every three to six months during the second year, and every six months starting two years after complete response. At these visits we perform a history and physical examination, complete blood count, chemistries, and lactate dehydrogenase. We do perform CT scans at months 6, 12, 18, 24, 30 or 36, and then yearly until five years after attainment of a complete remission. No more imaging is performed after five years unless an abnormality suggests the possibility relapse or the patient requests it.
Relapsed disease can be suggested by changes on imaging studies but can only be confirmed by biopsy. As such, a biopsy should always be obtained to document relapsed disease before proceeding to salvage therapy. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in medically-fit patients".)
SUMMARY — Intravascular large cell lymphoma (ILCL) is a rare subtype of large cell lymphoma that is characterized by the proliferation of lymphoma cells within the lumina of small blood vessels, particularly capillaries and post-capillary venules, without an obvious extravascular tumor mass or detectable circulating tumor cells in the peripheral blood.
●Patients present with a bewildering variety of symptoms caused by the occlusion of small vessels. These include constitutional B symptoms (ie, fever, night sweats, and weight loss), rapidly progressive neurologic signs (eg, dementia, progressive cerebral vascular accident, peripheral neuropathy), and skin lesions imitating inflammatory skin conditions such as thrombophlebitis and erythema nodosum. Laboratory abnormalities increased lactate dehydrogenase (LDH) and beta-2 microglobulin, anemia, and an elevated sedimentation rate. (See 'Clinical presentation' above.)
●The diagnosis of ILCL is made by demonstrating large lymphoma cells within small to medium blood vessels. If the diagnosis is considered, deep biopsies of lesional skin or random biopsies of "normal" skin without any obvious abnormality may be diagnostic. If this does not yield a diagnosis, biopsy of other sites of suspected involvement may be undertaken in the appropriate clinical setting. (See 'Pathology' above and 'Diagnosis' above.)
●The treatment of patients with intravascular large B cell lymphoma (ILBL) includes both systemic therapy and therapy directed at the central nervous system (CNS). (See 'Treatment' above.)
•For patients with ILBL, we suggest initial treatment with a combination of cyclophosphamide, doxorubicin, vincristine, and prednisone with the recombinant anti-CD20 antibody rituximab (R-CHOP) (table 1) (Grade 2B). (See "Initial treatment of advanced stage diffuse large B cell lymphoma".)
•For patients without tumor cells in the cerebrospinal fluid and normal imaging by MRI, we generally recommend CNS prophylaxis. (See "Secondary central nervous system lymphoma: Treatment and prognosis".)
•For patients with secondary involvement of the brain or spinal cord at the time of diagnosis, we administer specific treatment targeting these areas. Such treatment varies based on the exact disease site, but can include intrathecal chemotherapy, systemic high dose methotrexate, and/or radiation to the sites of involvement. The treatment of CNS involvement is presented in detail separately. (See "Secondary central nervous system lymphoma: Clinical features and diagnosis" and "Secondary central nervous system lymphoma: Treatment and prognosis".)
