The Western variant shows a higher prevalence of cutaneous disease, a younger age, and a more indolent clinical course. Approximately 26% of these cases include cases with skin-limited disease.³ The Asian variant is more frequently linked to hemophagocytosis (HPC) and less commonly has cutaneous dissemination.^3,4,5

IVLBCL is very rare, with an estimated frequency of ∼1 person per million. IVLBCL occurs slightly more frequently in men (male-to-female ratio of 1.1:1) and most often in the setting of advanced age (median age 67 years; range, 41 to 85 years).⁶ Ferreri et al.³ showed that the cutaneous variant, which comprises 10 (26%) of 38 IVLBCL patients in Europe, is characterized by the exclusive limitation of tumors to the skin at presentation and has an invariably female predominance.

The delays at the diagnosis can be quite pronounced. In fact, in some of the original case series, the diagnosis was made only on autopsy specimens.⁷ Most cases, nowadays, are diagnosed on routine biopsies.

The etiology of IVLBCL is unclear. The most distinctive property of intravascular lymphoma (IVL) cells is their tendency to grow within blood vessel lumina without substantial extravasation. Neoplastic B cells in IVL may be able to adhere to endothelial cells, but they seem to lack critical adhesion molecules, such as CD29 (β1 integrin subunit), for extravasation. Besides adhesion, other molecular defects in diapedesis have also been implicated.⁸ The relationship of IVL and infectious organisms is not clear. It has been suggested that the “Asian variant,” which is typically linked to HPC, could be related to the endemic presence of helminthic infections, as suggested by the detection of serum antibodies to Fasciola and Anisakis in some patients.⁹ Association with HHV-8 infection or blastomycosis has also been reported.^10,11

Approximately 15% of cases of IVLBCL have an association with preceding or concomitant neoplastic disorders. IVLBCL is most frequently associated with non-Hodgkin lymphomas (NHLs), particularly diffuse large B-cell lymphoma (DLBCL).^12,13 Less frequent associations include chronic lymphocytic leukemia, follicular and mucosa-associated lymphoid tissue (MALT) lymphomas. Association with nonhematopoietic neoplasms such as renal cell carcinoma, meningioma, angioleiomyomas, and cutaneous hemangiomas has also been described.^14,15 Interestingly, in those cases associated to other malignancies, IVL cells are present also, if not preferentially, within tumor-associated vessels, thus suggesting the expression of particular molecules by this cancer-associated endothelium. IVL colonizing cutaneous hemangiomas have been reported in a number of occasions.^{16,17,18,19,20,21}

IVL can virtually involve any organ and, because of this, every protean clinical manifestations have been described. An isolated cutaneous variant comprising 26% of IVL patients had been recently identified.^3,22 This variant entails a 3-year survival rate of 56%, compared with the survival rate of 22% seen in disseminated cases.²² Patients with the cutaneous variant are younger and lack peripheral blood cytopenias.

Systemic symptoms such as fever, weight loss, and night sweats are seen in ∼55% of cases.⁸ The patients usually present nonspecific symptoms and show a marked deterioration in their performance status. In some cases, a persistent fever of unknown origin leads to a bone marrow biopsy and then to a diagnosis of IVL.^7,23

Cutaneous lesions are present in 40% of cases, and are more typical in the Western variant. The lesions are typically nodules and/or plaques (49%) or macules (22.5%) of red (31%) or blue to livid (19%) color on the leg (35%), the thigh (41%), and the trunk (31%). Telangiectasis is present in only 20% of the patients. Edema (27.5%) of the legs and pain (24%) are often accompanying features.²⁴ Other unusual clinical presentations described in the skin include purpuric lesions with leukocytoclastic vasculitis,²⁵ erythema nodosum–like forms,^26,27 retiform purpura,²⁸ generalized telangiectasias,^29,30 and inflammatory lymphedema.³¹

Bone marrow involvement is very frequently seen in the Asian subtype and often accompanied by HPC (61%), symptomatic anemia (66%), thrombocytopenia (58%), and sometimes leukopenia (27%), neurologic manifestations, or cutaneous lesions.^{3,4,5,6,32,33,34,35} Approximately 14% of cases (most of which are within the Asian variant) show a monoclonal paraprotein.⁶

In the Western variant, ∼32% of cases show bone marrow involvement, hepatosplenic infiltration, and thrombocytopenia. Central nervous system (CNS) involvement is seen in ∼34% of cases. Symptoms attributable to CNS involvement vary, with sensory and motor deficits, meningoradiculitis, paresthesias, aphasia, dysarthria, hemiparesis, seizures, myoclonus, transient visual loss, vertigo, sensory neuropathy, and altered conscious states.³⁶ Rare cases can present as mononeuritis multiplex.^37,38 Prostatic acid phosphatase (PAP) as a diagnostic and potential prognostic marker of IVL had been proposed^39,40 recently.

Other clinical abnormalities include respiratory symptoms, with frequent dyspnea and associated pleural effusions.³³ Involvement of endocrine organs, particularly adrenal^33,41,42,43 and pituitary⁴⁴ glands, is common. Other commonly involved organs include thyroid,⁴⁵ prostate,^46,47 vulva,⁴⁸ gallbladder,⁴⁹ lung,⁵⁰ breast,⁵¹ eye (choroides),⁵² and uterus.⁵³

HPC is linked to disseminated disease, higher soluble levels of IL-2, and lower albumin concentration, but also less peripheral blood involvement and lower creatinin levels.⁶ Although HPC does not appear to have prognostic value, its presence increases the likelihood of stage IV disease (100% vs. 76%), fever (92% vs. 42%), jaundice (17% vs. 0%), hepatic involvement (58% vs. 26%), splenic involvement (58% vs. 26%), marrow involvement (75% vs. 30%), thrombocytopenia (83% vs. 32%), elevated alanine aminotransferase levels (42% vs. 6%), and high bilirubin levels (42% vs. 2%).³