Among the 11 reported cases of IVNKL, including the cases originally published in English and ours, six (54.5 %) were reported from Asia (2 from China, 2 from Taiwan, 1 from Japan and 1 from Korea), which is consistent with the distribution characteristics of extranodal NK/T-cell lymphoma, nasal type, which has a higher incidence in East Asia and Latin America, with EBV infection occurring in some cases . Of the 11 patients, six were female and five were male. The ages ranged from 23 to 72 years (median, 47 years). Dermatological manifestations were observed in 10 (91 %) cases. Multisystem involvement occurred in 5 patients, and 4 of 5 were CNS involvement. After a follow-up that ranged from half a month to 17 months, 7 of 11 patients died, and only 4 of 11 experienced temporary remission.
In the 11 cases in which the morphology of the IVNKL was described, the tumor cells were all confined within the vessels and had large cell sizes with pale or eosinophilic cytoplasms and irregular hyperchromatic nuclei. Mitotic figures and necrosis were routinely observed. In all 11 cases, typical NK cell immunophenotypes were observed: CD3+; CD56+; TIA-1+; granzyme B+; perforin+; CD4-; CD5-; CD8- and CD20-. EBER detection was performed in 11 cases and was positive in 10 of the 11 cases, indicating Epstein-Barr virus (EBV) infection. T-cell gene rearrangement analysis was performed in 7 of the 11 cases and was negative, confirming an NK-cell origin.
For diagnosis, large neoplastic lymphoid cells of IVNKL are restricted to the lumen of small vessels and exhibit the phenotype of a true NK cell, characterized by tumor cells with a CD2+, cytoplasmic CD3ε + and CD56+ immunophenotype and germline configuration of the TCR gene . Tumor cells also expressed cytotoxic granules, including TIA-1, granzyme B and perforin, and were often EBV positive. Thus, the similar morphology and immunophenotype of other cases, positivity of EBER and NK-cell origin help to confirm the diagnosis of our case as IVNKL.
As so far, IVNKL is not classified within the World Health Organization classification subtypes . However, in view of the unique characteristics of this disease, the diagnosis should be independent to collect more data to help with further study of this disease. Because of the similar morphology and immunophenotypes, TCR rearrangement results, and EBV infection status of intravascular NK-cell lymphoma, extranodal NK/T-cell lymphoma, nasal type (ENKTCL) and aggressive NK-cell leukemia [16, 17], we suggest that IVNKL should be distinguished from the other two subtypes. Patients with IVNKL had no nasal symptoms and obvious abnormalities in the peripheral blood but had the hallmark of intravascular dissemination of tumor cells. In ENKTCL and aggressive NK-cell leukemia, tumor cells were distributed in tissues rather than deposited in blood vessels. The other differential diagnoses of IVNKL include IVL of other lineages (in which the tumor cells have typical immunophenotypes, such as being positive for B or T-cell markers), metastatic neoplasms (for example melanoma or breast cancer, which are validated by medical history and immunochemical staining), and numerous inflammatory processes, including drug reactions and insect bites, showing atypical intravascular CD30+ T-cell proliferation mimicking intravascular lymphoma (which includes variable numbers of intravascular CD30-positive cells, but the extent of the intravascular proliferation is much less florid, and the cells show a mixture of CD4 and CD8 positivity without a monoclonal T-cell population by molecular testing) .
Regarding etiological hypotheses, we believe that not only EBV infection but also genetic inheritance is somehow involved in the pathogenesis of this rare lymphoma because of this patient’s remarkable family history. IVNKL treatments are ineffective and include chemotherapy, radiotherapy, and even stem cell transplantation, which cannot change the poor prognosis. Because patients with clinical presentation confined to skin have a better prognosis, the poor outcome may be due to multisystem or vital organ involvement.