The incidence of lymphoproliferative disorders is significantly higher in human immunodeficiency virus (HIV)-infected patients than in the normal population. The occurrence of AIDS-associated lymphoma is related to the duration and degree of immunosuppression caused by HIV infection, as well as to defects in immune regulatory surveillance and co-infection with other viruses such as EBV, HHV-8, and Kaposi’s sarcoma-associated herpesvirus infection. Approximately 2/3 of ARLs are of the diffuse large B-cell type, Birkitt lymphoma accounts for 25%, and other rare lymphoproliferative disorders include: T-cell lymphoma, Castleman disease, plasma cell malignant lesions, and primary exudative lymphoma.
Pathological features
1. AIDS-related NHL: The vast majority are highly progressive and highly malignant B-cell lymphomas, with cell types mostly of the small anaplastic cell type, large cell and immunoblast type. These include primary central nervous system lymphoma (PCNSL) and systemic lymphoma, the latter pathological histology is divided into four categories, including: Burkitt and atypical Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), immunoblast lymphoma (with plasma cell-like differentiation) and primary exudative lymphoma (PEL).
2.AIDS-associated HD: The tissue cell types are mostly mixed cell type and lymphocyte-ablative type, and the detection rate of EBV in tumor cells is 100%.
3.Other lymphoproliferative diseases
(1) T-cell lymphomas are large granular lymphocytosis, mesenchymal large cell lymphoma, Sézary syndrome and angiocentric T-cell lymphoma.
(2) Castleman’s disease pathology is characterized by polyclonal hypergamma globulin and plasma cells, perifollicular vascular hyperplasia of lymph nodes and vascular sclerosis of the germinal center.
(3) Plasma cell malignant lesion Morphologically the tumor cells resemble plasma mother cells and are usually positive for light chain, epithelial membrane antigen (EMA), immunoglobulin G, and Ki-67. Tumor cells are positive for VS38c, CD79a and CD138.
Clinical features
Common clinical features of ARL: most patients present with rapid enlargement of lymph nodes and systemic symptoms: fever, night sweats and weight loss. Extra-lymph node lesions are often present, invading the bone marrow, CNS, gastrointestinal tract, liver, skin and mucosa, and primary CNS lymphoma may occur.
Combination chemotherapy
Due to the specificity of ARL patients with varying degrees of decreased immune function, patients are prone to relapse and die from ARL if they receive reduced-dose chemotherapy, however, patients are prone to die from lethal infections if they receive adequate chemotherapy.
1. Reduced-dose chemotherapy: Reduced-dose chemotherapy is not easy to remove tumor cells. Little et al. applied a dose-adjusted EPOCH regimen with growth factor support and suspended antiviral therapy to 39 patients with ARL, in which adriamycin, vincristine and pedialyte glycosides were infused for 96 hours. In this group of cases, 59% of patients were at moderate to high risk according to IPI score and 41% had CD4 cells equal to or less than 100. Although this group of cases achieved a complete remission rate of 74% and a 53-month follow-up period, a disease-free survival rate of 92% and an overall survival OS of 60% despite the presence of many unfavorable features.
2, for patients in good general condition and tolerant to chemotherapy, standard dose CHOP regimen chemotherapy can be given with a CR rate of up to 48%, but for patients on concurrent antiretroviral drug (HAART) antiretroviral therapy, attention needs to be paid to the occurrence of myelosuppression and IV degree neutropenia more often occurs in the standard dose group.
3, high-dose chemotherapy: European researchers prefer high-dose chemotherapy, which can lead to better treatment results in ARL with good prognosis.
Antiretroviral drug (HAART) application.
HAART application resulted in a significant decrease in the incidence of primary brain lymphoma, from 1.99 cases/100 per year before HAART application to 0.3 cases (p0.001). The relative risk of ARL in primary CNS decreased from 0.50 before HAART to 0.35. The incidence of ARL was significantly higher in HAART-naïve patients with worse treatment outcomes.
The use of HAART has been shown in several studies to significantly improve patient prognosis by clinically suppressing the virus and reducing the incidence of HIV complications. 2001 Italian study group comparison showed that neutrophil toxicity and anemia were more pronounced in the CHOP-HAART group compared to the CHOP-like regimen alone, but the incidence of infection was significantly decreased.
Meroval application.
AMC randomized trial comparing CHOP with R-CHOP regimen: mortality associated with bacterial infection was significantly higher in the R-CHOP regimen group than in the CHOP group (14% δ 2%), with most deaths occurring in CD4 cell count 50/mm3, Phase II trial Spain: CR rate improved to 70% and 2-year overall survival improved to 64% in the R+CDE group compared with CDE alone, but the incidence of infection increased from 14% to 23%. It is recommended that melphalan should be used with caution in patients with CD4 cells 50/mm3.
Hematopoietic stem cell transplantation therapy.
Multiple single-center, small series have recently reported that high-risk first remission, relapsed, or refractory ARL treated with autologous hematopoietic stem cell transplantation is not yet definitive due to the small number and heterogeneity of cases reported across centers. According to these reports, the success rate of HSC collection is in the range of 80% to 100%, with a low incidence of implantation failure and normal stem cell quality. Transplantation failure has rarely been reported. Delayed implantation has been reported in 1 out of 20 patients due to the use of the antiviral drug cidovir during transplantation, although it is not clear whether cidovir can directly cause transplantation failure, and the authors recommend avoiding the use of cidovir during autologous transplantation. In patients with ARL, it is recommended that HIV disease be controlled with undetectable HIV viral load and CD4 cell count of 100/mm3 prior to transplantation.
There are very few reports of ARL treated with allogeneic HSCT. Kang et al. reported 2 patients who received reduced-dose allogeneic HSCT, 1 with AML still in remission after transplantation and the other with primary drug-resistant Hodgkin’s lymphoma who died of relapse 12 months after transplantation, although the number of cases is small, it is clear from the 2 reports that allogeneic HSCT for ARL is feasible.
Special types of ARL characteristics and treatment.
Primary central nervous system lymphoma (PCNSL) is often seen in the end stage of AIDS. Patients presenting with neurological and psychiatric symptoms for HIV infection should be on high alert for PCNSL, with clinical manifestations of intracranial hypertension and localized signs in the corresponding areas of brain damage. The diagnosis requires a brain tissue biopsy, and other tests such as cerebrospinal fluid cytomorphology, EBV testing, and brain imaging can be helpful for diagnosis and differential diagnosis in patients who cannot obtain a biopsy.PCNSL treatment can be local radiotherapy, high-dose MTX, and antiretroviral therapy according to NCCN guidelines. Hormones can reduce local edema and lower cranial pressure, but have the potential to aggravate infection and can be applied for a short period of time, in addition to the need for intensive supportive therapy.
Hodgkin’s lymphoma (HL) is associated with a 5-10 fold increase in the incidence of HL compared to the normal population, and HIV-associated HL is more aggressive and widespread, mostly associated with EBV infection, with mixed cell and lymphocytic atrophy histopathology.
Therapeutic measures: strong supportive therapy combined with antiviral, antifungal, granulocyte colony-stimulating factor and HAART based on standard doses of combination chemotherapy. For example, ABVD, EBVP, BEACOPP, MOPP/ABVD alternate, etc. Although response rates and cure rates are still significantly lower in infected than uninfected patients with strong supportive therapy, several studies have reported survival of 1-2 years. However, a recent series of reports have shown that after treatment with HAART for viral suppression, supportive therapy and standard dose ABVD regimens, the 5-year overall survival rate can be as high as 60% to 70% in some patients.
Primary exudative lymphoma (PEL) Primary exudative lymphoma accounts for 1-5% of ARL and is characterized by malignant exudate in the absence of lymph node lesions. It is of clonal B-cell origin and occurs mainly in HIV-infected patients in the late stage of AIDS when immune function is completely suppressed. The exudate contains a large number of lymphocytes, and the plasma membrane surfaces of adjacent organs may be infiltrated with a large number of malignant cells of immunoblast or interstitial macrophages. pEL cells lack expression of B-cell-associated antigens, but immunoglobulin gene rearrangements can be detected and are therefore of clonal B-cell origin. Associated with EBV as well as Kapozi’s sarcoma-associated herpesvirus (KSHV, HHV-8) infection. Simonelli et al. reported 11 patients treated with CHOP-like chemotherapy with a CR rate at 42% and a mean survival of 6 months.
Castleman disease Multicentric Castleman disease clinicopathology is characterized by polyclonal hypergamma globulin and plasma cells, perifollicular vascular proliferation in lymph nodes and vascular sclerosis in the germinal center, usually with hepatosplenomegaly and systemic symptoms. Laboratory tests usually show elevated C-reactive protein levels, sometimes autoimmune hemolytic anemia, cytokine dysregulation, especially IL-6, and the presence of HHV-8 viral antigens in tissues, which may play a major role. Treatment of multicenter Castleman disease is mostly unsatisfactory, with an average survival of only 14 months. Some patients die from conversion to NHL, while others die from chemotherapy-related toxicity and infection. Recently, it has been reported that some patients may benefit from HAART antiviral, melphalan, splenectomy or antiherpes zoster virus drugs such as ganciclovir therapy. Multicenter Castleman disease remains a clinical problem in an HIV-infected population for which standardized treatment is lacking.
Plasmacytoid lymphoma (PBL) Plasmacytoid lymphoma has also been reported to be found in HIV-negative patients, but is predominantly present in HIV-positive patients and was first described to occur in the oral cavity in 1997 by Delecluse et al. Plasmacytoid lymphoma can occur at various sites and has a younger age of onset than HIV-negative individuals, with a mean age of 33 years, negative for B- and T-cell markers but light chain, epithelial B cell and T cell markers are negative, but light chain, epithelial membrane antigen (EMA), immunoglobulin G, and Ki-67 are usually positive. Tumor cells were positive for VS38c, CD79a and CD138. Morphologically the tumor cells resemble plasma mother cells but express a mature plasma cell phenotype without the presence of monoclonal globulin, distinguishing them from multiple myeloma. Before HAART application, the prognosis was poor, with a mean survival of only 5.5 months. Two other cases reported a significant improvement in prognosis after HAART application.
T-cell lymphoma (TCL) The incidence of peripheral T-cell lymphoma is significantly increased in HIV-infected individuals, and Biggar et al. registered 6788 cases of AIDS-associated NHL in 11 regions of the United States with an incidence of T-cell lymphoma at 1.4% and a relative risk of 5.0 (95% CI,10.0-21.7), ,containing multiple T-cell subtypes. 1 Italian collaborative group reported 3 peripheral T cell ARL cytotoxic typing CD3+/CD8+/TIA-1+/granzyme B with TCR gene rearrangement. Another retrospective study analyzed 429 ARL cases, of which 11 had T-cell ARL, and T-cell had more skin and bone marrow invasion than B-cell ARL patients, but there was no difference in survival (10.6δ6.6 months p=0.13).