Lymphoproliferative disease associated with immunodeficiency in children
The incidence of lymphoproliferative disease or lymphoma is 100-fold higher in immunocompromised children than in the general population. The cause of such immune deficiencies may be a genetically inherited defect, secondary to human immunodeficiency virus (HIV) infection, or iatrogenic following transplantation (solid organ transplantation or allogeneic hematopoietic stem cell transplantation [HSCT]). EBV is associated with most of these tumors, but some tumors are not associated with any infectious agent.
NHL associated with HIV is usually aggressive, with most cases occurring in extralymphatic sites. HIV-associated NHL can be broadly grouped into three subcategories: systemic (nodal and extranodal), primary CNS lymphoma (PCNSL), and body cavity-based lymphoma, also referred to as primary effusion lymphoma (PEL). Approximately 80% of all NHL in HIV patients is considered to be systemic. PEL, a unique lymphomatous effusion associated with the human herpesvirus-8 (HHV8) gene or Kaposi sarcoma herpesvirus, is primarily observed in adults infected with HIV but has been reported in HIV-infected children. Highly active antiretroviral therapy has decreased the incidence of NHL in HIV-positive individuals, particularly for PCNSL cases. Most childhood HIV-related NHL is of mature B-cell phenotype but with a spectrum, including PEL, PCNSL, mucosa-associated lymphoid tissue (MALT), Burkitt lymphoma, and DLCL. NHL in children with HIV often presents with fever, weight loss, and symptoms related to extranodal disease, such as abdominal pain or CNS symptoms.
NHL observed in primary immunodeficiency usually shows a mature B-cell phenotype and large cell histology. Mature T-cell lymphoma and ALCL have been observed. Children with primary immunodeficiency and NHL are more likely to have high-stage disease and present with symptoms related to extranodal disease, particularly the gastrointestinal tract and CNS.
PTLD represents a spectrum of clinically and morphologically heterogeneous lymphoid proliferations. Essentially all PTLD following HSCT is associated with EBV, but EBV-negative PTLD can be seen following solid organ transplant. The WHO has classified PTLD into three subtypes: (1) early lesions, (2) polymorphic PTLD, and (3) monomorphic PTLD. Early lesions show germinal center expansion, but tissue architecture remains normal. Presence of infiltrating T cells, disruption of nodal architecture, and necrosis distinguish polymorphic PTLD from early lesions. Histologies observed in the monomorphic subtype are similar to those observed in NHL, with DLBCL being the most common histology, followed by Burkitt lymphoma, with myeloma or plasmacytoma occurring rarely. The B-cell stimulation by EBV may result in multiple clones of proliferating B cells, and both polymorphous and monomorphous histologies may be present in a patient, even within the same lesion of PTLD. Thus, histology of a single biopsied site may not be representative of the entire disease process. Not all PTLD is B-cell phenotype. EBV lymphoproliferative disease posttransplant may manifest as isolated hepatitis, lymphoid interstitial pneumonitis, meningoencephalitis, or an infectious mononucleosis-like syndrome. The definition of PTLD is frequently limited to lymphomatous lesions (low-stage or high-stage), which are often extranodal (frequently in the allograft). Although less common, PTLD may present as a rapidly progressive, high-stage disease that clinically resembles septic shock, which almost always results in death despite therapy.