Immunodeficiency-Related Lymphoproliferative Disorders

Clinical Features

According to the United Network for Organ Sharing (UNOS), the 5-year cumulative incidence of PTLD is 3.26% for children and 0.91% for adults (Organ Procurement and Transplantation Network [OPTN]/UNOS Ad Hoc Disease Transmission Advisory Committee Report to the Board of Directors 2009). PTLD is most common in children younger than 10 years and adults older than 60 years. It is the second most common posttransplant malignancy in children, and the second most common malignancy after skin cancer in adults. The risk of PTLD is greatest in the first year to 18 months but can occur any time after transplant. Treatment decisions are based on the histologic type, grade, stage, and site of tumor; assessment of clinical state, including transplant organ function; and capacity to tolerate therapy.

Patients who are EBV negative before transplantation and then seroconvert are at the greatest risk for PTLD. With early preventive strategies, late PTLD is becoming relatively more common. Greater risk occurs with more complex and multiple organ transplants, which require greater immunosuppression. In bone marrow transplant recipients, PTLD is of donor rather than recipient origin, and there is increased risk with T-cell depletion, severe graft-versus-host disease, anti-CD3 immunotherapy, and degree of HLA antigen mismatch.

Early or nondestructive lesions, such as plasma cell hyperplasia–infectious mononucleosis (IM)-like PTLDs, tend to occur in younger age groups, often children, and involve the head and neck, particularly tonsil and Waldeyer's ring. These lesions usually regress with surgical excision or reduction in immunotherapy. Cases of polymorphic PTLD may regress in response to decreased immunosuppression, but more aggressive lesions will either require chemotherapy (including the use of anti-CD20 rituximab), and/or radiation. In the more advanced forms of PTLD there may be no response or progression despite therapy. Monomorphic PTLDs are often extranodal but may present in bone marrow or lymph nodes. These PTLDs tend to involve older age groups (median age, 56 years) and are often aggressive despite chemotherapy or radiation therapy. T-cell PTLD is uncommon, usually EBV negative, and tends to be aggressive and refractory to therapy.

Pathologic Features

A spectrum of histologic appearances with PTLDs ranges from the early or non-destructive lesions (plasma cell hyperplasia-IM–like), polymorphic PTLD, and monomorphic PTLD, which includes malignant lymphoma and myeloma ( Table 10.1 ).

TABLE 10.1

Classification and Key Features of PTLD

Type of PTLD	Histology	Phenotype	Molecular
Early (non-destructive) lesions
Follicular hyperplasia Plasma cell hyperplasia Infectious Mononucleosis-like	Variable follicular hyperplasia EBV+ Numerous plasma cells Paracortical expansion with numerous immunoblasts	Polyclonal plasma cells T cells Most EBV+	Polyclonal or oligoclonal
Polymorphic
	Effacement of architecture; mixed population of lymphocytes, plasma cells, immunoblasts	B cells and T lymphocytes admixed with immunoblasts and plasma cells	Clonal Ig gene rearrangements; usually EBV+; plasma cells may show light chain restriction
Monomorphic
DLBCL Burkitt, myeloma, plasmacytoma, classic Hodgkin lymphoma, T-cell lymphoma	Resembles lymphoma type in nonimmunosuppressed population	Similar to lymphoma subtype; most EBV+; large cells may express EBER and LMP1 T-cell lymphomas usually EBV−	Clonal Ig gene rearrangements; often have other molecular abnormalities (e.g., MYC, BCL6, NRAS, p53)

DLBCL, Diffuse large B-cell lymphoma; EBER , EBV-encoded RNA ; EBV, Epstein-Bar virus; Ig, immunoglobulin; IM, infectious mononucleosis; LMP-1 , latent membrane protein PTLD, posttransplantation lymphoproliferative disorder.

Early lesions (termed non-destructive lesions in WHO 2017) are characterized by preservation of architecture although they form mass lesions. Follicular hyperplasia may be considered an early lesion if the hyperplastic follicles are positive for EBV. EBER expression may be variable in the follicles and/or interfollicular regions but characteristically involves one or more hyperplastic follicles. Hyperplasias generally involve lymph nodes, tonsils, and adenoids rather than extranodal sites. They tend to regress spontaneously or with excision or reduction of immunosuppression. In plasmacytic hyperplasia-IM–like PTLD, which often involves lymph nodes and tonsils, there is retention of the overall architecture with expansion of interfollicular areas by a proliferation of plasma cells, admixed with small lymphocytes and immunoblasts ( Fig. 10.1 ). The plasma cells are polytypic and do not have clonal gene rearrangements. Large cells or immunoblasts are usually single, and there is minimal cytologic atypia. They form mass lesions without destruction of architecture, and the majority regresses spontaneously with withdrawal of immunosuppressive agents.

In polymorphic PTLD, there is destruction of architecture and a lymphoid infiltrate showing variable plasmacytic differentiation including immunoblasts, which may be found in small clusters but do not fulfill diagnostic criteria for lymphoma. This is the most common form of PTLD in the pediatric age group. They characteristically exhibit a full range of B-cell stages and have clonal immunoglobulin gene rearrangements. Atypical lymphoid cells with irregular nuclear outlines may be present, and there may be foci of necrosis ( Fig. 10.2 ). The number of large cells is variable in polymorphic PTLD and the distinction from monomorphic PTLD is not always clear-cut. Immunoblasts may resemble Hodgkin or Reed-Sternberg cells. In some cases, in which T cells and histiocytes in the background predominate, separation from diffuse large B-cell lymphoma (DLBCL) with a T-cell/histiocyte-rich background may be particularly difficult. Most polymorphic PTLDs are EBV driven, with clonal immunoglobulin gene rearrangements but no other additional genetic abnormalities. They tend to respond to reduction in immunosuppression.

Mucocutaneous ulcer may also occur following transplantation as well as in other immunodeficiency settings. These present as well-circumscribed ulcerated masses in mucocutaneous sites. There is a spectrum of lymphoid cells and immunoblasts that are EBV+ and may resemble Hodgkin cells. The base of the ulcer characteristically consists of inflammatory cells without tissue invasion.

Monomorphic PTLD resembles lymphoma in the immunocompetent population and includes diffuse large B-cell lymphomas, which may have an immunoblastic appearance, Burkitt lymphoma (BL), myeloma/plasmacytoma, classic Hodgkin-type PTLD, and T-cell lymphomas. Indolent small B-cell lymphomas after transplant are generally not considered part of the spectrum of PTLD with the exception of EBV+ marginal zone lymphoma.

Burkitt lymphoma after transplant ( Fig. 10.3 ) often manifests with high-stage disease and bone marrow involvement. It usually occurs late after transplant (average, 4.5 years). Plasmacytoma-like PTLD is relatively rare ( Fig. 10.4 ) and is similar to extramedullary plasmacytoma in other settings, involving extranodal sites such as the gastrointestinal tract or lymph nodes.

Classic Hodgkin-type PTLD is a late-occurring PTLD (mean, 4 years after transplantation, but possibly 7 years or longer). It may be difficult to differentiate these lesions from other forms of PTLD in which there may be Reed-Sternberg and Hodgkin-like cells, and the diagnosis of classic Hodgkin lymphoma (CHL) in this setting requires application of stringent diagnostic criteria. In other forms of PTLD resembling HL there may be small and intermediate sized EBV+ cells in addition to the HL cells. Mixed cellularity type is the most common form of HL in this setting, and the Reed-Sternberg cells are EBV+ ( Fig. 10.5 ). Immunostaining may be helpful in the differential. Reed-Sternberg cells should have the classic phenotype CD15+, CD30+, usually negative for Octamer Transcription Factor-2 (OCT-2) or B-cell OCT binding factor-1 (BOB.1).

T-cell PTLDs range in incidence from 4% to 14% of PTLD. They should be classified according to the WHO classification of T-cell lymphomas and include the entire spectrum of T/NK cell neoplasms. T-cell PTLDs are usually EBV− and occur later than B-cell PTLDs. PTLDs of NK-cell lineage are rare and include T/NK-cell lymphoma nasal type, and large granular lymphocytic leukemia. T-cell PTLDs can occur subsequent to other types of PTLDs.

Prognosis and Therapy

For hyperplasias and polymorphic PTLDs, a graded approach is generally recommended, with observation and reduction in immunosuppression, to single-agent rituximab, and addition of combination chemotherapy in refractory or progressive cases. With early lesions in children, surgical excision may be sufficient, and these cases are only rarely associated with progression to a more aggressive form of PTLD. Monomorphic PTLDs are generally managed as the corresponding lymphoma type, but on occasion have responded to reduction in immune suppression.

Introduction and Definition

Because the spectrum of lymphoid hyperplasia associated with HIV infection is discussed in Chapter 4 , this chapter restricts discussion to neoplastic lymphoproliferative disorders. Acquired immunodeficiency syndrome (AIDS)-related lymphomas (ARLs) account for approximately 10% of all lymphomas in the United States and Europe. The introduction of highly active antiretroviral multiple-agent therapy (HAART) for HIV has significantly affected the incidence of AIDS lymphoma and has resulted in a 75% decline in mortality. Nevertheless, the incidence of non-Hodgkin lymphoma (NHL) remains higher in HIV+ individuals compared with the general population; paradoxically, the incidence of classic Hodgkin lymphoma appears to have increased with the widespread use of antiretroviral therapy. Before HAART, lymphoma was a late manifestation of HIV infection, occurring in severely immunocompromised individuals with extremely low CD4+ T-cell counts. Tumor pathobiology at the time of clinical presentation is becoming a critical determinant of outcome rather than the immune environment during treatment. The incidence of low-grade lymphomas in HIV-infected patients is also increasing.

The pathogenesis of AIDS lymphomas most likely relates to chronic antigen stimulation and EBV infection resulting in B-cell overproduction and secondary genetic abnormalities in the background of immune deficiency. Polyclonal and oligoclonal B-cell expansion frequently precedes the development of lymphoma. Recent evidence suggests that HIV may directly contribute to lymphomagenesis because HIV p17 protein enhances B-cell clonogenic activity. Unlike lymphomas in the transplant setting, ARLs are associated with both A- and B-type EBV. Viral infection (EBV and human herpesvirus 8 [HHV8]) may be associated with cytokine production including IL6, IL10, and IL13, which may also contribute to lymphoid proliferation and plasmacytoid differentiation of neoplastic cells.

EBV can be demonstrated in approximately 40% of cases of HIV-related lymphoma and is highest in cases with immunoblastic morphology and lymphomas involving the central nervous system (CNS; approaching 100%), compared with BL, where the incidence of infection of tumor cells with EBV resembles sporadic rather than endemic cases (approximately 40%, slightly higher in cases with atypical or plasmacytoid morphology). The incidence of EBV infection in AIDS-related centroblastic lymphoma is 20% to 30%. Cases of primary effusion lymphoma in patients with AIDS contain both EBV and HHV8. Plasmablastic lymphomas associated with HIV are usually EBV+, as are many cases of myeloma, including the plasmablastic variant.

Chromosomal translocations can result in the activation of MYC and, less commonly, other oncogenes, including RAS , BCL2, and TP53 . MYC activation and TP53 inactivation occur more often in cases of BL. MYC has also been associated with plasmablastic differentiation in cases of EBV+ plasmablastic lymphoma.

Clinical Features

Systemic B symptoms are usually present in patients with ARLs, and these include unexplained fever, drenching night sweats, and weight loss greater than 10% of normal body weight. Patients frequently have extensive disease at diagnosis, including involvement of the bone marrow, cerebrospinal fluid, and gastrointestinal tract. Any site can be involved by lymphoma; unusual sites include the oral cavity, adrenal glands, heart, kidney, and gallbladder. Multiple tumor masses may be present and can represent synchronous clonal neoplasms. There may be extensive organ infiltration leading to organ failure, particularly in the bone marrow and liver.

The incidence of primary central nervous system (CNS) lymphomas has fallen dramatically since the onset of HAART. These patients usually have one or more space-occupying lesions in the brain that can be deep seated. A computed tomographic scan of the brain may be confused with cerebral toxoplasmosis, although in the latter condition the lesions are usually multiple and smaller. In children with AIDS, primary lymphoma is the most common cause of focal or multifocal brain masses.