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Lymphoproliferative Disorder

Lymphoproliferative disorder is a general term that refers to any pathological condition associated with excess formation of lymphocytes.


Presentation

Due to the heterogeneity of LPD, symptoms may vary greatly. Also, there are hardly any symptoms specific for LPD. Lymphadenopathy, splenomegaly, hepatomegaly and fever are as common as recurrent infections, whereby the latter may be the most important indicator of immunodeficiency. A considerable share of LPD affects the gastrointestinal tract or the lungs, so digestion and respiratory problems may be detected in these patients.

Lymphocyte Disorder
  • The B cell lymphocytic disorders include B-chronic lymphocytic leukaemia, B cell prolymphocytic leukaemia, chronic lymphocytic leukaemia-prolymphocytic leukaemia, non-Hodgkin's lymphoma (including mantle cell lymphoma) in leukaemic phase, hairy cell leukaemia[ncbi.nlm.nih.gov]
  • disorders: Chronic lymphocytic leukemia Lymphoma-Hodgkin's disease Lymphoma-non-Hodgkin's Plasma cell disorders: Multiple myeloma Waldenström's macroglobulinemia Heavy chain disease Cancer Information: Classifying Hematological Disease Another way to[my.clevelandclinic.org]
Skull Mass
  • Imaging revealed numerous lytic lesions in the skull, most conspicuously a 4.1cm right frontal skull mass with prominent intracranial extension.[ncbi.nlm.nih.gov]
Elbow Swelling
  • After cessation of the MTX therapy, the elbow swelling regressed, and the patient was in remission of MTX-LPD. MTX-LPD should be considered in the differential diagnosis when a patient with RA develops severe joint swelling while on MTX therapy.[ncbi.nlm.nih.gov]

Workup

If clinical findings include lymphadenopathy, splenomegaly, and hepatomegaly without any signs of infection or if the medical history of the patient raises suspicion of immunodeficiency, complete blood count and blood biochemistry should be obtained. Infectious diseases should be ruled out. Serologic tests or molecular biological assays for Epstein-Barr virus may be helpful because the presence of this virus is associated with several B-cell and T-cell LPD. Increased lactate dehydrogenase levels may indicate the presence of neoplasms. More refined approaches and functional tests may be carried out if the involvement of certain organ systems, e.g., the gastrointestinal tract or the lungs, is suspected or confirmed.

Pathohistologic analyses of blood samples often reveal high quantities of immature lymphocytes that are usually oligoclonal. Monoclonal cell populations are more frequently found in primary malignant tumors than in LPD. Frequently, lymphocytes feature atypical morphologic characteristics that may, however, be shared among the lymphocyte population of the respective patient. Cytogenetic alterations are not common in LPD.

Imaging techniques may help to determine the extent of lymphadenopathy as well as presence and size of solid tumors. These may be more easily assessed in images obtained by magnetic resonance imaging or computed tomography, particularly if intravenous contrast agents are used to visualize the vascular system. Radiography may, however, be sufficient to evaluate lung involvement and disease progression. Bone scintigraphy may be applied to revise the skeleton for neoplasms.

Fine-needle aspirates may be obtained if solid tumors are detected. However, fast growing tumors may have necrotic centers that do not contain analyzable, characteristic tumor cells. Furthermore, lumbar puncture and analysis of cerebrospinal fluid as well as, bone marrow examinations may help to clarify if the central nervous system is affected and to distinguish primary tumors from metastases.

Treatment

Treatment largely depends on the cause of the LPD. Drug therapy needs to be adjusted accordingly. The overall aim of LPD treatment is to control the underlying LPD, to improve the patient's immune response and to avoid malignant transformation and tumor development.

Most LPD are treated with chemotherapy and/or irradiation. Common chemotherapeutic schedules including cyclophosphamide, doxorubicin, vincristine and prednisone are recommended. Chemotherapeutic, immunosuppressive side effects may be particularly severe in pediatric LPD patients and the corresponding preventive measures to avoid infection should be taken. Irradiation is the method of choice if local inhibition of lymphoproliferation is desired. Surgical tumor resection is of minor importance in LPD. If LPD patients develop solid tumors, there are usually several metastases throughout the body. Due to the nature of the disease, tumor cells are rapidly distributed via the vascular system and even if solitary tumors can be removed, recurrences and development of new tumors are likely. Surgical intervention may, however, be required to relieve the burden of vital organ structures.

LPD patients may further benefit from immunoglobulin therapy, interleukin-2 therapy or monoclonal antibody therapy.

A bone marrow transplantation may be the most promising therapeutic option for children with severe inherited LPD.

Because post-transplant lymphoproliferative disorders result mainly from immunosuppressive medication administered to avoid transplant rejection, cessation of such therapy will usually improve LPD. Low-grade post-transplant lymphoproliferative disorders may even be cured with a simple reduction of immunosuppressive therapy, but high-grade neoplasms often require additional treatment.

Prognosis

Prognosis depends on the specific LPD, the associated degree of immunodeficiency and the probability of malignant transformation. Lower degrees of immunodeficiency and lower probability of malignant transformation significantly improve the patient's prognosis with certain diseases remitting spontaneously. This is not to be expected in more severe LPDs, which is why these diseases require an aggressive therapeutic approach to avoid potentially lethal complications.

Etiology

Most LPDs are triggered by inherited gene mutations. Others may follow autoimmune disorders, infections, transplantations or cancerous diseases or may even be iatrogenically induced. These may affect cellular or humoral immunity as well as immune homeostasis.
Some examples include the following conditions:

  • X-linked lymphoproliferative diseases [1] [2]
  • Autoimmune lymphoproliferative syndrome [3]
  • HIV-associated lymphoproliferative disorder
  • Post-transplant lymphoproliferative disorder
  • B-cell lymphoma and T-cell lymphoma
  • Certain forms of leukemia

Epidemiology

Due to the heterogeneity of LPD, it is rather difficult to obtain overall incidence and prevalence.

No racial predilections have been observed in LPD. Males and females are equally affected by most LPDs. This does not apply to gonosomal genetic disorders that are more frequently observed in males. However, such entities should not be ruled out a priori in female patients, particularly if they are inherited with a dominant trait.

Often, LPD develops due to inherited genetic disorders but may nevertheless not manifest in infants and young children. In these cases, the age of 11 years has been reported as average for the development of lymphoid tumors in children [4]. The individual risk for LPD increases with age.

Morbidity and mortality depends on the specific type of LPD, the overall condition of the patient and the available treatment options. In general, immunodeficiency leaves the affected individuals more susceptible to any type of infection. Also, lymphocytes that proliferate in an unregulated manner may undergo malignant transformation. Immunodeficient patients have a significantly higher risk of dying from cancer than immunocompetent individuals of the same age.

Sex distribution
Age distribution

Pathophysiology

As mentioned earlier LPD comprises of a great variety of diseases with different pathogenetic background. Heterogeneity of LPD particularly stems from the fact that different sub-populations of lymphocytes are present in distinct lymphoid organs, e.g. in bone marrow, thymus, lymph nodes and spleen. That leaves a lot of possibilities for pathogenesis and manifestation of LPD. Here, pathophysiologic information shall be given exemplarily for some of the more common LPD.

  • X-linked lymphoproliferative diseases [1] [2].

80% of all cases are classified as XLP-1 diseases because they are triggered by mutations of the gene encoding for the SLAM-associated protein (SAP) that plays an important role in T-lymphocyte and natural killer cell signaling [5]. The remaining 20% of X-linked lymphoproliferative diseases result from mutations in the X-linked inhibitor of apoptosis protein (XIAP), an anti-apoptotic molecule expressed by T-lymphocytes and natural killer cells [6]. Interestingly, X-linked lymphoproliferative diseases render patients very susceptible to Epstein-Barr virus infections. Of note, there are other X-linked LPDs that do not correspond to what is referred to by the term X-linked lymphoproliferative diseases. For instance, X-linked agammaglobulinemia is associated with impaired B-cell maturation. In contrast, patients suffering from Wiskott-Aldrich syndrome, another X-linked disorder, show reduced antibody production and limited T-cell activity, which leads to recurrent infections [7] [8] [9].

  • Autoimmune lymphoproliferative syndrome [3] [10].

Different mutations that affect Fas-mediated signaling (e.g., Fas ligand, caspase-8 and caspase-10) trigger the autoimmune lymphoproliferative syndrome. They interfere with Fas-mediated apoptosis and inhibit programmed lymphocytic cell death. These lymphocytes may undergo malignant transformation.

  • HIV-associated lymphoproliferative disorder.

This type of LPD may be detected in children that prenatally contracted the human immunodeficiency virus. Affected individuals may suffer from generalized lymphadenopathy, but may also develop Kaposi's sarcoma, a neoplasm more commonly associated with infections with human herpes virus 8. Co-infections are likely to be the trigger for this disease.

  • Post-transplant lymphoproliferative disorder [11].

Rather than organ transplantation itself, the accompanying immunosuppressive therapy is what predisposes organ receivers for LPD. Most frequently, post-transplant lymphoproliferative disorders are B-cell disorders, but T-cell disorders have also been reported. Risk factors that could be identified so far are young age at the time of transplantation, seronegativity for Epstein-Barr virus, human leukocyte antigen disparities between donor and receiver as well as lung, small intestine and multiple organ transplantations [12]. The more common kidney, liver, heart and bone marrow transplantation are associated with minor risks. T-cell specific immunosuppressive therapy increases the risk for this type of LPD.

LPD are characterized by an uncontrolled and excessive formation of lymphocytes or dysfunctional mechanisms of lymphocytic cell death. These phenomena are provoked by important alterations in cell cycle and cell death regulation that predispose lymphocytes for malignant transformation. Thus, B-cell lymphoma, T-cell lymphoma as well as, lymphoblastic and lymphocytic leukemia should be considered as possible consequences of either of the aforementioned or any other LPD than as isolated entities.

Prevention

No preventive measures regarding LPD can be recommended.

Summary

Lymphoproliferative disorders (LPD) comprise several diseases in which lymphocyte formation is pathologically increased. As is the case with other types of immunoproliferative disorders, i.e. with diseases that involve the excessive formation of other immune cell types, the vast majority of LPD weakens the immune system of the affected individuals. These differ greatly in etiology, pathogenesis, and clinical symptomatology.

Most LPDs are provoked by genetic disorders, while other possible triggers are infections and iatrogenic causes.
Often, lymph nodes, spleen, and liver are compromised by LPD. Lymphadenopathy, splenomegaly, hepatomegaly and fever are common, yet are non-specific findings in LPD patients. Furthermore, they may present with recurring infections due to their weakened immune system. Laboratory analyses of blood samples as well as, other measures are usually required to diagnose and identify LPD.

If treatment options are available for the respective LPD, then treatment will be carried out. However, therapeutic options are often limited and symptomatic treatment is administered to alleviate symptoms and improve the overall immunity. LPD treatment may consist of home-based drug therapy, immunoglobulin therapy, chemotherapy, bone marrow transplant and others.

Patient Information

The term lymphoproliferative disorders (LPD) refers to a variety of diseases that share the common feature of excess lymphocyte proliferation or reduced lymphocyte death.

Lymphocytes are part of the immune system and exert important functions. For instance, they produce antibodies that mark pathogens as hostile organisms and thus prepare their elimination and they release several cytokines, molecules that regulate the overall immune response of the body. There are many types of lymphocytes in the human body. If an infection occurs, a very small share of these lymphocytes will be selected as appropriate for immune defense in this particular case and these lymphocytes will proliferate. The context behind this mode of operation is that the body cannot store huge amounts of lymphocytes for any possible infection. After an infectious disease is cured, proliferated lymphocytes have to be eliminated to make room for other lymphocytes in future infections. In LPD, lymphocytes either proliferate without any trigger or are not appropriately eliminated after successful immune responses.

Causes

The majority of LPD corresponds to genetic disorders. Gene mutations impair the correct synthesis of proteins that are essential for physiological lymphocyte function. In some cases, LPD may also be associated with viral infections, particularly with Epstein-Barr and human immunodeficiency virus infections. Individuals who receive organ transplants are frequently treated with immunomodulatory drugs in order to avoid transplant rejection. Such medication may also lead to LPD.

Symptoms

Symptoms vary greatly among the several types of LPD. Often, lymph nodes, spleen, and liver are affected. Due to the weakened immune system, recurring infections are frequently observed. Fever may be experienced.

Lymphocytes that proliferate in an uncontrolled manner pose a risk for malignant transformation. Therefore, tumors may be developed.

Diagnosis

Because symptoms associated with LPD are often very unspecific, further diagnostic measures are necessary to confirm the tentative diagnosis of LPD and to identify the specific disease. This is very important because subsequent therapeutic interventions need to be adjusted to the underlying disorder.
Blood samples are analyzed if LPD is suspected. Alterations regarding lymphocyte count and lymphocyte properties may support the diagnosis of LPD. Also, parameters obtained in blood chemistry analyses may already indicate the presence of tumors in the patient's body. This will usually be supported with different imaging techniques such as magnetic resonance imaging, computed tomography, and bone scintigraphy. Additional, more specific diagnostic measures may be required to diagnose specific LPD.

Treatment

Any LPD treatment aims at controlling lymphocyte proliferation, improving the patient's immune status and avoiding and/or reducing tumors. Treatment is mainly based on drug therapy, chemotherapy, and irradiation. Surgery is rarely an option but may be realized if solitary tumors compromise vital organ structures.

Also, immunoglobulin therapy, interleukin-2 therapy, monoclonal antibody therapy and bone marrow transplants may prove beneficial upon diagnosis of specific LPD.

References

Article

  1. Nichols KE, Ma CS, Cannons JL, Schwartzberg PL, Tangye SG. Molecular and cellular pathogenesis of X-linked lymphoproliferative disease. Immunol Rev. 2005; 203:180-199.
  2. Gilmour KC, Gaspar HB. Pathogenesis and diagnosis of X-linked lymphoproliferative disease. Expert Rev Mol Diagn. 2003; 3(5):549-561.
  3. Worth A, Thrasher AJ, Gaspar HB. Autoimmune lymphoproliferative syndrome: molecular basis of disease and clinical phenotype. Br J Haematol. 2006; 133(2):124-140.
  4. Spector BD, Perry GS, 3rd, Kersey JH. Genetically determined immunodeficiency diseases (GDID) and malignancy: report from the immunodeficiency--cancer registry. Clin Immunol Immunopathol. 1978; 11(1):12-29.
  5. Engel P, Eck MJ, Terhorst C. The SAP and SLAM families in immune responses and X-linked lymphoproliferative disease. Nat Rev Immunol. 2003; 3(10):813-821.
  6. Latour S. Natural killer T cells and X-linked lymphoproliferative syndrome. Curr Opin Allergy Clin Immunol. 2007; 7(6):510-514.
  7. Boztug K, Schmidt M, Schwarzer A, et al. Stem-cell gene therapy for the Wiskott-Aldrich syndrome. N Engl J Med. 2010; 363(20):1918-1927.
  8. Ishihara D, Dovas A, Park H, Isaac BM, Cox D. The chemotactic defect in wiskott-Aldrich syndrome macrophages is due to the reduced persistence of directional protrusions. PLoS One. 2012; 7(1):e30033.
  9. Notarangelo LD, Miao CH, Ochs HD. Wiskott-Aldrich syndrome. Curr Opin Hematol. 2008; 15(1):30-36.
  10. Dianzani U, Chiocchetti A, Ramenghi U. Role of inherited defects decreasing Fas function in autoimmunity. Life Sci. 2003; 72(25):2803-2824.
  11. Ohta H, Fukushima N, Ozono K. Pediatric post-transplant lymphoproliferative disorder after cardiac transplantation. Int J Hematol. 2009; 90(2):127-136.
  12. Weintraub L, Weiner C, Miloh T, et al. Identifying predictive factors for posttransplant lymphoproliferative disease in pediatric solid organ transplant recipients with Epstein-Barr virus viremia. J Pediatr Hematol Oncol. 2014; 36(8):e481-486.

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Last updated: 2018-06-21 19:52