Post-transplant lymphoproliferative disorder

Last updated
Post-transplant lymphoproliferative disorder
Other namesPTLD
Specialty Immunology   OOjs UI icon edit-ltr-progressive.svg

Post-transplant lymphoproliferative disorder (PTLD) is the name given to a B cell proliferation due to therapeutic immunosuppression after organ transplantation. These patients may develop infectious mononucleosis-like lesions or polyclonal polymorphic B-cell hyperplasia. Some of these B cells may undergo mutations which will render them malignant, giving rise to a lymphoma.[ citation needed ]

Contents

In some patients, the malignant cell clone can become the dominant proliferating cell type, leading to frank lymphoma, a group of B cell lymphomas occurring in immunosuppressed patients following organ transplant.

Signs and symptoms

Symptoms of PTLD are highly variable and nonspecific, and may include fever, weight loss, night sweats, and fatigue. Symptoms may be similar to those seen in infectious mononucleosis (caused by EBV). Pain or discomfort may result from lymphadenopathy or mass effect from growing tumors. Dysfunction may occur in organs affected by PTLD. Lung or heart involvement may result in shortness of breath.[ citation needed ]

Laboratory findings may show abnormally low white blood cell, red cell counts, and platelet counts. In addition, serum uric acid and lactate dehydrogenase levels may be elevated, while serum calcium levels may be decreased. All of these findings together can suggest tumor lysis syndrome.[ citation needed ]

Causes

The disease is an uncontrolled proliferation of B cell lymphocytes latently infected with Epstein–Barr virus (EBV). [1] [2] Production of an interleukin-10, an endogenous, pro-regulatory cytokine, has also been implicated.[ citation needed ]

In immunocompetent patients, Epstein-Barr virus can cause infectious mononucleosis in adolescents, which is otherwise asymptomatic in children during their childhood. However, in immunosuppressed transplant patients, the lack of T-cell immunosurveillance can lead to the proliferation of these EBV-infected B-lymphocytes.[ citation needed ]

However, calcineurin inhibitors (tacrolimus and ciclosporin), used as immunosuppressants in organ transplantation inhibit T cell function, and can prevent the control of the B cell proliferation.[ citation needed ]

Depletion of T cells by use of anti-T cell antibodies in the prevention or treatment of transplant rejection further increases the risk of developing post-transplant lymphoproliferative disorder. Such antibodies include ATG, ALG and OKT3 (muromonab-CD3).[ citation needed ]

Polyclonal PTLD may form tumor masses and present with symptoms due to a mass effect, e.g. symptoms of bowel obstruction. Monoclonal forms of PTLD tend to form a disseminated malignant lymphoma.

Diagnosis

Definitive diagnosis is achieved by biopsying the involved tissue, which will reveal lymphoproliferative neoplasia. Most lesions will show malignant B cells, whereas a minority will show T cell neoplasia. CT imaging may show enlarged lymph nodes or a focal mass. PET scan may be helpful in the evaluation, which may show an increase in metabolic activity (PET avid) lesion, potentially guiding decisions on where to direct biopsies.

Neurologic symptoms, such as confusion or focal weakness, which may suggest involvement of the nervous system. This may be evaluated with an MRI of the brain with gadolinium based contrast and lumbar spinal tap with testing of the cerebral spinal fluid for EBV viral levels.

The presence of respiratory symptoms, such as cough or shortness of breath, in the setting of immunosuppression may suggest infection. Opportunistic infections may present in a similar fashion to PTLD. Evaluation with sputum culture for bacteria, Pneumocystis carinii, and acid fast bacilli, and fungal infections are often helpful.

Treatment

PTLD may spontaneously regress on reduction or cessation of immunosuppressant medication, [3] and can also be treated with addition of anti-viral therapy. In some cases it will progress to non-Hodgkin's lymphoma and may be fatal. A phase 2 study of adoptively transferred EBV-specific T cells demonstrated high efficacy with minimal toxicity. [4]

Epidemiology

PTLD is the second most common malignancy that occurs as a complication following solid organ transplantation (skin cancer is the most common). Less commonly, PTLD occurs after hematopoietic stem cell transplantation. The incidence varies by the type of transplantation: the lowest rates are seen with bone marrow transplants and liver transplants. The highest rates of PTLD are seen with lung and heart transplants, which is primarily due to the need for higher levels of immunosuppression. The incidence of PTLD is highest in the first year after transplantation; roughly 80 percent of cases after transplant occur in the first year. Transplantation of unmatched or mismatched HLA bone marrow also increase the risk of PTLD. [ citation needed ]

The main risk factors for PTLD are the degree of immune suppression and the presence of Epstein-Barr virus. Specifically, higher levels of T cell immunosuppression increase the risk PTLD. Individuals who have never been infected by the Epstein-Barr virus (EBV negative) who receive an organ from a donor with prior EBV infection are 24 times more likely to develop PTLD. Similarly, CMV mismatching (with a CMV negative recipient from a CMV positive donor) increases the risk of PTLD.[ citation needed ]

Related Research Articles

Infectious mononucleosis Common viral infectious disease

Infectious mononucleosis, also known as glandular fever, is an infection usually caused by the Epstein–Barr virus (EBV). Most people are infected by the virus as children, when the disease produces few or no symptoms. In young adults, the disease often results in fever, sore throat, enlarged lymph nodes in the neck, and tiredness. Most people recover in two to four weeks; however, feeling tired may last for months. The liver or spleen may also become swollen, and in less than one percent of cases splenic rupture may occur.

Epstein–Barr virus Virus of the herpes family

The Epstein–Barr virus (EBV), formally called Human gammaherpesvirus 4, is one of the nine known human herpesvirus types in the herpes family, and is one of the most common viruses in humans. EBV is a double-stranded DNA virus.

Lymphoproliferative disorders (LPDs) refer to a specific class of diagnoses, comprising a group of several conditions, in which lymphocytes are produced in excessive quantities. These disorders primarily present in patients who have a compromised immune system. Due to this factor, there are instances of these conditions being equated with "immunoproliferative disorders"; although, in terms of nomenclature, lymphoproliferative disorders are a subclass of immunoproliferative disorders—along with hypergammaglobulinemia and paraproteinemias.

T-cell lymphoma Medical condition

T-cell lymphoma is a rare form of cancerous lymphoma affecting T-cells. Lymphoma arises mainly from the uncontrolled proliferation of T-cells and can become cancerous.

Intravascular lymphomas Medical condition

Intravascular lymphomas (IVL) are rare cancers in which malignant lymphocytes proliferate and accumulate within blood vessels. Almost all other tyes of lymphoma involve the proliferation and accumulation of malignant lymphocytes in lymph nodes, other parts of the lymphatic system, and various non-lymphatic organs but not in blood vessels.

Hemophagocytic lymphohistiocytosis Medical condition

Hemophagocytic lymphohistiocytosis (HLH), also known as haemophagocytic lymphohistiocytosis, and hemophagocytic or haemophagocytic syndrome, is an uncommon hematologic disorder seen more often in children than in adults. It is a life-threatening disease of severe hyperinflammation caused by uncontrolled proliferation of activated lymphocytes and macrophages, characterised by proliferation of morphologically benign lymphocytes and macrophages that secrete high amounts of inflammatory cytokines. It is classified as one of the cytokine storm syndromes. There are inherited and non-inherited (acquired) causes of hemophagocytic lymphohistiocytosis (HLH).

Lymphomatoid granulomatosis is a very rare lymphoproliferative disorder first characterized in 1972. Lymphomatoid means lymphoma-like and granulomatosis denotes the microscopic characteristic of the presence of granulomas with polymorphic lymphoid infiltrates and focal necrosis within it.

Aggressive NK-cell leukemia Medical condition

Aggressive NK-cell leukemia is a disease with an aggressive, systemic proliferation of natural killer cells and a rapidly declining clinical course.

Angioimmunoblastic T-cell lymphoma is a mature T-cell lymphoma of blood or lymph vessel immunoblasts characterized by a polymorphous lymph node infiltrate showing a marked increase in follicular dendritic cells (FDCs) and high endothelial venules (HEVs) and systemic involvement.

There are several forms of Epstein–Barr virus (EBV) infection. These include asymptomatic infections, the primary infection, infectious mononucleosis, and the progression of asymptomatic or primary infections to: 1) any one of various Epstein–Barr virus-associated lymphoproliferative diseases such as chronic active EBV infection, EBV+ hemophagocytic lymphohistiocytosis, Burkitt's lymphoma, and Epstein–Barr virus positive diffuse large B-cell lymphoma, not otherwise specified); 2) non-lymphoid cancers such as Epstein–Barr virus associated gastric cancer, soft tissue sarcomas, leiomyosarcoma, and nasopharyngeal cancers; and 3) Epstein–Barr virus-associated non-lymphoproliferative diseases such as some cases of the immune disorders of multiple sclerosis and systemic lupus erythematosis and the childhood disorders of Alice in Wonderland Syndrome and acute cerebellar ataxia.

Hydroa vacciniforme Medical condition

Hydroa vacciniforme (HV) is a very rare, chronic photodermatitis-type skin condition with usual onset in childhood. It was first described in 1862 by Bazin. It is sometimes called "Bazin's hydroa vacciniforme". A study published in Scotland in 2000 reviewed the cases of 17 patients and estimated a prevalence of 0.34 cases per 100,000 population. In this study they reported an average age of onset of 7.9 years. Frequently the rash first appeared in the spring or summer months and involved sun-exposed skin. The rash starts as a vesicular eruption, later becoming umbilicated, and resulted in vacciniform scarring. It is most frequently found on the nose, cheeks, ears, dorsum of the hand, and arms.

Extranodal NK/T-cell lymphoma, nasal type (ENKTCL-NT) is a rare type of lymphoma that commonly involves midline areas of the nasal cavity, oral cavity, and/or pharynx At these sites, the disease often takes the form of massive, necrotic, and extremely disfiguring lesions. However, ENKTCL-NT can also involve the eye, larynx, lung, gastrointestinal tract, skin, and various other tissues. ENKTCL-NT mainly afflicts adults; it is relatively common in Asia and to lesser extents Mexico, Central America, and South America but is rare in Europe and North America. In Korea, ENKTCL-NT often involves the skin and is reported to be the most common form of cutaneous lymphoma after mycosis fungoides.

Plasmablastic lymphoma (PBL) is a type of large B-cell lymphoma recognized by the World Health Organization (WHO) in 2017 as belonging to a subgroup of lymphomas termed lymphoid neoplasms with plasmablastic differentiation. The other lymphoid neoplasms within this subgroup are: plasmablastic plasma cell lymphoma ; primary effusion lymphoma that is Kaposi's sarcoma-associated herpesvirus positive or Karposi's sarcoma-associated Herpesvirus negative; anaplastic lymphoma kinase-positive large B-cell lymphoma; and human herpesvirus 8-positive diffuse large B-cell lymphoma, not otherwise specified. All of these lymphomas are malignancies of plasmablasts, i.e. B-cells that have differentiated into plasmablasts but because of their malignant nature: fail to differentiate further into mature plasma cells; proliferate excessively; and accumulate in and injure various tissues and organs.

Chronic active EBV infection or in its expanded form, chronic active Epstein–Barr virus infection is a very rare and often fatal complication of Epstein–Barr virus (EBV) infection that most often occurs in children or adolescents of Asian or South American lineage, although cases in Hispanics, Europeans and Africans have been reported. It is classified as one of the Epstein-Barr virus-associated lymphoproliferative diseases.

Cold autoimmune hemolytic anemia caused by cold-reacting antibodies. Autoantibodies that bind to the erythrocyte membrane leading to premature erythrocyte destruction (hemolysis) characterize autoimmune hemolytic anemia.

Epstein–Barr virus-associated lymphoproliferative diseases are a group of disorders in which one or more types of lymphoid cells, i.e. B cells, T cells, NK cells, and histiocytic-dendritic cells, are infected with the Epstein–Barr virus (EBV). This causes the infected cells to divide excessively, and is associated with the development of various non-cancerous, pre-cancerous, and cancerous lymphoproliferative disorders (LPDs). These LPDs include the well-known disorder occurring during the initial infection with the EBV, infectious mononucleosis, and the large number of subsequent disorders that may occur thereafter. The virus is usually involved in the development and/or progression of these LPDs although in some cases it may be an "innocent" bystander, i.e. present in, but not contributing to, the disease.

Mosquito bite allergy

Mosquito bite allergies, also termed hypersensitivity to mosquito bites, are excessive reactions of varying severity to mosquito bites.

Natural killer cell enteropathy, also termed NK cell enteropathy (NKCE), and a closely related disorder, lymphomatoid gastropathy (LG), are non-malignant diseases in which one type of lymphocyte, the natural killer cell, proliferates excessively in the gastrointestinal tract. This proliferation causes red, sore-like spots, raised lesions, erosions, and ulcers in the mucosal layer surrounding the GI tract lumen. Both disorders cause either no or only vague symptoms of GI tract disturbances such as nausea, vomiting, and bleeding.

Diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI) is a subtype of the Diffuse large B-cell lymphomas and a rare form of the Epstein–Barr virus-associated lymphoproliferative diseases, i.e. conditions in which lymphocytes infected with the Epstein-Barr virus (EBV) proliferate excessively in one or more tissues. EBV infects ~95% of the world's population to cause no symptoms, minor non-specific symptoms, or infectious mononucleosis. The virus then enters a latency phase in which the infected individual becomes a lifetime asymptomatic carrier of the virus. Some weeks, months, years, or decades thereafter, a very small fraction of these carriers, particularly those with an immunodeficiency, develop any one of various EBV-associated benign or malignant diseases.

Fibrin-associated diffuse large B-cell lymphoma (FA-DLBCL) is an extremely rare form of the diffuse large B-cell lymphomas (DLBCL). DLBCL are lymphomas in which a particular type of lymphocyte, the B-cell, proliferates excessively, invades multiple tissues, and often causes life-threatening tissue damage. DLBCL have various forms as exemplified by one of its subtypes, diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI). DLBCL-CI is an aggressive malignancy that develops in sites of chronic inflammation that are walled off from the immune system. In this protected environment, the B-cells proliferate excessively, acquire malignant gene changes, form tumor masses, and often spread outside of the protected environment. In 2016, the World Health Organization provisionally classified FA-DLBCL as a DLBCL-CI. Similar to DLBCL-CI, FA-DLBCL involves the proliferation of EBV-infected large B-cells in restricted anatomical spaces that afford protection from an individual's immune system. However, FA-DLBCL differs from DLBCL-CI in many other ways, including, most importantly, its comparatively benign nature. Some researchers have suggested that this disease should be regarded as a non-malignant or pre-malignant lymphoproliferative disorder rather than a malignant DLBCL-CI.

References

  1. Gottschalk S, Rooney CM, Heslop HE (2005). "Post-transplant lymphoproliferative disorders". Annu. Rev. Med. 56 (1): 29–44. doi:10.1146/annurev.med.56.082103.104727. PMID   15660500.
  2. Nourse, JP; Jones K; Gandhi MK. (May 2011). "Epstein-Barr Virus-related post-transplant lymphoproliferative disorders: pathogenetic insights for targeted therapy" (PDF). Am J Transplant. 11 (5): 888–95. doi: 10.1111/j.1600-6143.2011.03499.x . PMID   21521464.
  3. "Hematopathology". webpath.med.utah.edu.
  4. Haque T, Wilkie GM, Jones MM, Higgins CD, Urquhart G, Wingate P, Burns D, McAulay K, Turner M, Bellamy C, Amlot PL, Kelly D, MacGilchrist A, Gandhi MK, Swerdlow AJ, Crawford DH (Aug 2007). "Allogeneic cytotoxic T-cell therapy for EBV-positive posttransplantation lymphoproliferative disease: results of a phase 2 multicenter clinical trial". Blood. 110 (4): 1123–31. doi: 10.1182/blood-2006-12-063008 . PMID   17468341.