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.

• Anemia

  His labs were notable for hemoglobin as low as 6.0 g/dL, iron 34 μg/dL, and ferritin 21 ng/mL, consistent with iron-deficiency anemia. [acgcasereports.gi.org]

  We present a child with hepatitis-associated severe aplastic anemia who underwent an unrelated allogeneic hematopoietic stem cell transplantation and subsequently developed graft failure and an Epstein-Barr virus-positive monomorphic plasmacytoma-type [ncbi.nlm.nih.gov]

  Anemia in AIDS patients is a common finding (60-80%); however hemolytic anemia is unusual and when it is present, it is generally mild; severe anemia is associated with bad prognosis. [pesquisa.bvsalud.org]

  Anemia For chronic anemia, the underlying disease (infection, arthritis, heart, lung or kidney disease) is attended to, often improving the anemia. [my.clevelandclinic.org]

  […] associated with lymphoproliferative disorder Hemolytic anemia w lymphoproliferative disease Hemolytic anemia, lymphoproliferative disease Lymphocytic hypoplasia Lymphoproliferative disorder Mast cell neoplasm Myeloproliferative disorder Myeloproliferative [icd9data.com]

• Asymptomatic

  We present the case of a 36-year-old Caucasian woman with a purplish erythematous nodule, hardened, shiny, asymptomatic, on the left nasal ala, which had grown progressively for 45 days. [ncbi.nlm.nih.gov]

  The 3 patients who received prophylactic EBV CTLs in this series all remained asymptomatic. [bloodjournal.org]

  Symptoms and Signs X-linked lymphoproliferative syndrome is usually asymptomatic until EBV infection develops. [merckmanuals.com]

• Pathologist

  However, a pathologist noticed unusual structures in skin tissue samples. [ncbi.nlm.nih.gov]

  A templated format, excellent color photographs, authoritative content, and online access make this an ideal reference for busy pathologists. [euro-libris.ro]

  Clinicians, radiologists, and pathologists should exchange information to determine the diagnosis in individual patients. Potential causes (see Table: Causes of Interstitial Lung Disease ) are assessed systematically. [merck.com]

  Sometimes, the pathologist may perform special studies, which may include immunohistochemical stains, histochemical stains, molecular testing, and very rarely electron microscopic studies. [dovemed.com]

  Despite these limitations, several reviews have been written aimed at offering a guide for pathologists and clinicians in diagnosing and treating PTLD. [bloodjournal.org]

• Surgical Procedure

  If enough of an increase is demonstrated, then this agent can be used to support hemostasis during a minor surgical procedure. [my.clevelandclinic.org]

• Abdominal Pain

  Before transplant, he was admitted with severe abdominal pain, which turned out to result from ileal perforation. [ncbi.nlm.nih.gov]

  Presenting symptoms included abdominal pain, constipation, and hematochezia. [acgcasereports.gi.org]

• Vomiting

  A 50-year-old lady presented with a 12-week history of generalised throbbing headache, progressive vertigo, nausea and vomiting. Twelve years previously, she had a renal transplant for end stage renal failure secondary to atrophic pyelonephritis. [jnnp.bmj.com]

  Indications for endoscopy included abdominal pain, vomiting, hematemesis, irritability, growth failure, anemia, occult blood loss, and suspected PTLD. [journals.lww.com]

  The patient was administered famotidine, and the vomiting ceased. [springerplus.springeropen.com]

  Other symptoms may include an appetite loss, vomiting, nausea, a loss of weight, fatigue, weakness, lymph nodal swelling particularly in the groin, under your arms, in the collarbone area and your neck. [livestrong.com]

  It is most commonly used in combination with chemotherapy The radiation may be administered by a machine placed outside the body, or by placing a radioactive material inside the body The side effects of radiation therapy include nausea, vomiting, fatigue [dovemed.com]

• Nausea

  A 50-year-old lady presented with a 12-week history of generalised throbbing headache, progressive vertigo, nausea and vomiting. Twelve years previously, she had a renal transplant for end stage renal failure secondary to atrophic pyelonephritis. [jnnp.bmj.com]

  Other symptoms may include an appetite loss, vomiting, nausea, a loss of weight, fatigue, weakness, lymph nodal swelling particularly in the groin, under your arms, in the collarbone area and your neck. [livestrong.com]

  Central Nervous System Post-Transplant Lymphoproliferative Disorder in a Patient with Acute Lymphocytic Leukemia Summary A 27-year-old woman with acute lymphocytic leukemia, who underwent allogeneic hematopoietic stem cell transplantation, complained of nausea [dear-medic.jp]

  pain, risk of cancer later in life, and risk of heart disease Radiation can damage healthy cells in addition to cancer cells, causing further complications Supportive treatment: Anti-nausea medications and antibiotics may be used as supportive therapy [dovemed.com]

  Case Report A 6-year-old-girl with VATER syndrome, who had undergone renal transplantation at 3 years of age presented to the emergency department with a 6-week history of intermittent headaches, nausea, and vomiting. [ajnr.org]

• Heart Disease

  His additional comorbidities included severe aortic stenosis and heart failure of the transplanted heart, as well as paroxysmal atrial fibrillation (on warfarin) and chronic kidney disease. [acgcasereports.gi.org]

  […] chemotherapy The radiation may be administered by a machine placed outside the body, or by placing a radioactive material inside the body The side effects of radiation therapy include nausea, vomiting, fatigue, pain, risk of cancer later in life, and risk of heart [dovemed.com]

• Hypotension

  MEDICAMENTEUSE LYELL SYNDROME STEVENS JOHNSON SYNDROME ARTHRALGIE DORSALGIE SPASME MUSCULAIRE DOULEUR DANS LES MEMBRES HIRSUTISME ANOREXIE APPETIT PERTE SEPTICEMIE LEUCOENCEPHALOPATHIE NEOPLASME SYNDROME LYMPHOPROLIFERATIF CANCER CUTANE THROMBOEMBOLIE ISCHEMIE HYPOTENSION [codage.ext.cnamts.fr]

  The youngest patients (patients 4 and 6) had signs of sepsis (hypotension, tachycardia, respiratory acidosis). Patient 5 presented with gastrointestinal (GI) symptoms (diarrhea, weight loss, anorexia), and patient 4 had heme-positive stools. [pediatrics.aappublications.org]

• Ulcer

  As EVL is suspected to be associated with recurrent ileal ulcers, EVL was again switched back to MMF. The ileal ulcers resolved, without recurrence in 3 months of clinical follow-up. [ncbi.nlm.nih.gov]

  Small bowel enteroscopy showing a deep, cratered ulcer with an adherent clot in the distal duodenum. Biopsies of the ulcer edge revealed monomorphic posttransplant lymphoproliferative disorder (PTLD), plasmacytoma-like (Figure 3). [acgcasereports.gi.org]

• Pruritus

  […] progress from lymphomatoid papulosis (a recurrent skin eruption with Reed-Sternberg like cells infiltrating the skin, which may also progress to anaplastic lymphoma and Hodgkin’s) § Both MF and SS tend to affect the elderly (M>F) § Clinical features § Pruritus [ihaematology.com]

  […] typically involve the head and neck, unlike classic MF, which usually affects the sun protected areas of the trunk and buttocks (“bathing suit distribution”). 15, 17 Eyebrow involvement with plaques and alopecia is particularly representative, as is severe pruritus [pediatrics.aappublications.org]

• Confusion

  The combination of morphology and immunophenotype allowed the characterization of a new disorder, splenic lymphoma with villous lymphocytes, which was confused in the past with both CLL and HCL. [ncbi.nlm.nih.gov]

  DEFAILLANCE MULTIVISCERALE DOULEUR / OPPRESSION THORACIQUE POLYDIPSIE ANAPHYLAXIE REACTION ALLERGIQUE ATTEINTE HEPATIQUE HEPATITE CHOLESTASE ICTERE MALADIE VEINO-OCCLUSIVE HEPATIQUE THROMBOSE ARTERIELLE INSUFFISANCE HEPATIQUE DYSMENORRHEE METRORRAGIE INSOMNIE CONFUSION [codage.ext.cnamts.fr]

  Likewise, interlobular arteries entrapped within PTLD lesions may show lesions resembling vasculitis, which should not be confused with rejection. [tpis.upmc.com]

  […] autologous bone marrow transplant (are considered iatrogenic, not posttransplant) Sites Lymph nodes, GI tract, lungs, liver - common; CNS - rare; Bone marrow - uncommon; peripheral blood - rare Allograft involvement in solid organ recipients may cause confusion [pathologyoutlines.com]

  Call your medical team immediately if you have any symptoms of infection, including, but not limited to: fever (temperature above 38°C) shivering, with or without a fever chills and sweating feeling generally unwell, confused or disoriented earache, cough [lymphoma-action.org.uk]

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 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 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.

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

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.

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.

• B-cell lymphoma, T-cell lymphoma and certain forms of leukemia.

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.

No preventive measures regarding LPD can be recommended.

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.

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.

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