Hodgkin's disease, also known as Hodgkin lymphoma is a type of malignant lymphoma, representing approximately 7 percent of childhood cancers. It is seldom found in infants, but more frequent in the 15- to 19-year-old group. The malignant clone, the Reed-Sternberg cell confers unique behavior to this type of malignancy.
Childhood Hodgkin's disease patients usually present for the evaluation of painless, but persistent adenopathies, that are most commonly located in the latero-cervical region. The mediastinal localization is second most common, causing respiratory distress, cough, chest pain or superior vena cava syndrome (dyspnea, orthopnea, stridor, dysphagia, nausea, nasal stuffiness, distorted vision, headache, light-headedness, facial and arm swelling). This type of presentation is an oncological emergency, requiring immediate therapy. Sedation should be avoided in these patients because of the risk for respiratory failure.
Childhood Hodgkin's disease is a consumptive illness, therefore children exhibit an unexplained weight loss of at least 10%, fatigability, night sweats and unexplained fever. The classic Pel-Ebstein fever (high temperature for 1-2 weeks, followed by an afebrile period of 1-2 weeks) is rarely observed. Additional symptoms include urticaria, bone or back pain and pruritus. Physical examination reveals variably enlarged spleen and liver. The physician should conduct a careful examination of all superficial lymph node stations: laterocervical, occipital, pre-auricular, submandibular, supraclavicular, infraclavicular, axillary, epitrochlear, inguinal and popliteal, as well as one of the Waldeyer and tonsilar tissues. Adenopathies are most often asymmetrical. Signs of profound lymph node enlargement, such as those described in the superior vena cava syndrome should be also looked for. The reduction of the masses found on the initial examination during the course of therapy pleads for a good therapeutic response. The lymph nodes are not painful.
The central nervous system may also suffer in childhood Hodgkin's disease due to paraneoplastic syndromes. The pediatrician should keep in mind to look for signs of multifocal leukoencephalopathy, cerebellar degeneration, Guillain-Barre syndrome or neuropathy.
The hematological and biochemical panels are variable in childhood Hodgkin's disease. The complete cell blood count may show neutrophilia or eosinophilia, lymphopenia or monocytosis, anemia or thrombocytopenia. The anemia may have a hemolytic character or it may be caused by bone marrow infiltration. Hypoalbuminemia, as well as increased acute-phase reactants (C-reactive protein, erythrocyte sedimentation rate, ferritin, and copper), are other usual findings.
The lymph node biopsy is absolutely necessary in order to establish the diagnosis, while staging no longer requires invasive procedures nowadays, as it is performed using various imaging methods: computed tomography examination, positron emission tomography or nuclear imaging with gallium scan. Bone marrow biopsies are no longer mandatory either, being reserved for patients with advanced disease.
The Ann Arbor staging system recognizes four stages: I- only one lymph node region or one extranodal site are involved, II- more than one lymph node regions located on the same side of the diaphragm, III- involvement of lymph node regions on both sides of the diaphragm and IV- diffuse or disseminated disease. Stage IV patients have extralymphatic organs disease, with lung, liver or bone marrow implication. The stage number is accompanied by the letters "A" or "B". "B" means one of the following signs is present: night sweating, weight loss (more than 10% during the last 6 months) or unexplained fever, while "A" means none of the above are present. The letter "E" designates the presence of the extension of the disease in a contiguous, not metastatic manner to other extranodal sites. The term "bulky disease" is used in cases where a mass larger than 6 cm is found, or in patients presenting with large mediastinal adenopathies. The presence of bulky disease, suggested by increased lactate dehydrogenase, signals a poor prognosis.
Further useful biochemical tests include alkaline phosphatase, whose increased levels signals bony metastasis, as well as complete liver and kidney function assessment, keeping in mind that certain Hodgkin's disease patients present with nephrotic syndrome and marked proteinuria. Immunoglobulins A, G and M, protein electrophoresis and serology for hepatitis A, B and B, cytomegalovirus, Toxoplasma gondii, human immunodeficiency virus, herpes simplex virus, Epstein-Barr virus and varicella zoster virus should be obtained. Individual circumstances dictate the need for an electrocardiogram, echocardiogram, and electroencephalogram. Pleural and pericardial involvement should also be evaluated. Liver involvement implies that the patient is in stage IV of the disease.
A chest radiography is an easy and convenient method to initially evaluate bulky disease. Finding a mediastinal mass larger than one-third of the thoracic diameter holds prognostic importance, and evaluation is feasible on anteroposterior and lateral projections. Abdominal ultrasound can detect adenopathies, but this method's resolution is inferior to that of computed tomography and magnetic resonance imaging, while holding the advantage of implying no ionizing radiation use. Combining the benefits of good quality images and limiting the risk for future secondary malignancy, magnetic resonance imaging seems to be one of the most appropriate methods. Positron emission tomography with 2-[18F] fluoro-2-deoxy-D-glucose administration is also reliable in evaluating the extent of the disease. This method's validity in guiding radiation therapy has been demonstrated in adults  and is under evaluation in children.
Excisional biopsy specimen histological evaluation is always required in order to establish the diagnosis. When an entire lymph node cannot be obtained, fine-needle aspiration biopsy is also acceptable. However, the pathological material obtained this way is less suitable for examination because the architecture of the lymph node cannot be assessed. Evaluation of a fragment of another primarily affected organ is another possibility. The necessity to perform a bone marrow biopsy is currently under debate, given that it is a painful procedure that can to some extent be replaced by positron emission tomography. The anatomopathological examination will reveal the presence of the Sternberg- Reed cell, a giant, multinucleated, CD 30 and CD 15 positive cell. Some cases may have "popcorn cells" present, variants of the classical Sternberg- Reed cell. "Popcorn cells" are CD 20 positive and CD30 and CD15 negative.
Histological evaluation allows disease classification into the well-known types : nodular sclerosis, lymphocyte-rich. lymphocyte depleted, mixed cellularity and nodular lymphocyte-predominant Hodgkin lymphoma.
Childhood Hodgkin's disease patients should receive a combined therapeutic regimen, adapted to the subtype and stage of the disease. Risk and response adapted chemotherapy reduces late toxicity risk. In low stage disease, chemotherapy alone may be curative, but in high stage cases, radiotherapy must also be employed. There are several effective regimens, using agents such as vincristine, procarbazine, doxorubicin, prednisone, etoposide, cyclophosphamide, vinblastine, bleomycin, mechlorethamine and methotrexate . Five cycles of chemotherapy plus 21 Gy of involved-field radiation are usually curative. Relapse cases benefit from autologous stem cell transplantation in terms of disease-free survival. Another approach to these patients is represented by a combination of ifosfamide with vinorelbine or gemcitabine with vinorelbine . New therapeutic agents, currently under evaluation include Brentuximab Vedotin (an anti-CD30 antibody) and Bortezomib (an NF-kB pathway inhibitor).
Radiation protocols are seen as adjuvant therapeutic tools. The lowest effective dose applied to the smallest possible involved field is optimum, but regimens using extended fields do exist. Clinical trials evaluating the outcome of chemotherapy with no adjuvant radiotherapy are currently being conducted. Supportive medication includes blood or red blood cells transfusions, antifungal and anti Pneumocystis carinii prophylaxis, proton pump inhibitors, analgesics and antiemetics. Relapses most often occur during the first three years after therapy has been stopped. Long-term monitoring should focus on hypothyroidism, infertility, cardiac and pulmonary toxicity and secondary malignancy like breast cancer, non-Hodgkin lymphoma, thyroid cancer or acute leukemia.
Childhood Hodgkin's disease prognosis is good for all stages and excellent for stages I and II at diagnosis in developed countries. 5-year survival exceeds 70% for all cases and 90% for incipient phase patients.
Certain clinical and biological parameters have proved their prognosis validity in children. These include fever, large mediastinal adenopathy, stage IV disease and albumin level below 3.5 g/dL. These patients benefit from early augmentation of therapy  .
The etiology of childhood Hodgkin's disease remains unknown. Epstein-Barr virus may be involved in this condition's pathogenesis , as demonstrated by the presence of viral proteins in up to 30% of cases . Mixed cellularity cases more often demonstrate the presence of viral antigens , whereas nodular lymphocyte-predominant Hodgkin's disease rarely does . HIV-positive patients more often develop this condition, as do the siblings of affected children, thus suggesting a genetic predisposition . This may be attributable to an atypical immune response to a trigger. HLA-DRB1, HLA-DQB1 and single-nucleotide polymorphisms in the 6p21.32 region imply an increased risk for this disease  .
5.5 cases per million children under 15 are registered worldwide. Adolescents (aged 15 to 20) are more prone towards developing this condition, with rates as high as 12.1 cases per million population. Developing countries have a peak of incidence in male children, whereas teenagers are more frequently affected in developed nations. Boys younger than 10 years old develop this condition three times more frequently than girls, but the ratio becomes 1:1 after this age.
The disease accounts for 7% of childhood cancers and causes 1% of cancer-related deaths . Infants rarely develop Hodgkin's disease, but it is the most frequent type of malignancy in the 15 to 19 years old group.
Childhood Hodgkin's disease affects the lymphatic and reticuloendothelial systems . It is more intimately related to Epstein-Barr virus infection than adult Hodgkin's disease because children (aged 0 to 14) exhibit the viral DNA un their Reed-Sternberg cells more often than young adults (15 to 39). The Reed-Sternberg cell suffers from gene rearrangements and undergoes clonal expansion. Furthermore, they fail to undergo apoptosis , as other cells with unfavorable mutations may. This is believed to be caused by the interaction with Epstein-Barr virus or by a yet undetermined genetic predisposition. Identical twins of affected children are much more prone to develop Hodgkin's disease, as are patients suffering from acquired or congenital immunodeficiency disorders.
Childhood Hodgkin's disease cannot be effectively prevented because its causes have not yet been fully elucidated. However, keeping in mind that the Epstein-Barr virus has been incriminated in disease pathophysiology and the human immunodeficiency virus infection is known to increase the risk of developing this condition, it is rational to try to prevent viral infection, by counseling pregnant women and the general population about the risks associated with intravenous drug use and unprotected sexual intercourse. There is no proved way to prevent Epstein-Barr virus infection.
Childhood Hodgkin's disease accounts for approximately 40% of all cancer cases encountered during this life period, but it represents the most frequent malignancy in adolescence and early adulthood. It is considered a highly curable disease, with a prognosis that has improved over the years due to chemotherapy and radiotherapy use. However, treatment induces long-term toxicity, therefore the regimen to be used must be individualized according to patient risk.
The disease causes painless, but persistent adenopathies accompanied by fever, weight loss, fatigability, urticaria, bone pain and night sweats. Large mediastinal bulky disease causes superior vena cava syndrome. The diagnosis is established by anatomopathological examination of a lymph node, that reveals the presence of the pathognomonic Reed-Sternberg cell. Disease extension is established using imaging modalities, such as thoracic radiography, computed tomography, positron emission tomography or nuclear imaging with gallium scan and magnetic resonance imaging. The use of ionizing radiation during these procedures should be reduced to a minimum.
Treatment implies several combined chemotherapy regimens, designed to reduce long-term toxicity and adverse effects, such as infertility, leukemia and cardiopulmonary toxicity. Relapse cases benefit from autologous stem cell transplantation after salvage chemotherapy.
Childhood Hodgkin's disease causes the superficial or profound lymph nodes to enlarge and sometimes become palpable as a lump located on the lateral side of the neck, in the groin or in the armpit. The child experiences tiredness, lack of appetite and fever, loses weight and sweats abundantly during the night. Less common symptoms include chest pain and cough. The doctor will order several types of blood tests and will need to take out one of the enlarged lymph nodes in order to examine it. Several types of imaging methods are used in order to determine the extent of the disease. Treatment implies administration of a combined chemotherapy regimen, adapted to how serious and extensive the condition is.