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.
Presentation
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.
Hematological
- Hemophilia A
Thrombosis and Haemostasis, Medical Society of the State of New York, New York Academy of Sciences, Society for Pediatric Research, Southern Society for Pediatric Research, Children's Oncology Group, Eastern Society for Pediatric Research, National Hemophilia [emedicine.medscape.com]
Entire Body System
- Fever
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. [symptoma.com]
No fever, night sweats, or weight loss. Symptomatic (B). Symptoms of fever, night sweats, or weight loss. How is Hodgkin lymphoma treated in a child? Most children with Hodgkin lymphoma are treated successfully and cured. [urmc.rochester.edu]
However, there is increasing evidence that infections (such as the virus that causes glandular fever) may play a part in its development, especially when it occurs in children. [childrenwithcancer.org.uk]
In adults, lifestyle and environmental... read more Symptoms Symptoms of Hodgkin disease may include: fever night sweats unexplained weight loss enlarged lymph nodes, usually felt as painless lumps under the skin in the ... read more Diagnosis Your child [childrenscancer.canceraustralia.gov.au]
- Weight Loss
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. [symptoma.com]
No fever, night sweats, or weight loss. Symptomatic (B). Symptoms of fever, night sweats, or weight loss. How is Hodgkin lymphoma treated in a child? Most children with Hodgkin lymphoma are treated successfully and cured. [urmc.rochester.edu]
In adults, lifestyle and environmental... read more Symptoms Symptoms of Hodgkin disease may include: fever night sweats unexplained weight loss enlarged lymph nodes, usually felt as painless lumps under the skin in the ... read more Diagnosis Your child [childrenscancer.canceraustralia.gov.au]
Symptoms include Painless swelling of the lymph nodes in the neck, armpits, or groin Fever and chills Night sweats Weight loss Loss of appetite Itchy skin To diagnose Hodgkin disease, doctors use a physical exam and history, blood tests, and a biopsy. [medlineplus.gov]
- Anemia
Coombs' tests may continue to be persistently positive when anemia is absent. [ncbi.nlm.nih.gov]
Diagnostic methods Diagnosis is based on evidence of increased levels of homocystine in urine, and homocysteine or homocystine in plasma, and presence of megaloblastic anemia. Plasma methionine is frequently low. [orpha.net]
[…] http://www.ebi.ac.uk/efo/EFO_0005597 Methylmalonic acidemia with homocystinuria is an inborn error of vitamin B12 (cobalamin) metabolism characterized by megaloblastic anemia, lethargy, failure to thrive, developmental delay, intellectual deficit and [ebi.ac.uk]
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. [symptoma.com]
- Fatigue
Many people experience fatigue during radiation therapy. More-serious risks include heart disease, stroke, thyroid problems, infertility and other cancers, such as breast or lung cancer. [mayoclinic.org]
If your child has Hodgkin lymphoma, the following symptoms may be present: Swollen (but not sore) lymph nodes in the neck, chest, armpit or groin Extreme fatigue Loss of appetite Weight loss Fever Night sweats Itchy skin How is Hodgkin lymphoma treated [stjude.org]
They can include: Painless swelling of the lymph nodes in the neck, underarm, groin, or chest Trouble breathing (dyspnea) Coughing Chest pain Fever Night sweats Tiring easily (fatigue) Loss of appetite Weight loss Itching skin (pruritus) Frequent viral [urmc.rochester.edu]
- Epilepsy
Some patients with CBS deficiency may also suffer from connective tissue abnormalities and/or developmental delay, cognitive impairment and epilepsy. [docplayer.cz]
Respiratoric
- Cough
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. [symptoma.com]
Others may have one or more of these: swelling of the lymph nodes (swollen glands) in the neck, underarm, or groin unexplained cough and shortness of breath if the cancer involves the lymph nodes in the chest tiredness poor appetite itching rash nighttime [kidshealth.org]
Cough or breathlessness can occur if the glands in the chest are affected. Also fevers, sweats, itching and weight loss can occur. [childrenwithcancer.org.uk]
They can include: Painless swelling of the lymph nodes in the neck, underarm, groin, or chest Trouble breathing (dyspnea) Coughing Chest pain Fever Night sweats Tiring easily (fatigue) Loss of appetite Weight loss Itching skin (pruritus) Frequent viral [urmc.rochester.edu]
- Dyspnea
They can include: Painless swelling of the lymph nodes in the neck, underarm, groin, or chest Trouble breathing (dyspnea) Coughing Chest pain Fever Night sweats Tiring easily (fatigue) Loss of appetite Weight loss Itching skin (pruritus) Frequent viral [urmc.rochester.edu]
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 [symptoma.com]
S...Kong X 30157807 2018 14 Methylmalonic acidemia: Current status and research priorities. 38 Zhou X...Han J 29862147 2018 15 Whole-exome Sequencing Helps the Diagnosis and Treatment in Children with Neurodevelopmental Delay Accompanied Unexplained Dyspnea [malacards.org]
Cardiovascular
- Chest Pain
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. [symptoma.com]
They can include: Painless swelling of the lymph nodes in the neck, underarm, groin, or chest Trouble breathing (dyspnea) Coughing Chest pain Fever Night sweats Tiring easily (fatigue) Loss of appetite Weight loss Itching skin (pruritus) Frequent viral [urmc.rochester.edu]
Skin
- Night Sweats
No fever, night sweats, or weight loss. Symptomatic (B). Symptoms of fever, night sweats, or weight loss. How is Hodgkin lymphoma treated in a child? Most children with Hodgkin lymphoma are treated successfully and cured. [urmc.rochester.edu]
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. [symptoma.com]
In adults, lifestyle and environmental... read more Symptoms Symptoms of Hodgkin disease may include: fever night sweats unexplained weight loss enlarged lymph nodes, usually felt as painless lumps under the skin in the ... read more Diagnosis Your child [childrenscancer.canceraustralia.gov.au]
Symptoms include Painless swelling of the lymph nodes in the neck, armpits, or groin Fever and chills Night sweats Weight loss Loss of appetite Itchy skin To diagnose Hodgkin disease, doctors use a physical exam and history, blood tests, and a biopsy. [medlineplus.gov]
- Pruritus
They can include: Painless swelling of the lymph nodes in the neck, underarm, groin, or chest Trouble breathing (dyspnea) Coughing Chest pain Fever Night sweats Tiring easily (fatigue) Loss of appetite Weight loss Itching skin (pruritus) Frequent viral [urmc.rochester.edu]
Additional symptoms include urticaria, bone or back pain and pruritus. Physical examination reveals variably enlarged spleen and liver. [symptoma.com]
Neurologic
- Seizure
Clinical features include developmental delay, stomatitis, glossitis, seizures and methylmalonic aciduria responsive to vitamin B12. [malacards.org]
0005597 Methylmalonic acidemia with homocystinuria is an inborn error of vitamin B12 (cobalamin) metabolism characterized by megaloblastic anemia, lethargy, failure to thrive, developmental delay, intellectual deficit and seizures.intellectual deficit and seizures [ebi.ac.uk]
Clinical description Homocystinuria without methylmalonic aciduria manifests mainly in early childhood with failure to thrive, megaloblastic anemia, developmental delay, hypotonia, seizures and cerebral atrophy with white matter abnormalities. [orpha.net]
Congenital absences of molybdenum cofactor with combined XDH/XO/sulfite oxidase deficiency is usually associated with severe neurological disorders such as neonatal period intractable seizures, dysmorphic features, mental retardation and coma and elevated [docplayer.cz]
Workup
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 [1] 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 [2]: nodular sclerosis, lymphocyte-rich. lymphocyte depleted, mixed cellularity and nodular lymphocyte-predominant Hodgkin lymphoma.
X-Ray
- Mediastinal Mass
A mediastinal mass greater than 1/3 the thoracic width was present in 19 children of whom 18 achieved remission and none relapsed. An infradiaphragmatic presentation occurred in eight, all achieved remission and none relapsed. [ncbi.nlm.nih.gov]
Finding a mediastinal mass larger than one-third of the thoracic diameter holds prognostic importance, and evaluation is feasible on anteroposterior and lateral projections. [symptoma.com]
Serum
- Monocytosis
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. [symptoma.com]
- Lymphopenia
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. [symptoma.com]
Treatment
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 [3]. 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 [4]. 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.
Prognosis
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 [5] [6].
Etiology
The etiology of childhood Hodgkin's disease remains unknown. Epstein-Barr virus may be involved in this condition's pathogenesis [7], as demonstrated by the presence of viral proteins in up to 30% of cases [8]. Mixed cellularity cases more often demonstrate the presence of viral antigens [9], whereas nodular lymphocyte-predominant Hodgkin's disease rarely does [10]. HIV-positive patients more often develop this condition, as do the siblings of affected children, thus suggesting a genetic predisposition [11]. 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 [12] [13].
Epidemiology
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 [14]. Infants rarely develop Hodgkin's disease, but it is the most frequent type of malignancy in the 15 to 19 years old group.
Pathophysiology
Childhood Hodgkin's disease affects the lymphatic and reticuloendothelial systems [15]. 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 [16], 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.
Prevention
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.
Secondary prevention refers to minimizing the risk for a second malignancy due to treatment, and this is achieved by minimizing the use of radiation therapy in all types of childhood cancer.
Summary
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.
Patient Information
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.
References
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- Küppers R, Yahalom J, Josting A. Advances in biology, diagnostics, and treatment of Hodgkin's disease. Biol Blood Marrow Transplant. 2006;12(1 Suppl 1):66-76.
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- Cole PD, Schwartz CL, Drachtman RA, de Alarcon PA, Chen L, Trippett TM. Phase II study of weekly gemcitabine and vinorelbine for children with recurrent or refractory Hodgkin's disease: a children's oncology group report. J Clin Oncol. 2009;27(9):1456-61.
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- Pallesen G, Hamilton-Dutoit SJ, Rowe M, Young LS. Expression of Epstein-Barr virus latent gene products in tumour cells of Hodgkin's disease. Lancet. 1991;337(8737):320-2.
- Weiss LM, Chen YY, Liu XF, Shibata D. Epstein-Barr virus and Hodgkin's disease. A correlative in situ hybridization and polymerase chain reaction study. Am J Pathol. 1991;139(6):1259-65.
- Harty LC, Lin AY, Goldstein AM, Jaffe ES, Carrington M, Tucker MA, et al. HLA-DR, HLA-DQ, and TAP genes in familial Hodgkin disease. Blood. 2002;99(2):690-3.
- Cozen W, Li D, Best T, Van Den Berg DJ, Gourraud PA, Cortessis VK, et al. A genome-wide meta-analysis of nodular sclerosing Hodgkin lymphoma identifies risk loci at 6p21.32. Blood. 2012;119(2):469-75.
- Enciso-Mora V, Broderick P, Ma Y, Jarrett RF, Hjalgrim H, Hemminki K, et al. A genome-wide association study of Hodgkin's lymphoma identifies new susceptibility loci at 2p16.1 (REL), 8q24.21 and 10p14 (GATA3). Nat Genet. 2010;42(12):1126-30.
- Ward E, DeSantis C, Robbins A, et al. Childhood and adolescent cancer statistics, 2014. CA Cancer J Clin 2014; 64:83.
- Glaser SL, Clarke CA, Nugent RA, Stearns CB, Dorfman RF. Social class and risk of Hodgkin's disease in young-adult women in 1988-94. Int J Cancer. 2002;98(1):110-7.
- Ng AK, Mauch PM. Late effects of Hodgkin's disease and its treatment. Cancer J. 2009;15(2):164-8.