OVERVIEW
A chronic progressive, painless malignant tumor of the lymphatic tissue occurring in children and adolescents.
The main manifestations are unexplained fever, night sweats, weight loss, and enlarged lymph nodes.
The cause of the disease may be related to EBV infection, immunodeficiency and genetic factors.
The main treatment modality is chemotherapy combined with radiotherapy.
Definition
Hodgkin’s lymphoma (HL) in children and adolescents is a chronic progressive, painless malignant tumor of lymphoid origin [1,3].
Primary tumors tend to have a centrifugal distribution, originating in one or a group of lymph nodes, usually in the neck and supraclavicular region, followed by submandibular, mediastinal, axillary, and inguinal regions, and gradually spreading to adjacent lymph nodes and tissues [1-2].
Staging
Due to the differences in pathomorphology, prevalent populations, treatment principles, and prognosis, HL is categorized into two types: classic and nodular lymphocyte-predominant.
Classic type (CHL)
It can be subdivided into 4 subtypes: mixed cell type, nodular sclerosis type, lymphocyte-rich type, and lymphocyte-absent type.
These four subtypes are characterized by “classic” mirror cells with positive expression of CD30 and CD15, and approximately 50% of the pathologic tissue expresses EBV-encoded RNA (EBER) [3].
Nodular lymphocyte predominant type (NLPHL)
The presence of specific lymphocyte-predominant cells within the tumor, which usually do not express CD15 and CD30, but rather CD20, CD79α and CD75, is a specific HL subtype.
Nearly 50% of cases express epithelial membrane antigens in the pathologic tissue,but not EBER [3].
Morbidity
Hodgkin’s lymphoma in children and adolescents accounts for 5% of all childhood tumors and 15-20% of childhood lymphomas, with a higher incidence in boys than in girls, and a rare incidence under 5 years of age [2].
Etiology
Causes of the disease
The etiology is not clear, but some studies suggest that it may be related to viral infection and genetic factors.
Infection
It is currently believed that viral, especially Epstein-Barr (EB) virus infection may be closely related to the onset of the disease [2].
In China, the detection rate of EBV in HL tissues ranges from 48% to 57% [5].
Viral infection leads to sustained proliferation of lymphoid tissue, causing surface antigenic changes in lymphocytes of the thymic system. Such cells in turn interact with normal T-lymphocytes to form tumorigenic reticulocytes and terminal multinucleated giant reticulocytes (R-S cells), which deplete lymphoid immunity and lead to tumor development [2].
Genetic factors
HL occurs in clusters in family members and those with a family history of HL have a higher risk of developing HL than others.
Identical twins have a significantly higher risk of concurrent HL than dizygotic twins. In addition, specific alleles can increase HL susceptibility [5].
Immunosuppression or defects
People who are chronically immunosuppressed, have congenital immunodeficiencies, or have autoimmune diseases such as systemic lupus erythematosus may also be at increased risk of developing the disease.
Predisposing factors
In addition to genetic factors, viral infections and other causative factors, some studies have shown that regular exposure to some environmental chemical exposures may also be associated with the development of the disease [2].
Symptoms
Main Symptoms
Systemic symptoms
Children may present with unexplained fever, night sweats, and weight loss [1].
Localized symptoms of enlarged lymph nodes
Lymph node enlargement is the first symptom in 90% of children, and the most common symptom is painless enlargement of cervical lymph nodes [1].
Enlarged lymph nodes can cause a series of symptoms by compressing the surrounding tissues, such as pain caused by enlarged lymph nodes compressing nerves, and enlarged mediastinal lymph nodes can cause coughing, chest tightness, shortness of breath, etc. [5].
Symptoms of extra-lymph node involvement
With the progression of the disease can gradually spread to other non-lymph node tissues, which can involve spleen, liver, lungs, bones, etc [1].
Splenic metastasis: as a part of lymphatic tissue, spleen is one of the most common sites of involvement in HL, mostly mild enlargement without obvious symptoms, only when the spleen is significantly enlarged, abdominal pain.
Liver metastasis: manifested by loss of appetite, sometimes accompanied by nausea, vomiting, etc.; vague pain in the right upper abdomen, persistent or intermittent pain in the liver area, yellowing of the skin and sclera, ascites, itching of the skin.
Lung metastasis: dry cough, low fever, small amount of blood in sputum, dyspnea and other symptoms.
Bone metastasis: rare, can cause bone pain in the corresponding area, and severe invasion of the spinal cord can cause limb motor sensory impairment [5].
Other symptoms
Some children may be accompanied by fever, night sweats, weight loss, fatigue, itchy skin and other symptoms and manifestations [1].
Consultation
Department of Medicine
Pediatrics
Children and adolescents with painless enlargement of the lymph nodes in the neck or supraclavicular region, accompanied by unexplained fever, night sweats, and weight loss are advised to seek prompt medical attention.
Hematology
Children and adolescents may also visit the Department of Hematology if they experience any of the above conditions.
Preparation
Preparation for consultation: registration, preparation of documents, common problems
Tips for Consultation
Parents can keep a detailed record of the symptoms your child has experienced, as well as the time of occurrence and changes in the symptoms for the doctor’s reference.
It is recommended to dress your child in clothes that are easy to put on and take off for the doctor’s physical examination.
Preparation Checklist for Doctor’s Visit
Symptom list
Pay particular attention to the time of onset of symptoms, special manifestations, etc.
Does the child have fever, night sweats, weight loss, enlarged lymph nodes?
What is the highest temperature reached by the child’s fever? How long does each fever last?
How often does the fever occur and is there a pattern? Are there any obvious triggers for the fever?
How much weight has the child lost? How long has this been happening?
When did the child’s lymph nodes become enlarged? Is it painful to press? Is there any change in skin temperature on the surface of the lymph nodes?
Other than these symptoms, does the child have any discomfort in other parts of the body?
List of medical history
Does the child have a history of previous EBV or other viral infections?
Has the child had any previous immune system disorders?
Does the child have any relatives with a history of lymphoma or other tumors?
Diagnosis
Basis of diagnosis
Medical History
The child may have a history of EBV infection.
The child’s relatives may have a history of lymphoma or tumor.
Clinical manifestations
Symptoms
Common symptoms of lymphoma in children include systemic and localized symptoms.
Systemic symptoms: include unexplained fever, night sweats, and weight loss.
Local symptoms: Persistent painless swelling of cervical or supraclavicular lymph nodes is the most common clinical manifestation of HL in children. Symptoms such as itching and malaise may also be present [1].
Physical signs
Palpation may reveal enlarged cervical or supraclavicular lymph nodes, as well as submandibular, axillary, and inguinal, superficial lymph nodes.
The enlarged lymph nodes are easily palpable and are typically rubbery, hard and nontender [1].
Laboratory tests
Routine blood tests
Routine blood tests can help doctors know whether the patient’s white blood cells, lymphocytes, eosinophils, erythrocyte sedimentation rate and monocyte counts are normal or not, and know whether there is anemia, which can help doctors make a preliminary judgment on the patient’s condition.
Most of the tests find elevated white blood cells, mild to moderate anemia, lymphocytopenia, eosinophilia, and monocytosis, or there may be a decrease in the number of whole blood cells [1].
Blood biochemistry
Lactate dehydrogenase helps to infer the prognosis of the child.
Serum alkaline phosphatase or calcium may help to see if the lesion has invaded the bone.
Bone marrow biopsy
A bone marrow smear that reveals R-S cells indicates the presence of bone marrow invasion [1].
Imaging
Ultrasound
Ultrasound can detect enlarged lymph nodes that are missed on physical examination when palpating superficial lymph nodes [5].
X-ray examination
Chest radiographs are taken to understand mediastinal widening, enlarged lung hilums, pleural fluid and lung lesions.
CT.
Chest CT identifies enlarged mediastinal and hilar lymph nodes, and interstitial lung involvement, pleural effusion, pericardial effusion, and chest wall masses, all of which can be visualized on chest CT [5].
CT abdomen shows involvement of para-abdominal aortic lymph nodes, splenic hilar, hepatic hilar and mesenteric lymph nodes, as well as hepatic, splenic and renal involvement [5].
MRI.
The method of choice for the examination of lesions in the central nervous system, bone marrow, and muscular areas; it is also indicated for those for whom enhanced CT scanning is contraindicated, or as a further examination after a suspicious lesion has been detected on CT.
It is advantageous for identifying post-treatment fibrosis with residual or recurrent tumor [1].
PET-CT
PET-CT can sensitively and specifically detect lymphoma lesions and determine the efficacy of treatment, and can better identify necrosis, fibrotic tissue or tumor than CT or MRI.
It can be used as an important tool for lymphoma diagnosis and efficacy evaluation, and is the standard for HL staging [5].
Pathologic examination
Lymph node biopsy
Lymph node pathology is the main tool to determine the diagnosis of lymphoma.
The pathomorphologic features are typical HRS tumor cells, sparse tumor cells, and a large number of inflammatory background cells. Finding HRS cells is the basis for diagnosing the disease [1].
Lymphocyte differentiation antigen detection
In almost all cases of classical HL, RS cells express CD30, most express CD15, are negative for CD45, and a few cells are positive for CD20 with variable staining intensity.
Tumor cells in NLPHL usually retain expression of CD45 and B-cell lineage markers (CD20, Ig), but are negative for both CD15 and CD30 [5].
Gene rearrangements
Gene rearrangements of the B-cell heavy chain are found in the vast majority of classic HL cases, confirming B-cell origin [5].
Staging
Disease staging
Ann Arbor staging is currently the most widely used staging method for HL in children and adolescents [6].
Staging site of involvement
Stage I Involvement of a single lymph node region or lymphoid structures such as the spleen, thyroid, Ring of Weiss, etc. or other extra-nodal organs/sites (IE)
Stage I
Invasion of single lymph node area or lymphoid structures, e.g., spleen, thyroid gland, Vesiculocyte ring, etc. or other extra-nodal organs/sites (IE)
Stage II on one side of the diaphragm with invasion of two or more lymph node areas or plus limited invasion of 1 extra-nodal organ/site (IIE)
Stage II
On one side of the diaphragm, invasion of two or more lymph node areas, or plus limited invasion of 1 extra-nodal organ/site (IIE)
Stage III invasion of lymph node areas on both sides of the diaphragm (III), or plus limited invasion of 1 extrajunctional organ/site (IIIE) or spleen (IIIS) or both (IIISE)
Stage III
Invaded lymph node areas on both sides of the diaphragm (III), or additional limited invasion of 1 extranodal organ/site (IIIE) or spleen (IIIS) or both (IIISE)
III1 with or without splenic hilar, abdominal or hilar region lymph node involvement
III1
With or without splenic hilar, ventral or hilar lymph node involvement
III2 with para-aortic, iliac, and mesenteric lymph node involvement
Ⅲ2
With para-aortic, iliac, and mesenteric lymph node involvement
Stage IV Diffuse or disseminated invasion of 1 or more extranodal organs with or without lymph node involvement
Stage IV
Diffuse or disseminated invasion of one or more extranodal organs with or without lymph node involvement.
Children and adolescents with HL are staged in combination with the following letters of the alphabet, which have special meanings.
A asymptomatic
B fever (temperature over 38°C), nocturnal night sweats, unexplained weight loss of more than 10% over 6 months
B
Fever (temperature over 38°C), night sweats, unexplained weight loss of more than 10% within 6 months
E Single extranodal involvement, lesion involving lymph nodes/lymphatic tissues directly connected or adjacent organs/tissues
E
Single extranodal involvement with involvement of lymph nodes/lymphatic tissues directly connected or adjacent organs/tissues
S Splenic involvement
S
Splenic involvement
Risk stratification
The risk stratification of this disease varies among different collaborative groups and is based on the Chinese Society of Clinical Oncology (CSCO) Guidelines for the Management of Lymphoma in Children and Adolescents 2020 as follows.
Low risk: stage IA or IIA without associated large mass.
Intermediate risk: Stage IB or IIB lesions; Stage IA or IIA with large mass; Stage IAE or IIAE, Stage IIIA or IVA lesions with or without large mass.
High risk: stage IIIB or IVB lesions [6].
[Special reminder].
A large peripheral lymph node mass is defined as a single or multiple intermingled lymph nodes greater than 6 cm in diameter.
A large mediastinal mass is defined as a mediastinal tumor with a diameter of ≥10 cm on CT or greater than 1/3 of the internal diameter of the thorax on chest X-ray.
Differential diagnosis
Anaplastic large cell lymphoma (ALCL)
Many ALCL contain HRS-like cells, all with strong expression of CD30.
CHL is a B-cell disease, whereas most ALCL remain of T-cell origin. ALK gene positivity, T-cell markers or T-cell gene rearrangements in children are a strong basis for identifying CHL in ALCL [1].
Mediastinal (thymic) large B-cell lymphoma
known as PMLBCL, is clinically and pathologically similar to CHL. Features such as HRS-like cells can be found occasionally.
However, tumor cells in PMLBCL usually strongly express B-cell markers such as CD20. CD30 expression can be positive but not as strong as in CHL. Ig gene rearrangements are usually positive, whereas they are negative in CHL [1].
Lymphadenitis
Lymphadenitis is mostly characterized by foci of infection and enlarged lymph nodes with acute phase symptoms such as redness, swelling, heat and pain.
After the acute phase, the lymph nodes shrink and the pain disappears. Lymph node enlargement in chronic lymphadenitis is usually 0.5 to 1.0 cm, softer, flatter, and more mobile, unlike the large, plump, and tough texture of enlarged lymph nodes in HL [5].
Lymphadenopathy
It is most common in adolescents and middle-aged adults, mostly invades the lymph nodes, and may be accompanied by multiple enlarged lymph nodes, commonly with symmetrical enlargement of hilar lymph nodes, or with involvement of paratracheal and supraclavicular lymph nodes.
The lymph nodes are mostly within 2cm in diameter, and the texture is usually hard, which may be accompanied by prolonged low-grade fever. Biopsy pathology may reveal epithelioid nodules, and angiotensin-converting enzyme is elevated in both lymph nodes and serum [5].
Treatment
Aim of treatment: to completely eliminate tumor cells, so that the children can obtain clinical cure.
Treatment principle: according to the clinical staging, pathological staging and risk stratification, the corresponding treatment program is adopted according to the doctor’s prescription. The main focus is on comprehensive treatment combining small-dose radiotherapy and chemotherapy in the affected area [6].
Primary treatment program
Classic
Low-risk
Chemotherapy usually adopts 3 courses of AV-PC (Adriamycin + Vincristine + Prednisone + Cyclophosphamide) regimen ± Involved Region Radiotherapy (IFRT, 21Gy).
Or a 4-course ABVD (Adriamycin + bleomycin + vincristine + dacarbazine) regimen ± IFRT (21 Gy) [6-9].
Medium risk.
Take 4 courses of ABVE-PC (Adriamycin + Bleomycin + Vincristine + Etoposide + Prednisone + Cyclophosphamide) regimen ± IFRT (21Gy).
Or take 6 courses of COPP/ABV (cyclophosphamide + vincristine + procarbazine + prednisone/adriamycin + bleomycin + vincristine) regimen ± IFRT (21 Gy).
High risk.
CT or PET-CT evaluation after taking 2 courses of ABVE-PC regimen, complete remission on efficacy assessment or negative PET-CT is considered as fast response, otherwise it is considered as slow response.
Fast response: 2 courses of ABVE-PC regimen + radiotherapy (21 Gy in the area of the large mass at the onset of disease).
Slow response: take 2 courses of IV (isocyclophosphamide + vincristine) regimen + 2 courses of ABVE-PC regimen + radiotherapy (PET-CT positive area and any >2.5 cm lesion after 2 courses, 21 Gy) [6].
Nodular lymphocyte predominant type
Low-risk: take 3 courses of AV-PC regimen or 4-6 courses of COPP/ABV regimen ± radiotherapy (21Gy) or 4 courses of VAMP (vincristine + adriamycin + methotrexate + prednisone) regimen.
Intermediate risk: same as classic.
High risk: same as classic [6].
[Special Note
Gy is the unit of absorbed dose for radiation therapy and is used to define the amount of energy absorbed per unit mass of irradiated material.
Relapsed or refractory HL regimen
Low-risk at relapse and initial treatment without radiotherapy: salvage chemotherapy + RT according to the initial intermediate-risk or high-risk regimen.
Other relapsed refractory HL: salvage chemotherapy + high-dose chemotherapy combined with autologous stem cell transplantation.
Prognosis
Cure
Long-term survival is better in children and adolescents with Hodgkin’s lymphoma.
Most pediatric HL is cured with standard therapy, but 10% to 20% of patients still relapse or progress.
Relapsed/refractory pediatric HL can still have good survival with aggressive salvage therapy [6].
[Special reminder].
The overall survival time of cancer patients can be roughly predicted by the 5- or 10-year survival rate, which refers to the proportion of patients whose tumors survive for 5 or 10 years or more after a variety of comprehensive treatments.The probability of recurrence after 5 or 10 years is very low, and can generally be regarded as clinical cure.
Statistics such as the 5- or 10-year survival rate are for clinical research only and do not represent an individual’s specific survival period.
Prognostic Factors
Primary staging is relevant. If radiotherapy and chemotherapy are combined, the 5-year survival rate is as high as 90% for children with stage I and II, 80% for stage III, and only 25-50% for stage IV [2,10].
Hazards.
Enlarged lymph nodes can compress the adjacent organs and cause a series of discomforts which seriously affect the daily life and study of the children [5].
Repeated fever over a long period of time can deplete the body, seriously affecting the energy and stamina for study and life.
Superficial lymph node enlargement affects the appearance of children and may lead to low self-esteem and other psychological aspects.
Radiotherapy may lead to secondary tumors such as leukemia and other solid tumors [2].
Daily
Daily management
Care related to treatment related side effects
Leukopenia: low white blood cells are prone to infections, parents should pay attention to keeping the child warm and resting, avoiding catching cold and reducing close contact with people to reduce the risk of infection.
Anorexia, nausea and vomiting: Eat small meals and eat easily digestible and light food. If necessary, consult your doctor if you need to take anti-emetic drugs. If eating too little, supplemental enteral nutrition can be used to maintain.
Generalized fatigue: adequate rest and nutritional supplementation with sufficient calories and protein can help relieve discomfort.
Hair loss: Hair loss during radiotherapy is reversible and hair will grow back after the treatment is finished, so there is no need to worry too much.
Radiation skin damage: Parents should pay attention to protect the child’s radiotherapy irradiated area skin clean and dry, avoid sun exposure, hot and cold water, soap and other irritants to the skin stimulation, the use of soft and wide cotton underwear close to the body.
Emotion management
After diagnosis, children may have fear, loneliness, sensitivity and fear of pain. Parents should pay attention to accompany, communicate and encourage the children to keep confidence and optimism, and face the treatment positively.
Life management
Keep the living environment clean, disinfected regularly, with sufficient sunlight and suitable temperature and humidity.
Wear a good mask when going to and from public places.
Dietary management
Eat a balanced diet with a variety of food types.
Choose vitamin-rich vegetables and fruits (e.g. tomatoes, celery, kiwi, etc.) and protein-rich foods (milk, eggs, fish, etc.).
Rest and exercise
Children with fever and obvious pressure symptoms should rest in bed to reduce physical exertion, avoid staying up all night or exertion, and ensure sufficient sleep to promote recovery of the body.
When the condition improves, start with low intensity exercise such as walking, and gradually resume normal activities.
People with low platelets and easy bleeding should avoid excessive activities and trauma.
Disease monitoring
For children with advanced disease, the progress of the disease should be monitored. If symptoms worsen sharply, such as worsening dyspnea, confusion, convulsions, or cardiac arrhythmia, they should go to the emergency room of the hospital as soon as possible.