| disease | Hodgkin's Disease |
| alias | Hodgkin's Disease, Lymphoreticular Cell Fleshy Tumor, Lymphoma, Hodgkin's Disease |
Hodgkin's disease, also known as lymphoreticular fleshy tumor, is a chronic progressive and painless tumor of the lymphoid tissue. Its original follicular tumor often exhibits centrifugal distribution, originating from one or a group of lymph nodes, with the cervical lymph nodes being the most common primary site. It gradually spreads to adjacent lymph nodes and then invades tissues such as the spleen, liver, bone marrow, and lungs. Due to the varying sites of onset, its clinical manifestations are diverse. It rarely occurs before the age of 5, gradually increases thereafter, and shows a significant rise during adolescence, peaking between the ages of 15 and 34. The disease is more common in males than in females, with a male-to-female ratio of 3:1 in children aged 5–11 and 1.5:1 in those aged 11–19.
bubble_chart Pathological Changes
The affected lymph nodes are enlarged, with normal structure destroyed and partially or completely replaced by tumor tissue. Microscopically, the lymph nodes are infiltrated by granulomatous tissue, containing mononuclear or multinucleated Sternberg-Reed cells, along with infiltrates of lymphocytes, eosinophils, and plasma cells, and possible fibrous tissue formation. The identification of Sternberg-Reed cells is the basis for diagnosing this disease.
Recent studies have found that different pathological changes are closely related to prognosis. To adopt different effective treatments, further classification is necessary. Currently, the Rye classification is widely used internationally and domestically, dividing the disease into four types based on prognosis.
1. Lymphocyte-predominant type: This is the most differentiated type and can be considered an early stage of Hodgkin's disease, with relatively low malignancy. Lesions are often confined to one or a group of lymph nodes. Clinical symptoms are mild or absent. Microscopically, in areas where normal lymphoid structure is lost, lymphocytes and histiocytes proliferate in varying proportions, often with small lymphocytes predominating; Sternberg-Reed cells are rare and atypical. There is no necrotic change in the lymph nodes. This type is difficult to distinguish from inflammatory or sexually transmitted disease changes and is prone to misdiagnosis. It accounts for about 10–20% of cases and has the best prognosis.
2. Nodular sclerosis type: This type rarely transforms into other types. It commonly occurs in mediastinal lymph nodes and may also involve supraclavicular lymph nodes, but rarely affects abdominal lymph nodes. Clinical progression is slow. The lesions contain abundant collagen fibers that divide tumor cells into nodules. Sternberg-Reed cells are often found in lacunar spaces, hence called lacunar cells. This is the most common type in children, accounting for about half of cases, with a prognosis second only to the lymphocyte-predominant type.3. Mixed cellularity type: This may evolve from the lymphocyte-predominant type. Most patients have obvious clinical symptoms. The lymph node structure is diffusely effaced, though initially only partial destruction occurs. The lesions contain various cells, including lymphocytes, histiocytes, eosinophils, and plasma cells, along with typical Sternberg-Reed cells featuring binucleate, lobulated, or multinucleated forms with prominent nucleoli. This type is highly variable—typical cases are easily diagnosed, while atypical ones may resemble inflammatory granulomas, subcutaneous nodes, or reactive hyperplasia. It accounts for over 10% of cases. Extranodal infiltration is common at diagnosis, and the prognosis is poor.
4. Lymphocyte-depleted type: This may directly evolve from the lymphocyte-predominant type or transform from the mixed cellularity type. It represents the advanced stage of lymphoma and is the least differentiated type, with rapid progression. Lymphocytes are scarce in the lesions, which can be divided into two forms: one with diffuse sclerosis composed of hyaline collagen fibers and markedly reduced lymphocytes, leading to lymph node shrinkage; the other dominated by large numbers of atypical reticular cells, with Sternberg-Reed cells easily identifiable. This type accounts for about 10% of cases and has the worst prognosis.
Staging is highly valuable for prognosis assessment and treatment selection.
Stage I: Disease limited to one lymph node or one anatomic region of lymph nodes (I), or involvement of a single extranodal site (IE).
Stage II: Disease limited to two or more adjacent anatomic regions of lymph nodes, or two non-adjacent lymph nodes on the same side of the diaphragm (II), or involvement of an extranodal site and lymph nodes on the same side of the diaphragm (IIE).
Stage III: Disease on both sides of the diaphragm (III), with or without extranodal involvement (IIIE), splenic involvement (IIIS), or both (IIIES).
Stage IV The lesions extensively involve extranodal tissues, such as bone marrow, liver, lung, pleura, bone, skin, kidney, gastrointestinal tract, and other organs, with or without lymph node enlargement.
Each stage is further divided into Group A and Group B. Group A patients have no systemic symptoms, while Group B patients experience fever, night sweating, and unexplained weight loss of more than 10% within six months.
bubble_chart Clinical Manifestations
The clinical manifestations are diverse, primarily determined by pathological type, the location of the primary tumor, the organs involved, the early or advanced stage of the disease, and other factors.
The earliest manifestation is often painless, progressive enlargement of superficial lymph nodes, usually lacking systemic symptoms and progressing slowly. Approximately 60% originate in the cervical lymph nodes, while primary involvement of supraclavicular, axillary, and inguinal lymph nodes is less common. Initially, the lymph nodes are soft, not adherent to each other, and non-tender. In the late stage [third stage], they enlarge rapidly and may adhere to form a massive lump. A characteristic feature is the absence of inflammation in adjacent tissues, which cannot explain the cause of lymph node enlargement. Enlarged lymph nodes may cause local compressive symptoms, such as mediastinal lymph node enlargement compressing the trachea or bronchi, leading to dry cough. Unexplained abdominal pain may result from retroperitoneal lymph node enlargement. Systemic symptoms may include low-grade fever or a characteristic relapsing fever pattern, where high fever lasts for several days followed by days or weeks of afebrile periods (Pel-Ebstein fever). Common symptoms include loss of appetite, nausea, night sweats, and weight loss, which often do not appear when the lesion is localized. Pruritus is a common symptom in adults but is rare in children, even with widespread organ involvement. About one-fourth of pediatric patients have already metastasized to tissues beyond the lymph nodes at diagnosis, commonly involving the spleen, liver, lungs, bones, or bone marrow. Pulmonary infiltrates on X-ray often present as fluffy exudative changes, difficult to distinguish from fungal infections, and are frequently accompanied by tachypnea and fever, sometimes progressing to respiratory failure. Liver involvement may manifest as symptoms of intrahepatic bile duct obstruction, grade II hepatomegaly, scleral icterus, and elevated serum direct and indirect bilirubin and alkaline phosphatase levels. Bone marrow infiltration may lead to neutropenia, thrombocytopenia, and anemia. Gastrointestinal involvement can cause mucosal ulcers and gastrointestinal bleeding. Lymphomas occurring in the epidural space of the spinal canal may cause compressive symptoms. Additionally, various immune dysfunctions may occur, such as immune-mediated hemolysis, thrombocytopenia, or nephrotic syndrome.
bubble_chart Auxiliary Examination
The changes in blood picture are nonspecific, with significant variations among different types and stages. When the lesion is localized, the blood picture may be entirely normal; in cases of widespread lesions, leukocytosis, neutrophilia, and anemia may occur. In the advanced stage, leukopenia and lymphocytopenia are often observed. Reed-Sternberg cells may occasionally be seen in peripheral blood. The detection of Reed-Sternberg cells in bone marrow aspiration is of special diagnostic value, though they are rarely found. In stages III or IV of the disease, bone marrow biopsy may be performed, which yields a higher positive rate for Reed-Sternberg cells compared to aspiration smears.
During disease remission, erythrocyte sedimentation rate (ESR) and serum copper levels should be measured. Elevated values may indicate relapse. The normal serum copper level in school-aged children ranges from 73 to 114 μg/ml, whereas it is elevated in this disease and returns to normal after successful treatment. If enlarged lymph nodes regress and symptoms improve after treatment but serum copper remains elevated, the possibility of intra-abdominal lesions should be considered.
For persistent and unexplained cervical lymphadenopathy in older children, this disease should be suspected, as lymphadenopathy caused by upper respiratory tract infections is less common in this age group. Chronic lymphadenopathy of unknown origin in other regions should also raise suspicion of this disease. A detailed medical history and comprehensive physical examination are essential. The definitive diagnosis relies on pathological examination of the lymph nodes, and a larger, intact lymph node should be excised for pathological analysis. Fine-needle aspiration of lymph tissue is often unreliable due to insufficient sample size.
After diagnosis, further staging should be performed. Many patients initially diagnosed with stage I disease based on general examination—presenting only with cervical lymphadenopathy—often already have mediastinal or abdominal metastases. Clinical examination alone leads to inaccurate staging in approximately one-third of patients, so the following tests should be conducted.
(1) Chest and mediastinal tomography: Can reveal hilar lymphadenopathy and pulmonary infiltration.
(2) Inferior vena cava venography and intravenous pyelography: The former can detect enlarged lymph nodes near the aorta above the second lumbar vertebra, while the latter shows whether the ureters are displaced. Additionally, kidney localization is necessary for abdominal radiotherapy planning.
(3) Bipedal lymphangiography (pedal lymphogram): Can detect abdominal and para-aortic lymphadenopathy at an early stage.
(4) Skeletal X-rays to assess possible bone involvement.
(5) Serum alkaline phosphatase measurement: Elevated levels may indicate bone or liver metastases.
(6) Liver-spleen scanning and liver function tests if necessary: B-mode ultrasound scanning (ultrasound scanning) is highly useful for detecting abdominal lesions. If abdominal lymph node involvement is strongly suspected, exploratory laparotomy may be performed, along with splenectomy and pathological biopsy of abdominal, retroperitoneal lymph nodes, and liver tissue.
bubble_chart Treatment Measures
In recent years, due to the combined application of pathological classification, clinical staging, radiotherapy, chemotherapy, and surgical treatment, the efficacy has significantly improved. Early diagnosis and treatment may lead to a complete cure.
According to the treatment principles proposed by Kaplan et al., the treatment can be divided into five stages as follows.
1. **Stage I**: For well-differentiated high cervical lymph nodes, mediastinal and inguinal lymph node lesions, local radiotherapy is used. A dose of 30–40 Gy administered over 3–4 weeks can control local tumors in 80% of pediatric patients. The general maximum dose is 35 Gy, with only a few cases requiring an increase to 40 Gy.
2. **Stage II**: For mediastinal and para-aortic lymph node involvement, radiotherapy is also used, with the dose preferably not exceeding 30 Gy, as the heart and spine have poor tolerance to radiotherapy.
3. **Other types or locations of Stage I and II**: In addition to local radiotherapy, chemotherapy is added.
4. **Stage III**: Chemotherapy is the primary treatment, supplemented with radiotherapy.
5. **Stage IV**: Chemotherapy is the mainstay, with radiotherapy added for large tumor masses.
For Stage I lesions, surgery may also be performed, followed by radiotherapy.
During the rapid growth and development period of childhood, the side effects of treatment must be carefully considered. Since radiotherapy can affect bone and soft tissue development, and even growth, children under 8 years old should use radiotherapy as sparingly as possible, replacing it with surgery and chemotherapy. Splenectomy should be postponed until after the age of 5.
For poorly differentiated or high-risk Stage I and II lesions, or cases where further staging is not feasible, as well as all Stage III cases, a treatment plan alternating between chemotherapy and local radiotherapy should be adopted. For example, start with two courses of chemotherapy, followed by radiotherapy, and then additional courses of chemotherapy.
**Chemotherapy**: The commonly used effective regimens in childhood are as follows.
1. **MOPP regimen**: The most commonly used regimen in children, combining nitrogen mustard (mustargen), vincristine (oncovin), procarbazine (procarbazine), and prednisone. Treatment lasts 14 days, followed by a 14-day rest period, totaling 6 courses. For children over 8 years old or those under 8 whose tumor location does not affect growth, radiotherapy begins after two courses of chemotherapy, followed by additional chemotherapy courses. Cyclophosphamide (300 mg/m²) may also be used intravenously to replace nitrogen mustard (COPP), and methotrexate may replace procarbazine. 2 2. **MVPP regimen**: In this regimen, vincristine is replaced by vinblastine (6 mg/m²). 2 The above two regimens have relatively minor side effects, with bone marrow suppression recovering quickly during the rest periods between courses. Among patients who have not undergone chemotherapy or have relapsed after radiotherapy alone, approximately 80% achieve complete remission after 6 courses of these regimens.
If the above regimens prove ineffective, other combination therapies may be tried, such as adriamycin, bleomycin, dimethyltriazeno-imidazole-carboxamide (DTIC), and chloroethyl-cyclohexyl-nitrosureas (CCNU). The choice depends on the disease stage and bone marrow tolerance. Bleomycin has not been widely used in pediatric Hodgkin's disease. {|118|}
Relief is usually achieved after completing 6 treatment courses, at which point maintenance therapy should be continued by extending the intervals of the original regimen. For example, in the first year, repeat one course every 2 months; in the second year, repeat one course every 3 months; and in the third year, repeat one course every 6 months. There are differing opinions on whether maintenance therapy is necessary. Some believe that after achieving remission with 6 or 12 courses of MOPP, there is no difference in remission duration between stopping treatment and continuing with maintenance therapy.
For patients who relapse after radiotherapy, if the bone marrow can tolerate it, MOPP or other regimens can be used for treatment. If there is only local lymph node recurrence or recurrence of extranodal infiltration, but the patient cannot tolerate chemotherapy, local radiotherapy should be administered again.
The combined use of radiotherapy and chemotherapy results in greater side effects. Due to the application of immunosuppressants, the body's resistance is weakened, making it prone to viral, fungal, and protozoal infections. Supportive therapy through injections is necessary, and blood transfusions or antibiotic treatment may be required when needed.
Due to the prolonged treatment duration, attention should be paid to the secondary diseases of advanced-stage treatment. Radiotherapy administered during rapid growth and development stages (under 5 years or 12–13 years old) may lead to slowed growth. Radiotherapy in the upper diaphragm region may affect sitting height. Neck irradiation can cause stunted neck growth; mediastinal and chest irradiation may lead to breast dysplasia, pleural fibrosis, restricted lung function, and cardiac involvement. Treatment of advanced stages may result in hypothyroidism, and there have also been reports of esophageal stenosis. Patients who receive high-dose radiotherapy combined with chemotherapy are at risk of developing secondary malignancies, especially those who undergo retreatment after relapse. Among secondary malignancies, acute non-lymphocytic leukemia is the most common.
Hodgkin's disease is no longer an incurable condition with effective treatment. Foreign literature reports that 80% of patients in stages I and II have survived for more than 5 years. Nearly 50% do not relapse within 10 years. Currently, the remission period for stage IIIA has caught up with stages I and II, but the 5-year remission rate for stage IV patients is only 20%. Adult patients often experience infertility after the MOPP regimen. Although there is insufficient data for prepubescent children, it is speculated that the treatment may have some impact on normal development.
This disease must be differentiated from chronic suppurative lymphadenitis, subcutaneous lymph nodes, infectious mononucleosis, and lymph node metastasis of malignant tumors. Reactive hyperplasia of lymph nodes caused by local chronic inflammation is sometimes difficult to distinguish from this disease.
