Hodgkin's lymphoma C81.9

Hodgkin's lymphoma is a monoclonal B-cell lymphoma histologically characterized by atypical mononuclear (Hodgkin cells) or multinucleated (Sternberg-Reed cells), both monoclonal B-lymphocytes from the germinal centers of the lymph nodes) in a granulomatous tissue. For classical Hodgkin's lymphoma (cHL: about 95% of all cases), a low number of malignant Hodgkin-Reed-Sternberg cells is characteristic. In the early stage, it is a localized lymph node disease. The advanced stage is a systemic disease that also manifests haematogenously or per continuitatem in extralymphoid organs (bone marrow, liver).

Hodgkin lymphoma is classified according to the WHO classification:

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL): NLPHL affects about 5% of all Hodgkin lymphomas (the malignant cells are called L and H (lymphocytic and histiocytic), unlike classical Hodgkin lymphoma, are negative for CD30 and usually carry the B-cell antigens CD20 and CD79a).

Classical Hodgkin lymphoma (cHL): classical Hodgkin lymphoma affects about 93% of all cases.

Classical Hodgkin lymphoma is divided into:

• Nodular sclerosing type (NS: 60%)
• Mixed type (MC: 28%)
• Lymphocyte-rich type (LR: 5%)
• Lymphocyte-poor type (LD:0.3%)
• Non-classifiable HL.

Note: The tumor cells of classical Hodgkin lymphoma are referred to as Hodgkin and Reed-Sternberg (H-RS) cells and typically carry the antigens CD30 and CD15. Histologic subclassification within the diagnosis of cHL has no therapeutic consequences.

Staging (Staging is from stage I to IV according to the modified Ann Arbor classification).

• Stage I: Involvement in one lymph node region or presence of a single localized involvement outside the lymphatic system.
• Stage II: involvement of two or more lymph node regions on the same side of the diaphragm or localized involvement outside the lymphatic system and of lymph node regions on the same side of the diaphragm
• Stage III: Involvement of two or more lymph node regions or organs outside the lymphatic system on both sides of the diaphragm.
• Stage IV: Non-localized, diffuse or disseminated involvement of one or more extralymphoid organs with or without involvement of lymphoid tissue (Lymphoid tissue: lymph nodes, spleen, thymus, Waldeyer's ring of pharynx, appendix, Peyer's plaques).
• Supplement A: B-symptoms are not present (B-symptoms = fever not otherwise explicable above 38°C; night sweats not otherwise explicable -change of nightclothes-; weight loss not otherwise explicable of more than 10% of body weight within 6 months).
• Supplement B: B-symptoms are present.

Prognostic factors (risk groups according to GHSG): involvement of 3 or more lymph node areas ; high ESR (in the first hour; ≥50mm without B-symptoms, ≥30mm with B-symptoms); large mediastinal tumor (≥1/3 of the maximum transverse thoracic diameter on conventional chest radiography); involvement of ≥3 lymph node areas.

The incidence is 2-3/100,000 per year.

Unknown. HIV and EBV factors are co-factors (EBV 3-fold increased risk). Furthermore, immunosuppressive therapies, toxic environmental toxins.

The peak age is 32 years.

Uncharacteristic general symptoms: Patients often present with prolonged, sometimes undulating lymph node swellings, which are painless in most cases. Typical is a wavelike course of fever (>38oC), so-called Pel-Ebstein fever; in abdominal manifestations fever is frequent, night sweats (with change of clothes), weight loss, decrease in performance or pruritus may occur as accompanying symptoms. The alcohol-induced lymph node pain (alcohol pain), which is sometimes described as characteristic, is a rather rare symptom (approx. 5%).

Lymph node enlargement (painless): detectable in about 80% of patients at the time of diagnosis.

• Peripheral, mostly truncal lymph nodes (70%): mostly cervical involvement, less frequently axillary or inguinal involvement. Lymph nodes agglutinated to packets (Bulky-disease = LK>10cm ø).
• Mediastinal lymph nodes (30%): clinically possibly irritable cough.
• Abdominal lymph nodes (isolated 5%): clinically often combined with fever.

Hepatosplenomegaly

Neurological symptoms

Skeletal and pulmonary manifestations with organ-specific complaints

Skin manifestations:

Specific skin lesions (0.5-3.5% of patients): Indistinct, painless, reddish, firm, squamous or nodular infiltrates (Khalifeh I et al. 2009).

Also single, multiple, or appearing as papulo-nodular exanthema, brownish to livid-red, cutaneous-subcutaneous nodules.

Tendency to ulceration: Ulcus lymphogranulomatosus, especially on the trunk, lower abdomen, inguinal and thigh regions, and head.

Specific infiltrates in the lymphatic pharyngeal ring with tendency to ulceration.

Nonspecific skin lesions (in 30-50% of patients): excruciating pruritus with scratching effects, impetiginization, eczematization and lichenification, erythroderma, blistering, pyoderma, which can hardly be influenced by medication.

Chronic prurigo (prurigo lymphogranulomatotico- Serra-García L et al 2021).

Diffuse, Addison's disease-like hyperpigmentation on skin and mucous membranes.

Ichthyosis-like changes

Infectious tendencies: zoster generalisatus.

Autoimmune diseases and Hodgkin's lymphoma: Hodgkin's lymphoma is associated with various autoimmune diseases or diseases from the atopic form group (Landgren O et al 2006). These include:

• Ulcerative colitis
• Atopic diseases (atopic dermatitis, bronchial asthma - Rafiq M et al. 2020).
• Rheumatoid arthritis
• Systemic lupus erythematosus (Rahman A et al 2007).
• Sarcoidosis
• Immune thrombocytopenic purpura
• Paraneoplasitic pemphigus (Wang N et al. 2015)
• Mucinous pemphigoid (Durmus Ö et al. 2020)

Diagnostic confirmation by lymph node biopsy. If possible, a whole lymph node should be taken (fine needle aspiration is not sufficient). In case of initial assessment as "reactive change" and clinical progression, a new biopsy should be performed. Since the therapy of Hodgkin lymphoma is strictly stage-dependent, a precise determination of the initial stage (staging) is absolutely necessary.

Laboratory: blood count with differential, ESR, LDH, GOT, GPT, AP, gamma GT, uric acid, creatinine.

Imaging: X-ray thorax; CT neck (with contrast); CT thorax (with contrast); CT abdomen (with contrast).

PET-CT (assessment using Deauville score): Performing PET as part of initial staging is recommended (Cheson BD et al 2014). When positron emission tomography (PET) is performed for staging, bone marrow aspiration can be omitted if the findings are unremarkable with respect to the skeletal system and bone marrow. The negative predictive value of PET is 99%. PET-positive foci should be biopsied if they are stage-determining and thus relevant to therapy (El-Galaly TC et al. 2012).

Histology: bone marrow aspiration; aspirate (cytology); lymph node biopsy (histology). Liver biopsy: indicated only if diffuse liver involvement is suspected (e.g., unexplained AP elevation). If focal lesions are found in the liver during staging examinations (CT and/or ultrasound), these are to be considered as infestation.

Clinic (see above)

Laboratory: Often elevation of ESR or CRP; elevated LDH; frequently (25%) detectable lymphocytopenia >1000; this becomes more pronounced with progression of the disease; eosinophilia (30%); leukocytosis. There are no laboratory parameters specific to Hodgkin's lymphoma that can be used for diagnosis or follow-up.

Inflammatory lymph node enlargements of bacterial or viral origin (e.g. tuberculosis, toxoplasmosis, cat scratch disease, rubella, Epstein-Barr virus, cytomegalovirus, HIV).

Non-Hodgkin lymphomas

Lymph node metastases of solid tumours

Thymomas

Germ cell tumors

Non-malignant diseases such as sarcoidosis

Note: Patients with Hodgkin's lymphoma should be treated in clinical trials whenever possible.

If the patient wishes to have children, cryopreservation of sperm or oocytes may be necessary before starting therapy!

Today, more than 80% of all patients can be cured in the long term through stage-adapted therapy. This makes Hodgkin's lymphoma one of the most treatable oncological diseases in adults.

Initial diagnosis: Therapy should begin immediately after diagnosis, stage and risk group classification and, if necessary, completion of prophylactic measures for fertility preservation. The therapeutic approach at initial diagnosis is almost always curative. Dose reduction should only occur in well-justified exceptions. Only in extremely comorbid patients can a primary palliative therapy strategy be considered.

Stage-adapted therapy for initial diagnosis in patients between 18 and 60 years of age.

Abbreviations:

• ABVD: doxorubicin 25mg/m² d1/d15; bleomycin10mg/m² d1/d15; vinblastine 6mg/m² d1/d15; DTC 375mg/m² d1/d15.
• BEACOPPesc: cyclophosphamide 1250mg/m² d1; doxorubicin 35mg/m² d1; etoposide(-phosphate) 200mg/m² d1-3; procarbazine 100mg/m² d1-7; prednisone 40mg/m² d1-14; vincristine 1.4mg/m² (max 2mg) d8; bleomycin 10mg/m² d8; peg. G-CSF 6mg d4
• PVAG: prednisone, vinblastine, doxorubicin, gemcitabine.
• IS-RT: involved-site radiotherapy
• APBSCT (autologous peripheral blood stem cell transplant)
• RF=risk factors

Follow-up

PET-CT is nowadays a crucial investigation for response monitoring. However, it should always be accompanied by an additional CT with contrast medium.

In early stages, PET/CT should be performed after two cycles of ABVD. In case of a positive PET (DS4), an intensification of therapy can be considered in individual cases.

In intermediate stages, PET/CT should be performed after the end of chemotherapy with 2x BEACOPPescalated and 2xABVD. Only patients with a positive PET (DS4) should receive additional radiation (involved-site).

In advanced stages, a PET/CT check should be performed after two cycles of BEACOPPescalated to determine the duration of chemotherapy (another 2 cycles if PET is negative, another 4 cycles if PET is positive). At the end of chemotherapy, a new PET/CT control should be performed. Only patients with positive PET (DS4) should receive additional radiation to PET-positive remnants.

After completion of treatment, a pathologically elevated FDG uptake in PET may indicate persistent lymphoma foci. In doubtful cases, histological confirmation should be sought.

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The most common causes of death are (percentages of total deaths):

Uncontrollable disease with refractory recurrence: 50%.

Secondary neoplasia: 30%

Infections: 10%

Cardiopulmonary late complications after radiotherapy

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Prognosis

Disease-free 5-year survival:

• Limited stages >90%
• Intermediate stages: about 90%
• Advanced stages: up to 88%

In addition to detecting recurrence, follow-up also serves to detect late toxicities or secondary malignancies. About 75% of all recurrences are to be expected in the first two years, >90% in the first 5 years after completion of primary therapy. Follow-up care should be planned accordingly.

In the first year, follow-up examinations should take place every 3 months, up to the 4th year every 6 months and later annually: physical examination, laboratory value determinations with differential blood count, ESR, clinical chemistry. Monitoring of thyroid function, especially after radiotherapy of the neck region (1, 2 and 5 years after therapy).

Imaging by CT should be performed once approximately 3 months after primary therapy for all patients who are not in complete remission (CRu, PR, SD). Further CTs should only be performed in cases of clinical suspicion of recurrence.

Often recurrences are noticed by the patients themselves. If recurrence is suspected, repeat imaging using PET/CT and diagnostic CT is recommended. Histological confirmation is necessary to establish the diagnosis of recurrence.

Points to note are:

• Increased risk of second neoplasms (consequence of radio/chemotherapy): Breast carcinoma, Thyroid carcinoma, Acute myeloid leukemia, Secondary non-Hodgkin lymphoma.
• Pulmonary toxicity (after radiation and chemotherapy especially bleomycin)
• Cardiotoxicity (after radiation and chemotherapy mainly Adriamycin)
• Gonadal toxicity with infertility and amenorrhea

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