The incidence rate is at 2-3/100,000 per year. The age peak lies at approx. 32 years.

Classification of Hodgkin’s lymphomas is performed according to the WHO classification:

I. Lymphocyte-predominant Hodgkin’s lymphoma (NLPHL; synonyms: LPHD, nodular paragranuloma)

The NLPHL encompasses almost 5% of all Hodgkin’s lymphomas. As opposed to the classical Hodgkin’s lymphomas the malignant cells are referred to as L&H (lymphocytic and histiocytic) and most often display the B-cell antigens CD20 and CD79a.

II. Classical Hodgkin’s lymphoma (cHL)

• Nodular sclerosing (NS)

• Mixed cellularity (MC)

• Lymphocyte-rich (LR)

• Lymphocyte-depleted (LD)

• Not classified

Tumor cells of the classical Hodgkin’s lymphomas are referred to as Hodgkin and Reed-Sternberg cells (H-RS) and typically display CD30 and CD15 antigens. The histological subclassification within the cHL diagnosis is currently without therapeutic consequences.

Stage-adapted therapy allows long term cure in more than 80 percent of all patients. Hodgkin’s lymphoma is one of the oncological diseases with the highest cure rates in adults.

The histological diagnosis should be based on the surgical extirpation of an entire suspicious lymph node. A fine-needle aspiration (cytology) is insufficient considering the low percentage of H‑RS cells and the inability to evaluate the lymph node structure. As the diagnosis might present great difficulties to the pathologist, assessment by a reference pathologist is recommended. If “reactive alterations” have been initially diagnosed in spite of progressive clinical symptoms, another biopsy specimen should be taken.

As therapy of the Hodgkin’s lymphoma strictly depends on the stage of the disease, a precise assessment of the initial stage (staging) is an absolute necessity, see Table 1.

A liver biopsy will be indicated only if diffusive liver involvement is suspected (e.g. unclear increase of AP activity), provided that such information would have an influence on the selection of therapy. An involvement will have to be assumed if focal lesions in the liver (CT and/or sonography) are diagnosed during the staging procedure.

An explorative laparotomy with splenectomy is no longer recommended [II, A].

Positron emission tomography (PET) is not recommended as part of the initial staging, since no data indicate an influence on therapy outcome. However, PET may be considered in the event of suspicious lymph nodes in CT scan if an involvement would have an influence on therapy selection. In this case it must be kept in mind that inflammatory lymph nodes are also associated with an increased uptake of FDG in PET scans, eventually requiring histological confirmation.

Further tests are required to identify patients who have an increased risk for acute and/or late toxicity, see Table 2.

Staging is performed according to the modified Ann Arbor Classification, see Table 3.

Lymphatic tissue: lymph nodes, spleen, thymus, Waldeyer’s tonsillar ring, appendix, Peyer’s glands.

B symptoms:

Fever of unknown origin > 38^oC

Night sweats of unknown origin (change of night clothes)

Unintentional weight loss of more than 10% of the body weight within a period of six months

Treatment stratification based on staging and risk factors is used by all international study groups [II-III, A]. Increasingly, the various European study groups (GHSG, EORTC, ) are using similar approaches in recent years, so that only few differences exist by now. Studies by the German Hodgkin’s Study Group (GHSG) are based on the following classification which has proved successful in the practice, see Figure 1.

• Involvement of 3 or more lymph-node regions (see Figure 1)

• High erythrocyte sedimentation rate (within the first hour: ≥50mm in the absence of B symptoms, ≥30mm in the presence of B symptoms)

• Large mediastinal mass (≥1/3 of the maximal chest diameter in conventional chest X-rays)

• Extranodal site

Differential diagnostics include all inflammatory lymph-node enlargements of bacterial or viral etiology (e.g. tuberculosis, toxoplasmosis, Epstein-Barr virus, cytomegalovirus, HIV). In addition, other malignant lymphomas, lymph-node metastases of solid tumors, thymomas, germinal cell tumors, or sarcoidosis must also be either included or excluded in the process of differential diagnostic considerations.

The standard therapy for early stages is a combination therapy consisting of a short chemotherapy followed by involved-field radiotherapy (IF-RT). This combination is superior to radiotherapy or chemotherapy only for the control of tumor growth. Standard chemotherapy consists of two cycles of the ABVD regime. Standard dose of radiotherapy is 20Gy [I, A].

At present, the contribution of the single cytostatic agents within the ABVD regime is being reviewed by the GHSG in a clinical trial. Thus far, two of the four therapy arms (ABV and AV) have been prematurely closed because of an increased rate of events.

The question whether radiation therapy is indispensable in all patients, is currently under investigation in clinical trials such as the HD16 Study of the GHSG, see chapter 8.

Standard therapy for intermediate stages is a combination therapy consisting of chemotherapy followed by involved-field radiotherapy (IF-RT). The most widely accepted standard therapy consists of four cycles ABVD followed by 30Gy IF-RT [I, A]. However, the final evaluation of the GHSG HD-14 Study demonstrated an improvement of tumor control (PFS after 5 years) from 89.1% to 95.4% when two cycles of BEACOPPescalated were, followed by two cycles of ABVD (2+2) and 30Gy IF-RT. The moderately increased toxicity of the BEACOPPescalated arm did not result in an increased mortality rate. Neither was fertility decreased in the “2+2” regime (2x BEACOPPescalated + 2x ABVD) as compared to 4x ABVD, nor was the rate of secondary hematological neoplasias increased. The benefit of the “2+2” regime is seen in all intermediate stage risk groups. Overall survival rates were not improved due to effective salvage treatment. Therapy with 4x ABVD is an acceptable alternative for patients who either are not eligible for BEACOPPescalated therapy due to limiting comorbidity or who refuse to undergo therapy with BEACOPPescalated.

The GHSG HD11 Study investigated the potential reduction of radiation dose from 30Gy to 20Gy after 4 cycles of ABVD. The final evaluation revealed a decrease of FFTF (-4.7% after 5 years), so that even inferiority cannot be excluded. After four cycles of ABVD radiation with 30Gy IF should therefore be applied. The question whether the size of radiation fields could be further decreased (involved-node RT), is currently being investigated by clinical trials (HD17 Study of the GHSG).

Standard therapy in advanced stages consists of intensive chemotherapy with BEACOPPescalated. [I, A]. As compared to ABVD this regimen results in a distinct improvement of tumor control. The HD15 Study of the GHSG showed that just six cycles of BEACOPPescalated are less toxic but more effective than the previous standard consisting of eight cycles BEACOPPescalated (FFTF 89.3% vs. 84.4%; OS 95.3% vs. 91.9%).

Bauer et al. conducted a systematic review for comparison between ABVD and BEACOPPescalated. A total of 2,868 HL patients in intermediate or advances stages from four randomized studies were evaluated. All studies compared BEACOPPescalated to ABVD or its variants. As far as PFS was concerned, a significant benefit of BEACOPPescalated could be demonstrated, more pronounced in advanced stages than in intermediate stages (hazard ratio at 0.53 with a number-needed-to-treat (NNT) of 7). The same also applied to the rate of complete remissions, however, not to overall survival. There were more toxicities and more secondary leukemias under BEACOPPescalated than under ABVD. However, no significant differences were seen in the total number of secondary neoplasias and in therapy-associated mortality. The authors concluded that a better tumor control could be achieved with BEACOPPescalated. A longer follow-up is needed to assess the impact on overall survival.

The concept of ABVD induction and PET-guided therapy adaptation is also being examined in clinical trials. The HD15 Study of the GHSG further investigated whether radiation could be limited to patients with residual PET-positive lymphomas of ≥2.5cm after chemotherapy. It showed that patients with PET-negative residual lymphomas ≥ 2.5cm, even without additional radiotherapy, had a prognosis identical to those who had a CR/Cru after completion of chemotherapy. The negative predictive value (NPV) of PET in this situation is 94%. Whether this also holds true subsequent to an ABVD-based strategy still remains uncertain.

Patients with PET-positive residual lymphomas should receive a local radiation therapy with a dose of 30Gy. On account of the good prognosis of these patients (PFS after 4 years: 86.2%) an intensification of therapy, for example, by means of high-dose therapy is not justified. The question whether PET scans conducted at an early stage in the course of therapy could lead to a significant reduction of chemotherapy is currently under investigation in clinical trials (HD18 Study of the GHSG).

Patients above the age of 60 years should not be treated with BEACOPPescalated because of its increased toxicity. It is recommended to treat these patients stage-adapted with 2, 4 or 6-8 cycles of ABVD [I-II, A].

Alternatively, 6-8 cycles of PVAG can be applied in intermediate or advanced stages in the event of contraindications for single componentsof the ABVD regime.

Patients in early or intermediate stages should receive radiation with 30Gy IF-RT, whereas patients in advanced stages should undergo a local radiation of residual lymphomas ≥1.5cm.

Stage IA patients without risk factors have an excellent prognosis. These patients require IF radiation therapy with 30Gy, only [III, A].

Patients with more extensive disease should be treated stage-adapted, in analogy to the therapy recommendations that apply to cHL.

Due to the expression of CD20 the application of an anti-CD20 antibody (off-label use) is an option for relapsed patients, in addition to the recommendations for cHL [III, B].

In general, patients with an early relapse (3-12 months after termination of primary therapy) are distinguished from those with late relapse (>12 months after termination of primary therapy). The prognosis in patients with an early relapse is worse than in those with late relapse. Figure 4 shows an algorithm for patients treated in first relapse outside of clinical trials.

Re-induction therapy followed by high-dose chemotherapy with subsequent autologous stem cell transplantation is the treatment of choice for most patients in first relapse [I, A]. This concept is superior to a single conventional chemotherapy as far as relapse-free survival is concerned.

Chemotherapy regimens such as DHAP or IGEV can be used for re-induction and stem cell mobilization. The efficacy of other chemotherapy has only been poorly studied.

The final evaluation of the GHSG HD-R2 Study demonstrated that two cycles of DHAP followed by HDCT/APBSCT constitute the standard. A further intensification of induction therapy prior to HDCT did not improve the outcome.

An intensified conventional chemotherapy, for example, with six cycles of BEACOPPescalated [IV, B] might be taken into consideration for a small subgroup (first-line therapy with two cycles ABVD plus IF-RT, late relapse).

Radiation therapy only may be considered for patients with localized relapse, no B symptoms or anemia and relapse outside the initial radiation field [IV, B].

No standard has been defined for patients with relapse after HDCT/APBSCT. Choice of therapy selection should take into account the general condition of the patient, previous therapies, and comorbidity.

In 2011, the antibody-drug-conjugate (ADC) brentuximab vedotin was authorized in the United States for relapse therapy subsequent to autologous stem-cell therapy. Marketing authorization in Europe is expected in 2012.

Allogeneic stem cell transplantation is not a standard therapy for HL patients with relapse after APBSCT. However, it may be taken into consideration in young patients who are sensitive to chemotherapy and are in good general health [II-III, B]. This therapy should be performed within clinical trials. An important requisite is a very good (ideally a complete) remission prior to the start of conditioning. Reduced intensity conditioning (RIC-allo) markedly decreased transplantation-associated mortality, however, relapse rates continue to be high.

A second high-dose chemotherapy followed by APBSCT may be considered for patients with a late relapse after APBSCT [IV, B].

Therapeutic options in palliative concepts include local radiation therapy, monotherapy with gemcitabine (off-label use), vinblastine, vinorelbine (off-label use), low-dose etoposide either alone or in combination with steroids.

At present, the efficacy of monoclonal antibodies, immunotoxins, histone deacetylase inhibitors (HDAC), or immune modulators (e.g. lenalidomide) are tested in phase I/II trials.