Often the aetiology remains unclear. Most of the DLBCL develop as a new disease, so called primary DLBCL, others can transform from other lymphatic neoplasia, so called secondary DLBCL. Prior exposure to agents causing DNA-damage and primary and secondary immunodeficiencies are associated with an increased risk of the development of a DLBCL. Certain chronic virus infections are associated with the occurrence of DLBCL, such as HCV, HIV and EBV. In elderly patients secondary lymphoma are more common than in younger ones. The EBV positive DLBCL in elderly patients should be classified as own entity and are associated with a worse prognosis than the EBV negative one [4].

The origins of DLBCL are not well understood. Usually, it evolves from normal B cells, but it can also result from malignant transformation of other types of malignant lymphatic neoplasia.

In general DLBCL encompasses a biologically and clinically diverse group of diseases, many of which cannot be separated from one another by well-defined and widely accepted criteria. Therefore new methods of genetic analysis are used for further characterization. DLBCL, NOS can be separate in germinal centre B-like DLBCL (GCB), activated B-like (ACB) DLBCL [5]. Lymphoma cells in the germinal centre B-cell-like subgroup resemble normal B cells in the germinal centre closely, and are generally associated with a favourable prognosis. Activated B-cell-like tumour cells are named from studies showing the constant activation of physiologic B-cell- antigen pathways. They are associated with a poorer prognosis [6]. One of the important pathways involved is the NF-κB pathway, which normally helps transforming B cells into plasma cells [7]. ACB subtype is more common in older patients, but compared to other molecular changes, which loose their prognostic importance when age was added as factor, age and ACB subtype independently contributed to poor prognosis [8].

In addition, gene expression studies found out more about cells and microscopic structures that are spreading within the malignant B- cells and form the tumour microenvironment. In particular, gene expression signatures that are linked with macrophages, T cells, and remodelling of the extracellular matrix seems to be associated with an improved prognosis and better overall survival [9]. On the other hand, the expression of genes involved in enhanced angiogenesis is associated with poorer survival [7].

Only a few genetic aberrations constituted valuable prognostic factors so far. Of these, the translocation of the MYC- oncogene has been associated with inferior survival. An additional translocation in BCL2 leads to an even worse prognosis and are named “double hit lymphomas”) [10].

With the help of the above diagnostic criteria derived from primary lymphoma tissue, one can distinguish few important subtypes: the T cell/histiocyte rich large B-cell lymphoma and the Primary cutaneous DLBCL, leg type and the Epstein-Barr virus (EBV) DLBCL of the elderly for which data on modern genetic testing come up as well [11, 12]. Other additional subtypes of large- B-cell lymphomas that are diagnosed and treated in the same way are, such as primary mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, ALK + large B-cell lymphoma, plasmoblastic lymphoma and follicular Lymphoma Grade 3B. The DLBCL of the central nervous system displays great differences concerning disease biology and treatment and will thus not be discussed here.

Data on age associated differences in biology of DLBCL are still limited. Patterns of gene expression are not routinely determined in clinical practice but will gain importance. However, as new therapeutic options might help to overcome negative prognostic molecular changes, the tests will become part of routine [13].

DLBCL is cancer of rapid growth which can occur in any part of the body. Typical first signs of this disease are fast growing masses of lymphatic tissue. Others may present as a tumour of unknown origin, with histology revealing a lymphoma instead of a carcinoma. Age associated changes in presentation have not been reported so far. Elderly patients more often present with extranodal disease [14]. In one third of the patients systemic symptoms are present at diagnosis, such as concomitant fever (>38 °C for at least 3 consecutive days), weight loss (>10 % during the 6 months prior to diagnosis), and night sweats, called B-symptoms [15].

Examination serves (a) the diagnosis of the disease, (b) the extend of the disease and (c) the judgment of the patients fitness for treatment.

The diagnosis is based on a histological examination of a biopsy, preferable from palpable lymph nodes, when ever possible as excisional biopsy. Core needle biopsy should be restricted to cases where no other surgical access is possible, without major surgery.

The procedures to diagnose the extend of the disease are listed in the following Table 11.2. They do not differ between younger and older patients.

The stage of the disease is classified according to the Ann-Arbor-Classification, see Table 11.3. No differences in staging system between younger and older patients exist.

Systemic Symptoms as fever, weight loss or night sweats are also included in the staging process: “A” means these symptoms are not present and “B” means they are.

The judgment of a patients fitness for treatment includes cardic, renal and pulmonary function test. In addition a structured geriatric assessment (GA) is recommended at least for patients aged 70 years and older [18]. A screening tool is less specific but might be an approach in a busy clinic [19]. Results of GA are associated with survival in patients with malignant lymphoma [20, 21].

A geriatric assessment was better in judging the patients prognosis than physicians. Tucci et al. included patients with newly diagnoses DLBCL in a prospective cohort trial. All patients received a geriatric assessment. The treating physician was blinded for the results of the geriatric assessment when deciding on patients´ fitness for treatment. Most of the patients were considered fit for an R-CHOP regimen, others not, they received attenuated dose regimens, corticosteroids or single agent Rituximab. The geriatric assessment classified more patients as not fit for R-CHOP. The prognosis of patients classified by physicians as fit but by assessment as unfit was identical to the prognosis of those classified as unfit by the physicians and the assessment [22].

Patients’ fitness for treatment should be assessed at the time of diagnosis and after a prophase treatment (see below) [15].

Prognostic factors predicting overall survival can be related to the disease (stage, LDH, extranodal involvement) and to the patients (age, performance-status) and the treatment, as response after treatment is a highly predictive factor for survival.

The following factors have been identified as independently associated with survival and thus are included in the International Prognostic Index (IPI) scoring system. In addition an age-adapted version (aaIPI), was established, see Tables 11.4 and 11.5 [23].

As the prognostic classification according to the IPI and aaIPI was established based on data, prior to the inclusion of Rituximab into the treatment, the scores were re-evaluated based on data of patients treated with Rituximab containing regimes. The data are reported in Table 11.6. Sehn et al. suggest based on their data analysing population based data, to use three instead of four prognostic categories: very good, good, and poor; and renamed the IPI to a revised IPI [24]. The former distribution had separated only two different prognostic groups, factors 0–2 and factors 3–4. The median age of the included patients was 61 years. Ziepert et al. analysed treatment results of clinical trials including patients aged 60 years and older with DLBCL. They confirmed the prognostic value of the aaIPI regarding PFS, EFS and OS [25]. As age above 60 years is a factor of IPI, older patients per se can not be in a very good risk group.

None or delayed treatment leads to death within weeks to few months. Treatment decision should into account the stage of the disease and the IPI in addition to patients´ fitness. Chemotherapy with CHOP is the backbone of treatment in patients with DLBCL. It was established in 1976. The initial trial included patients with a median age of 53 years [26].

As the IPI identified age, below and above the age of 60 years, as major prognostic factor, as treatment toxicity increases with age, and as in younger patients, strategies to increase dose of chemotherapy, with the hope of increased remission and survival rate, trials often used age limit of 60 years as definition of elderly patients.