Lymphomas comprise a highly heterogeneous group of solid tumors composed of neoplastic lymphoid cells. They are often regarded either as Hodgkin or non-Hodgkin lymphomas. Non-Hodgkin lymphomas are one of the most common cancers, accounting for about 4% of all cancers, while non-Hodgkin lymphomas are at least ten times less frequent. The incidence of different types of lymphomas varies greatly across the world and is often associated with the prevalence of infections with several viruses: Epstein-Barr virus (EBV), Human T-lymphotropic virus type 1 (HTLV-1), Human Immunodeficiency Virus (HIV), Human herpesvirus 8 (HHV-8). Infection with H. pylori is associated with lymphomas of the stomach. Non-Hodgkin lymphomas are more common in individuals who received some chemotherapy drugs or radiotherapy in the treatment of other cancers, especially in childhood. People with autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, Sjogren disease, celiac disease, and others, have a higher risk for developing lymphoma. They develop as a consequence of the hyperstimulation of immune system and the use of immunosuppressive drugs in the treatment of the disease.

The symptoms differ depending on the type of lymphoma. Most often the result in the enlargement of lymph nodes, in one or different body regions. Lymphomas can be associated with persistent fever, often as the first symptom and “fever of unknown reason”. Drenching night sweats are also common. Lymphomas may arise in organs other than lymph nodes, like skin, gut, stomach, and others, and may infiltrate the bone marrow, or be present as circulating cells in the blood, like in leukemia.

Classification of lymphomas is complex and is based on their morphological and phenotypical features (assessed by immunohistochemistry) together with molecular characteristics. Traditionally, lymphomas can be low-grade and clinically indolent or high-grade and clinically aggressive. In a broad view, lymphomas are classified into Hodgkin lymphomas and B-cell or T/NK-cell non-Hodgkin's lymphomas.

Hodgkin lymphomas are mainly B-cell tumors and can be sub-classified depending on morphological features: type of tumor cells and amount and composition of other, often inflammatory cells, around tumor cells. Classical Hodgkin lymphoma is the most common type and it encompasses four different subtypes: nodular sclerosis, lymphocyte rich, lymphocyte depleted, and mixed cellularity classic Hodgkin lymphomas. Characteristic tumor cells are large with large nuclei and prominent eosinophilic nucleolus, either as mononuclear (Hodgkin cells) or with two nuclei resembling “owl’s eyes” (Reed-Sternberg cells). Unlike classical Hodgkin lymphoma, a nodular lymphocyte predominant type has large tumor cells with multilobulated or round nucleus, thin nuclear membrane, finely granular chromatin, and variable small nucleoli (named popcorn cells).

B-cell lymphomas are the most common type of lymphoma and can be sub-classified according to morphology, protein expression patterns, and genetic alterations. The most frequent variants of B-cell lymphomas include small lymphocytic lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma.

Small lymphocytic lymphoma is an indolent lymphoma that is characterized by a monotonous population of small lymphocytes replacing the normal architecture of a lymph node. Mitotic figures are uncommon and necrosis is typically not a feature. Approximately one-third of all patients with small lymphocytic lymphoma develop lymphocytosis and a clinical picture that is indistinguishable from chronic lymphocytic leukemia (CLL). Between 5 and 10% of patients will have a transformation of small lymphocytic lymphoma into aggressive diffuse large B-cell lymphoma (Richter’s transformation).

Follicular lymphoma is a tumor of germinal center B-cells (centrocytes and centroblasts). The tumor is characterized by a follicular growth pattern that in part mimics that of the normal lymph node architecture (germinal center with surrounding lymphoid cells in a lymph follicle). The grading of follicular lymphoma is based on the number of centroblasts per high power field and has prognostic relevance.

Diffuse large B-cell lymphomas represent 25 - 30% of adult non-Hodgkin lymphoma. They are characterized by diffuse infiltration of large atypical lymphoid cells. Tumor cell nuclei are large and irregular with coarsely reticulated chromatin and one central nucleolus (resembling immunoblasts) or several nucleoli opposed to the nuclear membrane (resembling centroblasts). Mitotic figures are common and can be atypical.

T-cell lymphomas account for approximately 15 % of the lymphomas of non-Hodgkin type. One of the most common forms is lymphoma arising in the skin named mycosis fungoides. Some T-cell lymphomas are associated with virus infection (EBV, HTLV-1). Adult T-cell leukemia/lymphoma is more common in the Pacific region due to a higher prevalence of HTLV-1 infection.

The distinction between over 50 variants of lymphoma is based on a microscopical examination, using morphology and immunohistochemistry to determine the type of the present cells (tumor cells and background cells) and the stage of differentiation of the tumor cells. Immunohistochemistry has played a vital role in the understanding and classification of lymphoma and several of the well-known CD markers are used for differential diagnostics. Markers such as CD20, CD79, Pax5, Oct2 (POU2F2), CD2, CD3, CD5, and CD43 (SPN) are used in the differentiation between B- and T/NK-cell types. In B-cell lymphomas, it is important to determine the stage of differentiation of cells (including pre- or post-germinal center differentiation) using antibodies against bcl-2, Ki-67 (MKI67), CD23, bcl6, CD10, MUM1, and cyclin D1. Antibodies against CD4, CD8, TIA1, Granzyme, CD30, CD56, and gamma chain of the T-cell receptor (TCRγ) are useful for further distinction of T/NK- cell lymphomas.

Genetical characteristics of lymphomas defined by chromosomal translocations and gene mutations provide a basis for adequate classification of lymphoma and have a prognostic impact. Chromosomal rearrangements of BCL2, BCL6, and CMYC genes are important in the classification of diffuse large B-cell lymphomas. Sometimes, differentiation between reactive lymphoid proliferations in inflammatory diseases and lymphomas is a diagnostic pitfall. In such cases, of great help may be a clonality assessment, performed by molecular analysis of genes encoding for T-cell receptor genes (TCRγδ or TCRαβ) or light and heavy chains of immunoglobulins (IGH, IGL). Many lymphomas have specific genetical characteristic which can be proven by molecular studies, and readers are pointed to other resources for further information on this subject.

Therapy and prognosis of lymphomas primarily depend on the type of lymphoma. In addition to that, some lymphoma types have specific clinical staging systems that govern therapy and determine prognosis. Such staging systems take into consideration the extent of disease spread (number of involved nodal areas, involvement of bone marrow), the presence of symptoms such as fever, and serum levels of lactate dehydrogenase (LDH) or eta 2 microglobulin.