Histopathology forms the basis for the diagnosis, classification, treatment and prognosis of non-Hodgkin malignant lymphomas. Nowadays several reliable methods are being used in the pathology laboratories for the identification of the various cell types of the normal lymphoid tissues and their neoplastic counterparts; such methods are aimed at a better understanding of the nature of the malignant lymphomas and their reasonable classification. They include classic morphology, histochemistry, immunohistochemistry, image analysis/ flow cytometry and molecular pathology techniques such as gene rearrangement methodology, polymerase chain reaction (PCR), in situ hybridization and DNA clonality. Morphology is the mainstay of the malignant lymphoma examination process. It includes the cell morphology itself as well as the patterns of homing of either T or B zones of the lymphoid tissues by the neoplastic cells. Although cell morphology can be used to identify accurately only some cell types (e.g. plasma cells), in most instances it can provide substantial information on the B or T-cell nature of the lymphomatous cells. It is undoubtedly sufficient to distinguish substantial morphological categories of malignant lymphoma (e.g. centroblastic/centrocytic, lymphoplasmacytoid/cytic, and some types of peripheral T-cell lymphomas). It seems unreasonable to use more sophisticated methods of investigating lymphomas when they are not preceded and supported by the data of the traditional morphological methods which are more simple, inexpensive and offer significant directory possibilities. Cytochemical and histochemical (on frozen or paraffin sections) enzyme stains are useful to reach a differential diagnosis. Acid phosphatase, acid non-specific esterase, chloroacetate esterase and terminal deoxynucleotidyl transferase (TdT) are the most valuable ones. Not only mere enzyme positivity but also the pattern of their intracellular distribution is of importance. For example acid phosphatase and acid non-specific esterase are negative or fine granularly positive in B cells and strongly and diffusely positive in histiocytes. T lymphocytes show a focal spotty positivity for both enzymes. In particular, acid phosphatase is present in the lymphoid cells of the central lymphoid organs (e.g. thymocytes) and in peripheral T-cell lymphocytes as well, while acid non-specific esterase characterizes only the peripheral T lymphocytes and mainly CD4 helper T cells. Chloroacetate esterase positivity is expressed by cells of granulocytic series and mast cells. TdT characterizes the lymphoid cells of thymic and prethymic stage as well as those of Pre-B type. These enzyme staining are being applied less and less and are substituted by the immunohistochemical use of monoclonal antibodies either against enzymes or, more importantly, against epitopes characterizing various cell categories of lymphocytic, monocytic or even myelocytic origin. Of great help in the differential diagnosis of malignant lymphomas is the immunohistochemical demonstration of various surface or cytoplasm markers: immunoglobulins, enzymes such as TdT, lysozyme and elastase of leukocytes as well as antigens characterizing various categories of cells (e.g. antigens of lymphocyte differentiation, antigens specific for T or B cells, antigens of monocytes/histiocytes, CALLA, HLA-antigens, antigens of IL-2R, TCR etc). It must be emphasized that new monoclonal antibodies are being produced that recognize special cell subcategories such as the follicular center lymphoid cells, the helper (CD4) and suppressor (CDS) T cells, the follicular dendrite cells (FDRC), the interdigitating reticulum cells (CD6), the NK cells (CD57), etc. In addition, monoclonal antibodies which can recognize on paraffin sections epitopes characterizing B or T cells, dendritic cells and monocytes/histiocytes (e.g. CD20, LN1, LN3, UCHL1, beta F1, CD21, CD68, MAC etc.) become more and more numerous. Even with the use of various specific monoclonal antibodies a certain percentage of malignant lymphomas remain negative for both B and T-cell markers, thus deserving the designation of "null cell" lymphomas. The use of molecular pathology techniques [12-15] offers a substantial aid in such instances as well as in problems concerning cell origin, aetiopathogenicity and prognosis. In fact, gene rearrangement analysis has shown that many of the "null" lymphoblastic malignant lymphomas have rearrangements of the immunoglobulins genes while a considerable number of "null" large cell lymphomas have T-cell receptor rearrangements . In-situ hybridization is useful for the demonstration of specific RNA or DNA corresponding to cellular or viral components (Igs-RNA, EBER and EBNA for EBV etc.). It must be emphasized that the polymerase chain reaction (PCR) and in-situ hybridization can in many instances be applied to paraffin-embedded material [17,18]. Moreover, the PCR technique can be used to raise the sensitivity of in-situ hybridization in paraffin sections. An applicable classification should combine scientific correctness with a high prognostic value, a high rate of reproducibility and significant clinical and epidemiological correlation. During the past few decades several more or less successful attempts to classify lymphomas have been made. Two classifications prevail: the Kiel classification and the international working formulation, IWF . The use of one or both of these classifications is necessary since pathologists and clinicians require a common reference. However, it must be stressed that in many cases the two classifications are not automatically interchangeable and therefore the degree of the pathologist's experience is decisive. Both classifications apply better to lymph node malignant lymphomas, since the extranodal lymphomas frequently display significant peculiarities in their morphology, phenotype, genotype and clinical behavior. Such cases are lymphomas of the gastrointestinal tract and the so-called MALTomas in general , lymphomas of the skin [25,26], large cell lymphomas of the mediastinum , and lymphomas of the nasal cavities . Both classifications, Kiel and IWF, have their advantages and disadvantages. The Kiel classification has the advantages of a) incorporating morphology and immunology and distinguishing categories of B and T-cell lymphomas; b) separating lymphomas into low and high grade of malignancy; c) subdividing T-cell malignant lymphomas into several groups; d) including peculiar categories of lymphomas such as marginal zone/B-monocytoid cell and large cell (Ki-1+) anaplastic lymphomas. The only disadvantage of the Kiel classification is that it designates as low-grade malignant lymphomas some entities like centrocytic (mantle cell), AILD-like, T-zone and peripheral pleomorphic small T-cell lymphomas, although their course is either relatively aggressive or unpredictable. The IWF classification, on the other hand, is purely descriptive and does not distinguish between B and T-cell entities. The T-cell distinction is completely absent. In addition to high and low grade of malignancy, the IWF distinguishes a third, intermediate grade. This distinction seems unnecessary as most of the lymphomas belonging to this latter group behave and are treated like those of high-grade malignancy [30,31], while some of them should be placed in the low-grade category. In the present work the Kiel classification is used primarily, and an attempt is made to correlate it with the IWF. Some peculiar lymphoma entities of histopathogenic, prognostic or differential diagnostic importance which are difficult to incorporate into either of the above classifications are described separately. Low Grade Malignant Lymphomas Low-grade malignant lymphomas are histologically characterized by the presence of small or medium-sized lymphoid cells. Sometimes they are mixed with limited numbers of larger blastic cells, for example in the so-called centroblastic-centrocytic malignant lymphomas. Lymphocytic Lymphoma The malignant lymphomas included in this group consist mainly of lymphocytes or their forms of prolymphocytes and hairy cells. They belong more frequently to the B than to the T-cell lineage. Chronic lymphocytic leukemia of B-cell type (B-CLL) This is characterized by infiltration with B lymphocytes that do not show any transformation to Ig-secretory cells such as lymphoplasmacytoid and plasmacytic cells. This interruption of maturation could be attributed partly to defective CD4+ helper T cells and partly to an increased activity of CD8+ suppressor T cells . Immunohistochemically the neoplastic lymphocytes express the B-cell antigens CD20, CD22 and CD23, are either kappa or lambda monoclonal and show SIg of the IgM class, frequently together with IgD. However, not rarely B-CLL lymphocytes especially after micro-wave retrieval may show some intracytoplasmic Ig-positivity. This fact, in conjunction with the positivity for CDS antigen, raises the possibility of B-CLL and lymphoplasmacytoid immunocytoma being variants of the same entity . They seem to be histogenetically related to CDS-positive lymphocytes of the primary follicle or the follicular mantle zone . B-CLL does not occur in subjects under 20 years of age. It shows generalized lymphadenopathy and usually a leukemia picture with bone marrow infiltration. According to Rappaport's group cases of lymphocytic lymphoma [32,36] may exist without any synchronous or metachronous leukemia picture. Effacement of the normal lymph node structure is observed histologically due to diffuse infiltration with maturing lymphocytes [34,36-38]. Among these larger lymphocytes, the prolymphocytes , are found with less dense chromatin and prominent nucleoli as well as large cells, the paraim-munoblasts with basophilic cytoplasm, oval nuclei and central, prominent nucleoli. They are sometimes dispersively distributed but more frequently form clusters (pseudofollicular foci or proliferation centers, Fig. 1). Mitoses and positivity for the proliferation antigen Ki-67 are present only in prolymphocytes and paraimmunoblasts where also most of the p53 oncoprotein positivity is expressed . The greater the proliferation centers, the more tumors is the appearance of the lymph nodes. About 4% of the cases eventually develop into true, high-grade malignant lymphoma, usually immunoblastic (Richter's syndrome) . In some cases a development of giant cells similar to Hodgkin and Sternberg-Reed cells superimposes the B-CLL morphology. Such cells are positive for Epstein-Barr virus elements (LMP, EBER) and Ki-1 (CD30) antigen, a fact which renders possible a relationship of such cases with Hodgkin's disease . Patients usually survive for many years without any substantial therapy. The extent of bone marrow infiltrates and their way of distribution are of particular importance . More favorable prognosis have the cases with nodular patterns (Fig. 2) while cases with diffuse distribution survive less. The prognosis also seems to depend on the size and number of proliferation centers in the lymph nodes . Chronic lymphocytic leukemia of T-cell type (T-CLL) In T-CLL the lymph nodes are less pronounced and the spleen enlargement is more prominent than in B-CLL. The bone marrow is not always infiltrated while skin involvement is frequent. The diffusely infiltrated lymph nodes show proliferation of postcapillary venues. Proliferation centers are absent. The neoplastic lymphocytes have morphological and immunohistochemical characteristics of either CD4+ helper or CD8+ suppressor T cells [45,46]. Rare cases show a mixed immunophenotype with simultaneous CD4 and CDS positivity in the same cells. Hairy cell leukemia Hairy cells often show hair-like projections of their cytoplasm  on hematological smears and imprints. These projections are better recognized by electron microscopy. In the majority of cases the cells represent a peculiar, not fully defined B-cell variety [48,49]. Some authors relate hairy cells to B-monocytoid marginal zone cells of the lymph node cortex and to centrocyte-like cells of mucous-associated lymphoid tissue [50,51]. In very rare instances the hairy cells reveal characteristics of a T-cell  or even a monocytic [53,54] phenotype. Hairy cells are identified by their positivity to tartrate-resistant acid phosphatase and to acidify non-specific esterase . In addition, monoclonal antibodies exist which recognize antigenic epitopes on hairy cells . The usual immunophenotype of hairy cells corresponds to CD22, CD20 and CD29 positivity and CD5 and CD23 negativity. Hairy cells are also stained for HML-1 antibody, which was initially found to recognize intraepithelial T lymphocytes . They also show positivity for CD11 c (KiM1 and KiM1 P in frozen and paraffin sections, respectively). Hairy cells are larger than typical lymphocytes with irregular ellipsoid or reniform nuclei. They stay apart from each other because of their relatively abundant cytoplasm which is hardly recognizable in H+E stained paraffin sections . Lymph nodes are involved in advanced stages of the disease. Organs which are infiltrated early and whose biopsy contributes to the establishment of the diagnosis are bone marrow, spleen and liver. In bone marrow (Fig. 3) reticular fibers and even fibrosis are abundant  and responsible for the dry-tap reported by hematologists. In the spleen the infiltrates mainly occupy the cords of the expanded red pulp. The picture of the peripheral blood is not always clearly leukemia. Hairy cell leukemia in which the HTLV-2 virus has in some way been implicated  displays a rather indolent and long lasting course especially after appropriate therapy. The percentage of Ki-67-positive hairy cells is very low. However, second malignancies do occur in hairy cell leukemia patients Lymphoplasmacytic/Lymphoplasmacytoid Lymphoma (LP-immunocytoma) Histologically, LP-immunocytoma resembles B-CLL. In addition it shows various numbers of Ig-secreting cells of plasmacytic or lymphoplasmacytoid appearance . The latter have moderate to abundant cytoplasm with rough endoplasmic reticulum-like plasma cells and a nucleus reminiscent of lymphocytes. PAS-positive intranuclear inclusions, representing Igs, are often found. Immunohistochemically plasmacytic and plasmacytoid cells reveal cytoplasm monoclonal immunoglobulins [34,60, 61], which in descending frequency belongs to IgM, IgG or IgA. In 35% of the cases a paraproteinaemia is present. LP-immunocytoma is the tissue ground of the so-called macroglobulinaemia of Waldenstrom. In rare cases neoplas-tic cells produce only heavy or light chains of Igs, resulting in heavy (IgM, IgG) or light-chain disease, respectively. Two histological subtypes of LP-immunocytoma are described. The lymphoplasmacytoid subtype is morphologically and immunophenotypically more like B-CLL. It shows lymphoplasmacytoid cells and a phenotype of CD19+, CD20+, CD22+, CD5+ and CD23+ . It not infrequently shows a leukemia picture and borderline cases to B-CLL exist . The Lymphoplasmacytic subtype includes among the other neoplastic lymphocytes classic monoclonal plasma cells. The phenotype of neoplastic cells corresponds to CD19+, CD20+, CD22+, CDS- and CD23+/-. The presence of follicular dendritic cells, a feature reminiscent of MALTomas, characterizes more than half of the cases of the Lymphoplasmacytic subtype [63,64]. The prognosis of LP-immunocytoma is slightly more unfavorable than that of B-CLL. Accordingly, the percentages of Ki-67-positive lymphoid cells are slightly higher in LP-immunocytoma than in B-CLL. Paradoxical-ly it seems that leukemia cases have a better prognosis than aleukaemic cases . The high-grade malignant lymphomas which may develop from LP-immunocytoma are usually immunoblastic. Plasmacytic Lymphoma (Plasmacytoma) Plasmacytes represent the end stage of differentiation of B cells after antigenic stimulation. From this point of view Plasmacytoma must be considered as a kind of lymphoma. Here we mainly discuss the extramedullary Plasmacytoma , which more frequently involve the upper respiratory tract. However, Plasmacytoma of the gastrointestinal tract, the testes and the lungs, among other organs, are no curiosities. Primary lymph node Plasmacytoma represents about 0.8% of non-Hodgkin lymphomas. The neoplastic plasma cells display Immunohistochemically monoclonal CIg, usually of the IgA, less frequently of the IgG and rarely of the IgM class . Their immunophenotype corresponds to CD19-, CD20-' CD22- and PCA1/CD38+ [67,68]. Not infrequently, however, they express one or more haematopoietic and non-haematopoietic antigens, thus complicating the differential diagnosis . Basically there is no histogenetic difference between extramedullary Plasmacytoma and multiple myelomas. Moreover, solitary Plasmacytoma of the bone occur [70,71] and extramedullary Plasmacytoma may develop typical multiple myelomas. Extramedullary Plasmacytoma do not often display paraproteinaemia. Their prognosis is much better than that of multiple myelomas. Mantle Cell Lymphoma This type, formally called centrocytic lymphoma , corresponds to intermediate lymphocytic lymphoma of the Rappaport group [73,74]. It has been proved that it derives from mantle cells of the follicles and has nothing to do with the centrocyte of the follicular (germinal) centers [75,76]. Histologically, the neoplasm consists of small to medium-sized centrocyte-like cells (Fig. 5a) with irregular, cleaved nuclei [72,74]. By definition no neoplastic cells with blastic appearance are found among the cleaved cells. Instead, a small number of T cells can be found. Very often the vessel wall, mostly of the capillaries, is thickened and hyalinized. The growth pattern is rather diffuse, but not infrequently a modularity is seen. in early stages of growth a mantle-like neoplastic infiltration around reactive germinal centers is observed. Immunophenotypically they are strongly and simultaneously positive for surface IgM and IgD [75-77]. Their phenotype corresponds to a subtype of cells of the follicular mantle zone being CD19+, CD20+, CD22+ and especially CD5+ and CD23-. The phenotypes of the various categories of centrocyte-like cells are given in Table 3. The mean number of mitoses and Ki67-positive neoplastic cells is much higher than that found in B-CLL, LP-immunocytoma and centroblastic/ centrocytic malignant lymphoma. Mantle cell lymphoma can also be distinguished from the latter on the basis of molecular genetic differences. It shows the translocation t(11;14) (q13;q32) causing bcl-~\ gene rearrangement, while very often centroblastic/centrocytic lymphoma (especially the nodular type) shows the translocation t(14;18) causing bcl-2 gene rearrangement [75,78]. Mantle cell lymphoma has a much worse prognosis than B-CLL, LP-immunocytoma and centroblastic/centrocytic lymphomas . It has been shown that t(11 ;14) chromosomal translocation occurring in mantle cell lymphoma results in overexpression of a cyclin gene, PRAD1 . The median survival time is less than 4 years. Mantle cell lymphomas represent 10% of non-Hodgkin lymphomas and the great majority occur at ages over 20. According to the IWF classification most of the cases of mantle cell lymphoma can be categorized as either "diffuse small cleaved cell" or "diffuse large cleaved cell" lymphoma, although the reverse does not apply. Centroblastic/centrocytic Lymphoma uНКmitoses. Immunohistochemically these cells display a phenotype of mature T cells: CD2+, CD3+, CD5+ and CD4+ [133,134]. Ki-67 positivity is almost exclusively seen in the CD4-positive neoplastic cells and not in the coexistent CDS-positive reactive cells. TCP gene rearrangement studies have confirmed the T-cell origin of Lennert's lymphoma [135,136]. Some neoplastic cells have a pale to clear cytoplasm and may even become larger and immunoblastic. In very rare cases may the cells resemble Stemberg-Reed cells. Small numbers of eosinophils and plasma cells may be found. Formally this kind of lymphoma was confused with Hodgkin's disease and angioimmunoblastic lymphadenopathy [137,138] or even with LP-immunocytoma [134, 138] containing numerous epithelioid cells. Development into a high-grade malignant lymphoma of the T-immunoblastic, Ki-1+ large cell anaplastic and large T-cell pleomorphic type is not infrequent [133,139]. The prognosis of Lennert's lymphoma is rather unfavorable. Survival depends on the clinical stage of the disease and its median value does not exceed 12 months. It is said that sufficiently aggressive therapy may improve the survival rates [140, 141]. According to the IWF Lennert's lymphoma in its typical form .could be categorized as "diffuse, mixed small and large cell malignant lymphoma". T-cell Lymphoma of AILD Type (AILD-like ML) Immunoblastic  or angioimmunoblastic  lymphadenopathy appears clinically as a systemic disease with generalized lymphadenopathy, spleen and liver enlargement, Coombs-positive hemolytic anemia, polyclonal hyperglobulinaemia, drug hypersensitivity and skin eruptions. Histologically the effacement of the lymph node architecture is complete or almost complete. Some "burnt-out"  pale stained germinal centers may be found. Arborizing vessels of the post-capillary venules type show strong proliferation even outside the lymph-nodal capsule. PAS-positive amorphous material in thickened vascular walls and among cells characterizes most of the cases. The infiltrating cell population is polymorph, consisting of lymphocytes, plasma cells, dispersed immunoblasts, histiocytes and eosinophils [142-144]. In some cases the presence of epithelioid cells is prominent [142, 145]. AILD, occurring more frequently in elderly patients, was initially considered as a hyper-immune reaction [142-143] due to drugs or other immunogens. After the first description in Japan of peripheral T-cell lymphoma resembling immunoblastic lymphadenopathy , it became gradually obvious that the majority of so-called AILD represent a real T-cell lymphoma. The elements which favor such a view are: a) in most cases and in the vicinity of the proliferating vessels accumulations of atypical T cells with clear cytoplasm are found b) in many cases chromosomal abnormalities (trisomy 3 or 5) are documented [147,148]; c) TCR gene rearrangement methods have demonstrated clonality of T cells regarding TCR-B and tcr-y chain genes [149-151]. However, in part of the cases there is an additional IgH-chain gene rearrangement . Immunohistochemically the proliferating T cells (Ki-67+) are most frequently CD4 positive whereas in a minority of cases the proliferating cells show CDS positivity . The latter is related to the presence of IgH chain gene rearrangement. Another histological and immunohistochemical characteristic of AILD-type lymphoma is the abundance of hyperplastic follicular dendritic cells  inside as well as outside the "burnt-out" germinal cells, even among the Arborizing vessels. Although non-neoplastic, immunoreactive cases of AILD occur , the prognosis is generally poor, especially for cases of AILD-type T-cell lymphoma. The mean survival time was about 24 months after combined prednisone and chemotherapy . It seems that the group with CDS positivity and IgH chain gene rearrangement has a relatively better prognosis . In over 10% of AILD-type T-cell lymphomas transformation into high-grade malignant lymphoma of the large T-cell pleomorphic, T-immunoblastic or large cell anaplastic (Ki-1+) type occurs. The finding of light chain (k or ^) monoclonal plasma cells and immunoblasts [154,155] could be explained either as a true B-cell lymphoma or as reactive B-cell clone expansion induced by the helper activity of the CD4-positive neoplastic cell clone. Aetiopathogenetically AILD-type T-cell lymphoma has been related to viruses such as rubella , herpes-like  and Mazon-Pfizer monkey virus . Pleomorphic Small T-cell Lymphoma Although occurring also in childhood, pleomorphic small T-cell lymphoma shows its incidence peak after 60 years of age. The tumor cells may be HTLV-1 positive, especially in Japan and the Caribbean area. Histologically the lymph nodes are diffusely involved by small-sized (Fig. 11a) pleomorphic cells. Their nuclei are gyroid, indented or irregular with small nucleoli. The cytoplasm is rather scarce and pale to clear [20,120,159]. Skin involvement is common. Usually, all types of peripheral T-cell lymphomas show more mitoses than their morphological analogues among B-cell lymphomas. In addition, they frequently show epidermotropism/epitheliotropism and angiotropism. Immunohistochemically they have the phenotype of helper CD4-positive T cells (Fig. 11b). With molecular methods they reveal clone gene rearrangement for tcr-y or TCR-B. Despite the "cytic" appearance of the neoplastic cells and the initial absence of "blastic" cells, the prognosis of pleomorphic small T-cell lymphomas is poor. Neoplastic cells undergo an early activation and transformation to large cells, resulting in development of high-grade malignant T-cell lymphoma. Pleomorphic small T-cell lymphoma is rather difficult to be categorized in the IWF.