2. Hodgkin lymphoma In 1832, Sir Thomas Hodgkin provided the first description of the process in a paper entitled “On Some Morbid Appearances of the Absorbent Glands and Spleen.” The typical “diagnostic” cells were independently described by Beresovsky in 1890 in Russia, by Sternberg in 1898 in Germany and by Dorothy Reed in 1902 in USA. These cells are called Beresovsky-Sternberg (in russian literature) or Reed-Sternberg (in english literature), they are the substratum of the tumor This lymphatic malignansy has granulomatous structure. This fact differs HL and NHL.

3. Specific cells in HL (Hodgkin-cells, BS/RS-cells)

4. BS (RS) cells

5. Although much has been learned about the derivation of the HRS cells, little is known about the basic mechanisms underlying malignant transformation of HL. Because HL was frequently clinically associated with tuberculosis, for a long time it was considered to be a peculiar form of a granulomatous disease such as tuberculosis. Despite the very strong evidence for the malignant nature of HL over the past century, it has been only recently shown that Hodgkin and Reed-Sternberg (HRS) cells are definitely clonally expanding, preapoptotic, germinal center- derived B lymphocytes that resemble true malignant cells The HRS cells in HL are derived from preapoptotic germinal center B cells in most cases, which can be proved by identyfying CD20 и СD79а antygenes on BS (RS)-cells’ surface. Several studies have focused on the apoptosis-resistant phenotype of BS/RS cells, and some data suggest that constitutively expressed Flice-inhibitory protein (FLIP), a protein that inhibits FAS-mediated apoptosis, contributes to apoptosis resistance in HL

6. Granulemas In granulemas BS/RS-cells are only 0,1-2%. The reactive milieu—which can even represent 99% of the whole examined population of cells—consists of small lymphocytes, histiocytes, epithelioid histiocytes, neutrophils, eosinophils, plasma cells, fibroblasts, and vessels in different proportions depending on the histological subtype of HL.

7. Epidemiology HL shows a typical bimodal age distribution with a peak at approximately 20 years of age and a second peak in late life. Slightly more men than women (1.4-2 : 1) develop this malignancy. Among the group of young adults, the most common subtype is nodular sclerosing HL (NSHL), which occurs at a higher frequency (2 : 1) than the mixed-cellularity subtype of HL (MCHL). The frequency of MCHL increases with age, whereas incidence of the NSHL subtypes reaches a plateau in the group of young adults older than 30 years. There is a great difference in incidence of this disease between developing and industrialized countries. In developing countries, the disorder occurs predominantly during childhood, and its incidence decreases with age, whereas in industrialized countries, young children are much less commonly diagnosed with HL compared with adolescents or young adults.

8. Pathogenesis Despite significant progress in understanding the cellular origin of BS/RS cells, little is known about the mechanisms responsible for the initial transformation event. EBV has been identified as a virus with potential involvement in the transformation of a subpopulation of HL cases. The events underlying the transformation process in the EBV-negative cases, however, are still not understood. Violations in the genome in classical HL cells result in nuclear division without cell division. This is the reason of presenting clone of giant multinucleate cells.

9. Clinical features Patients with classical HL most often present with lateral-cervical lymph node enlargement, in 90% - l.n. above the diafragm. In 15% of cases there is a primary lesion of the mediastinal l.n., the tumor may grow into pleura, lung parenchima, pericardium, trachea, oesophagus. Approximately 50% of patients are staged I or II. Systemic symptoms—fever, night sweats, and body weight loss—are detected in approximately 25% of patients. HL starts in a single group of lymph nodes and then spreads by the lymphatic route, there is mounting evidence that the gradually more aggressive tumor cells tend to disseminate through the bloodstream rather early and disseminate to organs such as bone marrow, liver, and lungs. 5-25% of patients have a specific symptom; alcohol ingestion may precipitate pain in enlarged nodes. Systemic symptoms (fever, weight loss, pruritus and drenching night sweats) occur in 25%. Extranodal disease is uncommon but lung, CNS, skin and bone involvement may occur. Infection caused by defective cell-mediated/humoral immunity

13. Stage I: involvement of a single lymph node region or structure; Stage II: involvement of two or more lymph node regions on the same side of the diaphragm; Stage III: involvement of lymph node regions or structures on both sides of the diaphragm; Stage IV: involvement of other organs, e.g. liver, bone marrow, CNS. A: no intoxication symptoms; B: fever, night sweats, weight loss >10% in preceding 6 months. + involvement of the organs!

14. Staging influences both treatment and prognosis. Clinical staging with careful physical examination is followed by cervical, thoracic, abdominal and pelvic CT or MRI scanning. Bone marrow aspirate and trephine are performed to detect marrow involvement.

15. Laboratory features Non-specific: Anaemia (normochromic, normocytic). Leucocytosis (occasionally eosinophilia). Raised erythrocyte sedimentation rate (ESR), raised lactate dehydrogenase (LDH)—useful as prognostic marker and for monitoring response—and abnormal liver function tests. No blasts in peripherial blood – HL never tranforms into leycosis (despite the opportunity of the bone marrow involving)

16. Diagnosis 1. Morphology (specific cells) 2. Hystological type 3. Immunology Although regarded as diagnostic, Hodgkin and RS (H&RS) cells are not exclusive of HL, because similar elements may be observed in reactive lesions (such as infectious mononucleosis), B- and T-cell lymphomas, carcinomas, melanomas, or sarcomas. Thus, the presence of an appropriate cellular background— along with the results of immunophenotyping—is basic for the diagnosis.

17. Hodgkin-cells, BS/RS-cells

18. Histotypes: 1. Lymphocyte-rich (nodular, diffuse) 3-5% of HL cases. 2. Nodular sclerosis (grades I and II, cellular phase, syncytial), in 75% of HL cases. 3. Mixed-cellularity, in 20-25% of HL cases. 4. Lymphocyte-depleted(fibrotic, sarcomatous), in 1-2% of HL cases

19. Nodular sclerosis represents the most frequent subtype of classical HL, it corresponds to 75% to 80% of all HL cases; the tumor is characterized by sclerosis, lacunar cells, and a nodular pattern

20. Approximately 15% to 25% of HL cases belong to the mixed-cellularity classical HL group. The term mixed-cellularity classical HL reflects the cellular composition of the reactive milieu that consists of plasma cells, epithelioid histiocytes, eosinophils, and T lymphocytes (CD3 +, CD57 - ) forming rosettes around neoplastic elements

21. Lymphocyte-depleted HL is indeed rare, accounting for approximately 1% of HL cases, and is associated with the worst clinical behavior and prognosis. In most instances, patients present with III–IV disease and display B symptoms and bone marrow involvement. Histopathologically, it is characterized by the paucity of the lymphoid component, absolute or relative abundance of RS cells, and variable fibrotic reaction.

22. Prognosis 1. Good: lymphocyte-rich and nodular sclerosis (grade I) 2. Poor: mixed-cellularity and especially lymphocyte- depleted; B-symptoms Stage is of paramount importance for HL. While >90% of stage I and II may be cured, the rate falls progressively to 50–70% of stage IV patients.

23. Treatment Depends principally on the stage: Radiotherapy alone may be used for patients with clinical or pathological stage IA or IIA disease with favourable histology. Advanced stages (IB, IIB, III and IV) HD should be treated with combination chemotherapy (CCT) using one of the standard regimes (e.g. six cycles of Adriamycin, Bleomycin, Vinblastine and Dacarbazine, ABVD); chemotherapy + radiotherapy

24. Long-term prognosis Patients with 1 st, 2 nd stages have good prognosis: 98% have complete remission, 81% live for 10, more years without relapses; 60% live for 20 and more years after treatment. Patients with 3 rd, 4 th stages: 43-50% have complete remission; 10-20% of patients live for 6 years without relapses.

25. Death reasons 41% - the progress of the disease 26% – secondary tumors 16% – cardiovascular, lung diseases.

26. Thank you for your attention! Questions are welcome.