HODGKIN’S LYMPHOMA.pptx

Hodgkin lymphoma pathology

1. HODGKIN’s LYMPHOMA Dr. Anjana K.C 2 nd year Resident Department of Pathology 2022-06-28

2. LYMPHOMA Neoplastic proliferation of immune system , originates from Lymphoid tissue ; Rarely from Central Nervous System (AIDS) LYMPHOID TUMORS Hodgkin’s Lymphoma Non-Hodgkin’s Lymphoma Lymphocytic Leukemia Plasma cell dyscrasis

3. Hodgkin’s Lymphoma Accounts for ~ 30% of all malignant lymphomas. Lymphoid neoplasm usually affecting lymph node composed of, Large dysplastic Mononuclear and Multinucleated cells Surrounded by a heterogenous population of Non-Neoplastic Inflammatory cells . Named after Thomas Hodgkin , who discovered it in 1832. Dorothy Reed & Carl Sternberg , discovered the malignant cells of HL called Reed Sternberg cells.

4. TYPES of Hodgkin's Lymphoma: Based on the basis of Immunophenotype and Morphology of the Neoplastic cells and the Cellular background . WHO Classification (2017): 1) Nodular Sclerosis 2)Mixed Cellularity Classical Hodgkin Lymphoma (90%) 3)Lymphocyte Rich 4)Lymphocyte depleted 5)Nodular Lymphocytic Predominance Hodgkin Lymphoma (10%)

5. ETIOLOGY The etiology of Hodgkin lymphoma is Unknown. Epstein Barr Virus (EBV) responsible for Infectious mononucleosis plays a major role in the pathogenesis of Classical Hodgkin Lymphoma(CHL). Immunodeficiency status, such as HIV infection may predispose to EBV associated CHL. Family history of CHL, most common in monozygotic twins & siblings (3-7 folds). Socioeconomic class is associated with a higher risk of Hodgkin lymphoma.

6. PATHOGENESIS More than 98% of Neoplastic cells are derived from , B cells Origin at the Germinal Center stage of Differentiation and contain CLONAL IgG gene Rearrangements & Somatic hypermutation within IgG ↓ Activation of the transcription factor NF- κ B is a common event in Classical Hodgkin Lymphoma. ↓ (Antiapoptotic activity) Promotes the growth and survival of Reed- Sternberg cells, cannot synthesize Immunoglobulin

7. Role of Epstein Barr Virus EBV +ve Tumor cells Express Latent Membrane Protein 1(LMP-1) ↓ Transmits Signals ↓ Activation of NF- κ B ↓(antiapoptotic) Proliferation of HRS cells & Secretion of Cytokines which produces systemic features. *(NF κ B~ Nuclear Factor Kappa B pathway) (HRS~ Hodgkin Reed Sternberg cells) EBV –ve Tumor Cells Acquired Loss of functional mutations in I κ B or TNF- α induced protein 3 ↓ Activation of NF κ B *(I κ B~ Inhibitor kappa B) (TNF- ~Tumor Necrosis factor)

8. Clinical Features Firm, rubbery, Painless lymphadenopathy. Most common site: Cervical region . B symptoms (Constitutional) in 40% cases: Fever, Night sweats, Unintended weight loss. Other symptoms: Pruritus, Alcohol associated pain (Rare but pathognomic) Paraneoplastic syndromes, bone pain, skin lesions. Extra nodal manifestations: Organomegaly

9. Macroscopically Enlarged and encapsulated Lymph node. On cut section: Fish-flesh tumor. In NSCHL- Prominent nodularity, Dense fibrotic bands, Thickened capsule. Splenic involvement usually shows scattered nodules within the white pulp. CHL in the thymus can be associated with cystic degeneration and epithelial hyperplasia.

10. CLASSIC REED STERNBERG CELL Large cell (45micron in diameter) Binucleated or bilobed Two mirror image nuclei ( OWL’S EYE) Each nucleus with a large inclusion like eosinophilic central nucleoli ,about the size of small lymphocyte (5-7 micron in diameter), surrounded by clear halo. Abundant eosinophilic cytoplasm.

11. VARIANTS OF REED STERNBERG CELLS MONONUCLEAR VARIANT (Hodgkin cells Single ,large, round nucleus Large eosinophilic inclusion like single Nucleolus.

12. Lacunar Variant of RS cells Large, folded or multilobed irregular nucleus. Small one or more eosinophilic nucleoli. Finely dispersed chromatin. Abundant pale cytoplasm.

13. Lymphocyte predominant (LP) /Lympho-Histiocytic variant( L&H cells)/Popcorn cells Polypoid nuclei (popcorn) Inconspicuous nucleoli Moderate pale cytoplasm

14. Mummified Variant Degenerate L&H cells or RS cells. Dark stained and retracted nucleus. Eosinophilic Cytoplasm. Morphologically represents expression of apoptosis.

15. Cells that Mimick Reed Sternberg CELLS Immunoblasts Plasmablasts Megakaryocytes Anaplastic Lymphoma Cells Large Cell Lymphoma Cells Melanoma Large Cell Carcinoma

16. NODULAR LYMPHOCYTE PREDOMINANT HODGKIN LYMPHOMA Epidemiology : Male>>Female 4 TH -5 TH decades, also common in Children EBV +ve (<5% cases) Clinical Features: Localized peripheral lymphadenopathy Stage I or II (Ann Arbor Classification) ~20% presents with advanced stage disease. Localization: Usually involves Cervical, axillary or Inguinal Lymph node. Mesenteric, mediastinal involvement rarely. Spleen and Bone marrow involvement in advance stage.

17. Microscopic features: Total or partial effacement of lymph node architecture by; Nodular, diffuse or nodular and diffuse infiltrations comprising of; small lymphocytes admixed with histiocytes, epithelioid cells and LP cells. Frequent L & H Reed Sternberg cells of Popcorn Variant are seen. Follicular dendritic cells are seen. Classic Reed Sternberg cells are difficult to find. Neutrophil and eosinophils are rarely seen. *(LP~ Lymphocyte Predominant) (L & H ~Lymphocyte & Histiocytic)

18. 4x: Popcorn cells

19. Cytopathological Findings: Monotonous population of slightly irregular small lymphocytes with Relatively few scattered large pale multinucleated giant cells corresponding to Popcorn cells in histology, usually without distinct nucleoli seen.

20. Ancillary test. IMMUNOPHENOTYPING CD20 BCL6 +ve CD 15 CD 30 -ve GENETIC PROFILE Clonal rearrangement of IGH genes BCL6 rearrangements .

21. DIFFERENTIAL DIAGNOSIS 1)Lymphocyte Rich Classic Hodgkin Lymphoma Has RS cells but not LP cells. No background of small reactive B cells. 2)T cell/histiocyte Rich Large B cell Lymphoma. Diffuse, not Nodular. No LP cells. 3) Follicular Lymphoma. No LP cells. Background shows atypical cells. No reactive small B cells. * (LP ~Lymphocyte Predominant)

22. CLASSICAL HODGKIN LYMPHOMA

23. NODULAR SCLEROSIS (~70%) Epidemiology: Female>>Male (Only subtype without a male predominance) ~70% common in Western countries 15-35 years of age EBV -ve Clinical Features: Stage I or II (Ann Arbor Classification) Localization: Cervical and Frequent Mediastinal involvement

24. MICROSCOPIC FEATURES: Total or partial effacement of nodular architecture. Nodular growth pattern of lymph node, with nodules surrounded by collagen bands (nodular sclerosis) Criteria: Atleast one nodule surrounded by collagen bands. Frequent Lacunar RS cell variant Syncytial variant (aggregation of lacunar cells) may be associated with necrosis and histiocytes resembling Necrotizing Granuloma.

25. Cont.. Occasionally diagnostic Reed Sternberg cells seen. Background shows numerous Neutrophils , plasma cells and T lymphocytes. Few eosinophils and histiocytes seen.

26. Cytopathological Findings Presence of fibroblast and collagen fragments in the smear. Presence of Lacunar variant/ Syncytial variant of Reed Sternberg cell. Background shows Neutrophils, lymphocyte, plasma cells, macrophages and few eosinophils.

27. Ancillary test. IMMUNOPHENOTYPING CD15 CD30 PAX5 +ve CD 45 -ve Other B and T cells markers -ve GENETIC PROFILE Clonally rearranged IG gene.

28. DIFFERENTIAL DIAGNOSIS Fibro-histiocytic variant of Nodular sclerosis CHL may mimics a reactive process or a mesenchymal neoplasm. Syncytial variant of nodular sclerosis CHL. D/D: Anaplastic large cell lymphoma or Non-Lymphoid neoplasm Large cell Non Hodgkin lymphoma Germ cell tumor Thymoma

29. MIXED CELLULARITY CLASSIC HODKING LYMPHOMA (20-25% of CHL) Epidemiology: Male>>Female Most Common in HIV and developing countries Bimodal age distribution, Peak in Young adults & >55 years. ~75% associated with EBV +ve Associated with B symptoms Clinical Features: >50% Stage III or IV (Ann Arbor Classification) Localization: Peripheral Lymph node involvement (most common) Mediastinal involvement uncommon ~30% Splenic, 10% Bone marrow, 3% Liver, 1-3 % Other organ.

30. MICROSCOPIC FEATURES Diffuse effacement of involved lymph node by heterogenous cellular infiltrates , including neutrophils, T cells, eosinophils, plasma cells and macrophages. Admixed with frequent Diagnostic Reed Sternberg’s cells and Mononuclear variant of RS cells. May form granuloma like epithelioid cells clusters particularly in EBV associated cases. Fine Interstitial fibrosis may be seen. Fibrous and Capsular bands are usually absent.

31. CYTOPATHOLOGY Typical Reed Sternberg cells are usually easy to find. Many plasma cells and eosinophils are seen. Histiocytes in the background cell population.

32. Ancillary test. IMMUNOPHENOTYPING GENETIC PROFILE Clonally rearranged IG gene. Similar to Nodular Sclerosis i.e. CD15 & CD30 +ve. But, EBV encoded LMP-1 & EBV encoded small RNA (EBER) Are more frequent , i.e. > 75%

33. Differential Diagnosis 1)Diffuse Large B cell Lymphoma. 2) T- Cell Lymphoma 3)Anaplastic Large cell Lymphoma. 4) Infectious Mononucleosis. 5)Angioimmunoblastic T cell Lymphoma

34. LYMPHOCYTE RICH CLASSIC HODGKIN LYMPHOMA (rare) Epidemiology: Male>>Female Older adults ~40% associated with EBV +ve Clinical Features: Very good or excellent prognosis. Localization: Peripheral Lymph node involvement (most common) Mediastinal involvement uncommon

35. Microscopic FEATURES Two Growth Patterns are seen. (i) Nodular Growth pattern/ Nodular Variant: Nodules are composed of small lymphocytes with presence of residual B-Cell follicles. Classic Hodgkin Reed Sternberg’s cell and mononuclear RS cell seen with in the nodules. Eosinophils and neutrophils are absent in the nodules but can be seen in interfollicular zones and present in small number.

36. (ii)Diffuse pattern/ diffuse variant Small lymphocytes of the cellular background admixed with histiocytes with or without epithelioid features.

37. Ancillary test. IMMUNOPHENOTYPING CD 15 CH20 +/- ve CD30 +ve GENETIC PROFILE BCL6 expression is found frequently as compared to other CHL.

38. DIFFERENTIAL DIAGNOSIS 1)Nodular lymphocytic predominant B cell Lymphoma : Intact germinal centers are frequent.

39. LYMPHOCYTIC DEPLETED CLASSIC HODGKIN LYMPHOMA (<5%) Epidemiology: Male>>Female Most common: older males, rare in children Most Common in HIV and developing countries. ~75% associated with EBV +ve B symptoms in advanced stage. Clinical Features: Presents with febrile illness with pancytopenia, hepatomegaly Stage III or IV (Ann Arbor Classification) Localization: Sub-diaphragmatic region, abdominal organs, bone-marrow, retroperitoneal lymph node. Peripheral Lymph node involvement may be seen.

40. Microscopic FEATURES Predominance of Classic Hodgkin Reed Sternberg’s cells. Scarcity of background lymphocytes in relation to neoplastic cells. Two Patterns are seen. In one there is diffuse fibrosis , numerous histiocytes and some small lymphocytes. Lacks eosinophils and plasma cells. In second pattern, there is rich neoplastic cells Anaplastic and pleomorphic features are seen often.

41. Ancillary test. IMMUNOPHENOTYPING RS cells CD15 & CD30 +ve EBV/ LMP 1 frequently +ve CD 79 -ve CD30 & PAX 5 helps to differentiate from ALK –ve Anaplastic large cell lymphoma GENETIC PROFILE IGH gene rearrangements shows B cell clonality.

42. DIFFERENTIAL DIAGNOSIS 1) Large cell Non-Hodgkin Lymphoma. 2) Nodular Sclerosis Hodgkin Lymphoma.

43. Laboratory studies For Hodgkin’s lymphoma CBC : Anemia, Lymphopenia, Neutrophilia, Eosinophilia. Platelets : Increased/Decreased ESR : may be raised (worse prognosis) Serum calcium, Na, Creatinine (Increased) LFT (may be raised if liver involvement) LDH (worst prognosis) RFT (Increased prior treatment) Albumin HIV testing Beta-2-macroglobulin: Correlates with tumor burden , systemic symptoms and prognosis.

44. Other tests: Chest X-ray: Mediastinal mass CT Scan: Thorax/abdomen/pelvis (For stagging) Others: PET Scan, Gallium scan Excisional Biopsy (Mandatory test): Nodal effacement & histological classification. Bilateral bone marrow (To determine extent of disease, Patchy infiltrates seen) Staging Laparotomy: Staging (Ann Arbor classification)

45. Tumor staging is important than Histologic type for current treatment and prognosis.

46. PROGNOSIS : Early stage disease: 5 year survival 99% Advanced stage disease: 5 year survival 90% Relapses common within first 3 years from Diagnosis. Relapses treated with Autologous stem cell Transplantation.

47. RECENT CHANGES

48. Take Home Message Hodgkin Lymphoma are Lymphoid neoplasm usually affecting Lymph node composed of large dysplastic mononuclear Hodgkin cell and multinucleated Reed Sternberg cells, in the background of non-neoplastic inflammatory cells. EBV is associated in >75% cases in Mixed cellularity and Lymphocytic depleted CHL. Nodular sclerosis is most common in Females, other subtypes are common in males. B symptoms are associated in Mixed cellularity and Lymphocyte depleted CHL.

49. L & H cells --Nodular Lymphocytic predominant B cell Lymphoma: Lacunar variant of RS cells -- Nodular sclerosis CHL. Frequent Classic Hodgkin RS cells –Mixed cellularity. Scattered Hodgkin RS with predominant small lymphocytes—Lymphocyte Rich CHL. Diffuse form of Classic Hodgkin RS cell against few lymphocytic background—Lymphocyte Depleted CHL. Tumor staging is important than Histologic type for current treatment and prognosis. Patients respond well to chemotherapy and cure rate is about 80-90% .

50. Reference: Robbins & Cotran Pathologic Basis of Disease 10 th edition. WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues 2017 Revised Edition. Rosai and Ackerman’s Surgical pathology 11 th edition. Sternberg’s diagnostic surgical pathology 6 th edition Orell & Sterrett’s 5 th edition. Koss’ Diagnostic cytology 5 th edition.