HODGKIN’S LYMPHOMA.pptx

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

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

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.

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%)

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.

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-κB is a common event in Classical Hodgkin Lymphoma.
↓ (Antiapoptotic activity)
Promotes the growth and survival of Reed- Sternberg cells, cannot synthesize Immunoglobulin

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

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

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.

CLASSICREED 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.

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

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

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

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

Cells that Mimick Reed SternbergCELLS
• Immunoblasts
• Plasmablasts
• Megakaryocytes
• Anaplastic Lymphoma Cells
• Large Cell Lymphoma Cells
• Melanoma
• Large Cell Carcinoma

NODULAR LYMPHOCYTEPREDOMINANTHODGKIN LYMPHOMA
• Epidemiology: Male>>Female
4TH -5TH 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.

Microscopicfeatures:
• 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)

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.

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

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)

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

MICROSCOPICFEATURES:
• 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.

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

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.

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

1) Fibro-histiocytic variant of Nodular sclerosis CHL may mimics a reactive process or a
mesenchymal neoplasm.
2) Syncytial variant of nodular sclerosis CHL.
D/D: Anaplastic large cell lymphoma or
Non-Lymphoid neoplasm
3) Large cell Non Hodgkin lymphoma
4) Germ cell tumor
5) Thymoma

MIXEDCELLULARITYCLASSICHODKINGLYMPHOMA(20-25%of CHL)
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.

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.

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

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%

LYMPHOCYTERICH CLASSICHODGKINLYMPHOMA(rare)
Older adults
• Clinical Features: Very good or excellent prognosis.
• Localization: Peripheral Lymph node involvement (most common)
Mediastinal involvement uncommon

MicroscopicFEATURES
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.

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

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

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

LYMPHOCYTICDEPLETEDCLASSICHODGKINLYMPHOMA (<5%)
Most common: older males, rare in children
Most Common in HIV and developing countries.
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.

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.

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.

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

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.

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)

Tumor stagingis important than Histologictype for current treatment and prognosis.

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.

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.

• 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% .

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

HODGKIN’S LYMPHOMA.pptx

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