Lymphomas are primary malignancies of lymph nodes and the peripheral lymphatics. Neoplastic proliferative process of the lymphopoietic portion of the lymphoid system that involves cells of either the lymphocytic or histiocytic series in varying degrees of differentiation & occurs in an essentially homogenous population of a single cell type. The first lymphoma type recognised was by Dr Thomas Hodgkin in 1832. In 1865 Dr Samuel Wilks recognised additional cases, rediscovered the report by Hodgkin, and designated this neoplasm as ‘Hodgkin disease’. Hodgkin lymphoma (HL) represents about 10% of all lymphomas. HL is distinct from other non-Hodgkin lymphomas, clinically by the contiguous spread of tumour along the lymphoid system, and morphologically by the presence of a spectrum of neoplastic cells, including mononuclear Hodgkin (H) cells, classic multinucleated Reed–Sternberg (RS) cells, and mummified (degenerating) cells against an inflammatory background. The background inflammatory cells actively attracted by HL tumour cells may include T cells, B cells, histiocytes, plasma cells, neutrophils, eosinophils and mast cells. The etiology of HD is unknown. Infectious agents, especially the Epstein-Barr virus (EBV), may be involved in the pathogenesis. In as many as 50% of HD cases, the tumor cells are EBV-positive. EBV positivity is higher with mixed cellularity Hodgkin disease (60–70%) than the nodular sclerosis Hodgkin disease (15–30%). Epstein–Barr virus (EBV), also called human herpes virus 4 (HHV-4), is a member of the herpes family and is one of the most common viruses in humans. In immunocompetent hosts, EBV-infected B cells are in a resting state under host T-cell immune surveillance. In hosts with immune dysfunction, EBV-infected cells in the reservoir may be reactivated and proliferate. In EBV-infected cells, based on the viral proteins expressed, three latency transcription programs of EBV are designated: growth program (latency III) with expression of EBV nuclear antigens 1–6 (EBNA1-6), latent membrane proteins (LMP1, 2A and 2B); default program (latency II) expressing EBNA1, LMP1 and LMP2A; and latency program (latency I), with none or only expression of LMP2A. In EBV-positive cases, usually all HRS cells are positive, indicating that the infection was an early event in lymphoma development. The EBV+ HRS cells typically show an EBV latency II gene expression profile, meaning expression of the viral proteins EBV nuclear antigen 1 (EBNA1) and latent membrane proteins 1 and 2a (LMP1 and LMP2a). EBNA1 is essential for replication of the episomal viral genome in proliferating cells. LMP1 mimics an active CD40 receptor and hence stimulates NF- B and PI3K/AKT activity. As BCR and CD40 signalling are main survival signals for GC B cells, EBV infection of GC B cells may be a way how GC B cells with destructive mutations survive and become HRS precursor cells.

1. Round cell tumors
Dr Purva Pihulkar

2. Contents
• Tumours of hematolymphoid origin
– Lymphoma
– Classification
– Hodgkin’s lymphoma
• Etiology
• Clinical features
• Oral manifestation
• Histologic features
• Types
• Treatment and prognosis
– Non-Hodgkin’s lymphoma

3. Lymphoma
• Lymphomas are primary malignancies of lymph nodes
and the peripheral lymphatics.
• Neoplastic proliferative process of the lymphopoietic
portion of the lymphoid system that involves cells of
either the lymphocytic or histiocytic series in varying
degrees of differentiation & occurs in an essentially
homogenous population of a single cell type.

4. Classification
Rappoport classification (1966)
• Nodular or follicular lymphomas.
• Diffuse lymphomas.
Each was further classified according to the degree of
differentiation of neoplastic cells into:
-well differentiated
-poorly differentiated
-histiocytic ( large cells ) type of both nodular and
diffuse lymphomas.

5. • Real Classification (1994): Revised European-
American Classification of Lymphoid Neoplasms (REAL)
Leukaemias and lymphomas of B – cell origin ( Pan-B,
CD19, CD20 positive ).
• Indolent B – cell malignancies.
• Aggressive B – cell malignancies.
Leukaemias and lymphomas of T – cell origin (CD2, CD7
positive).
• Indolent T – cell malignancies.
• Aggressive B – cell malignancies.

6. Updated Real /
WHO Classification (2001)

7. WHO 2008: the mature B-cell neoplasms.
• Chronic lymphocytic leukemia/small
lymphocytic lymphoma
• B-cell prolymphocytic leukemia
• Splenic marginal zone lymphoma
• Hairy cell leukemia
• Splenic lymphoma/leukemia, unclassifiable
splenic diffuse red pulp small B cell lymphoma
hairy cell leukemia variant
• Lymphoplasmacytic lymphoma
• Waldenström macroglobulinemia
• Plasma cell myeloma
• Solitary plasmacytoma of bone
• Extraosseous plasmacytoma
• Extranodal marginal zone B-cell lymphoma of
mucosa-associated lymphoid tissue (MALT
lymphoma)
• Nodal marginal zone B-cell lymphoma (MZL)
• Pediatric type nodal M Z L
•Follicular lymphoma
•Pediatric type follicular
• Primary cutaneous follicle center lymphoma
•Mantle cell lymphoma
•Diffuse large B-cell lymphoma (DLBCL), not
otherwise specified
•Lymphomatoid granulomatosis
•Primary mediastinal (thymic) large B-cell
lymphoma Intravascular large B-cell lymphoma
•Primary cutaneous DLBCL, leg type
•ALK+ large B-cell lymphoma
•Plasmablastic lymphoma
•Primary effusion lymphoma
•Large B-cell lymphoma arising in HHV8-
associated multicentric
• Castleman disease
•Burkitt lymphoma
•B-cell lymphoma, unclassifiable

8. • Hodgkin Lymphoma
• Nodular lymphocyte-predominant Hodgkin lymphoma
• Classical Hodgkin lymphoma
 Nodular sclerosis classical Hodgkin lymphoma
 Lymphocyte-rich classical Hodgkin lymphoma
 Mixed cellularity classical Hodgkin lymphoma
 Lymphocyte-depleted classical Hodgkin lymphoma

9. WHO 2008: the mature T-cell and NK-cell neoplasms.
• T-cell prolymphocytic leukemia
• T-cell large granular lymphocytic leukemia
• Chronic lymphoproliferative disorder of
NK-cells *
• Aggressive NK cell leukemia
• Systemic EBV + T-cell lymphoproliferative
disease of childhood (associated with
chronic active EBV infection)
• Hydroa vacciniforme-like lymphoma
• Adult T-cell leukemia/lymphoma
• Extranodal NK/T cell lymphoma, nasal type
• Enteropathy-associated T-cell lymphoma
• Hepatosplenic T-cell lymphoma
•Subcutaneous panniculitis-like T-cell
lymphoma
•Mycosis fungoides
•Primary cutaneous CD30+ T-cell
lymphoproliferative disorder
•Primary cutaneous small/medium CD4+ T-cell
lymphoma
•Peripheral T-cell lymphoma, not otherwise
specified
•Angioimmunoblastic T-cell lymphoma
•Anaplastic large cell lymphoma (ALCL), ALK+
•Anaplastic large cell lymphoma (ALCL), ALK- *

10. 2016 WHO classification of mature lymphoid,
histiocytic, and dendritic neoplasms
Mature B-cell neoplasms
• Chronic lymphocytic leukemia/small lymphocytic lymphoma
• Monoclonal B-cell lymphocytosis*
• B-cell prolymphocytic leukemia
• Splenic marginal zone lymphoma
• Hairy cell leukemia
• Splenic B-cell lymphoma/leukemia, unclassifiable
• Lymphoplasmacytic lymphoma
• Monoclonal gammopathy of undetermined significance
(MGUS), IgM*
• Monoclonal gammopathy of undetermined significance
(MGUS), IgG/A*
• Plasma cell myeloma
• Solitary plasmacytoma of bone
• Extraosseous plasmacytoma Monoclonal immunoglobulin
deposition diseases*
• Extranodal marginal zone lymphoma of mucosa-associated
lymphoid tissue (MALT lymphoma)
• Nodal marginal zone lymphoma
• Pediatric nodal marginal zone lymphoma
•Follicular lymphoma
•Pediatric-type follicular lymphoma*
•Large B-cell lymphoma with IRF4 rearrangement*
•Primary cutaneous follicle center lymphoma
•Mantle cell lymphoma
•Diffuse large B-cell lymphoma (DLBCL)
• T-cell/histiocyte-rich large B-cell lymphoma
•Primary DLBCL of the central nervous system (CNS)
•Primary cutaneous DLBCL, leg type EBV1 DLBCL, NOS*
• EBV1 mucocutaneous ulcer*
•Lymphomatoid granulomatosis
•Primary mediastinal (thymic) large B-cell lymphoma
Intravascular large B-cell lymphoma
•ALK1 large B-cell lymphoma
•Plasmablastic lymphoma
•Primary effusion lymphoma
•Burkitt lymphoma
•B-cell lymphoma, unclassifiable, with features
intermediate between DLBCL and classical Hodgkin
lymphoma

11. Mature T and NK neoplasms
• T-cell prolymphocytic leukemia
• T-cell large granular lymphocytic leukemia
• Chronic lymphoproliferative disorder of NK cells
• Aggressive NK-cell leukemia
• Systemic EBV1 T-cell lymphoma of childhood*
• Hydroa vacciniforme–like lymphoproliferative disorder*
• Adult T-cell leukemia/lymphoma
• Extranodal NK-/T-cell lymphoma, nasal type
• Enteropathy-associated T-cell lymphoma
• Monomorphic epitheliotropic intestinal T-cell lymphoma*
• Indolent T-cell lymphoproliferative disorder of the GI tract*
• Hepatosplenic T-cell lymphoma
• Subcutaneous panniculitis-like T-cell lymphoma
• Mycosis fungoides S´ezary syndrome
•Primary cutaneous CD301 T-cell lymphoproliferative
disorders
•Lymphomatoid papulosis
•Primary cutaneous anaplastic large cell lymphoma
•Primary cutaneous gd T-cell lymphoma
•Primary cutaneous CD81 aggressive epidermotropic
cytotoxic T-cell lymphoma
•Primary cutaneous acral CD81 T-cell lymphoma*
•Primary cutaneous CD41 small/medium T-cell
lymphoproliferative disorder*
•Peripheral T-cell lymphoma, NOS
•Angioimmunoblastic T-cell lymphoma
•Follicular T-cell lymphoma*
•Nodal peripheral T-cell lymphoma with TFH phenotyp
Anaplastic large-cell lymphoma
•Breast implant–associated anaplastic large-cell
lymphoma*

12. Hodgkin lymphoma
• Nodular lymphocyte predominant
• Hodgkin lymphoma Classical Hodgkin
• lymphoma Nodular sclerosis classical
• Hodgkin lymphoma
• Lymphocyte-rich classical Hodgkin lymphoma
• Mixed cellularity classical Hodgkin lymphoma
• Lymphocyte-depleted classical Hodgkin
lymphoma

13. Hodgkin lymphoma
• The first lymphoma type recognised was by Dr Thomas Hodgkin in 1832. In 1865 Dr
Samuel Wilks recognised additional cases, rediscovered the report by Hodgkin, and
designated this neoplasm as ‘Hodgkin disease’.
• Hodgkin lymphoma (HL) represents about 10% of all lymphomas.
• HL is distinct from other non-Hodgkin lymphomas, clinically by the contiguous spread
of tumour along the lymphoid system, and morphologically by the presence of a
spectrum of neoplastic cells, including mononuclear Hodgkin (H) cells, classic
multinucleated Reed–Sternberg (RS) cells, and mummified (degenerating) cells against
an inflammatory background.
• The background inflammatory cells actively attracted by HL tumour cells may include T
cells, B cells, histiocytes, plasma cells, neutrophils, eosinophils and mast cells.

14. Etiology
• The etiology of HD is unknown. Infectious agents, especially the Epstein-Barr virus
(EBV), may be involved in the pathogenesis.
• In as many as 50% of HD cases, the tumor cells are EBV-positive. EBV positivity is
higher with mixed cellularity Hodgkin disease (60–70%) than the nodular sclerosis
Hodgkin disease (15–30%).
• Epstein–Barr virus (EBV), also called human herpes virus 4 (HHV-4), is a member of
the herpes family and is one of the most common viruses in humans.

15. • In immunocompetent hosts, EBV-infected B cells are in a resting state under host T-cell immune
surveillance.
• In hosts with immune dysfunction, EBV-infected cells in the reservoir may be reactivated and
proliferate.
• In EBV-infected cells, based on the viral proteins expressed, three latency transcription programs of
EBV are designated: growth program (latency III) with expression of EBV nuclear antigens 1–6
(EBNA1-6), latent membrane proteins (LMP1, 2A and 2B); default program (latency II) expressing
EBNA1, LMP1 and LMP2A; and latency program (latency I), with none or only expression of LMP2A.
LMP1 antigen

16. • In EBV-positive cases, usually all HRS cells are positive, indicating that the infection was an early
event in lymphoma development.
• The EBV+ HRS cells typically show an EBV latency II gene expression profile, meaning expression of
the viral proteins EBV nuclear antigen 1 (EBNA1) and latent membrane proteins 1 and 2a (LMP1 and
LMP2a).
• EBNA1 is essential for replication of the episomal viral genome in proliferating cells. LMP1 mimics an
active CD40 receptor and hence stimulates NF- B and PI3K/AKT activity.
• As BCR and CD40 signalling are main survival signals for GC B cells, EBV infection of GC B cells may
be a way how GC B cells with destructive mutations survive and become HRS precursor cells.
• Indeed, in vitro, EBV can rescue crippled GC B cell from apoptosis and all cHL cases with destructive
mutations that prevent BCR expression were found to be EBV-positive.

18. • Almost 100% of HIV-associated HD cases are EBV-positive.
• Patients with HIV infection have a higher incidence of HD compared to
the population without HIV infection.
• However, HD is not considered an AIDS-defining neoplasm.
• Genetic predisposition may play a role in the pathogenesis.
• Approximately 1% of patients with HD have a family history of the
disease. Siblings of an affected individual have a three to seven-fold
increased risk for developing HD. This risk is higher in monozygotic
twins. HLA-DP alleles are more common in HD.

19. Clinical features
• Hodgkin lymphoma almost always begins in the lymph nodes, and the most
common sites of initial presentation are the cervical and supraclavicular nodes
(70% to 75%) or the axillary and mediastinal nodes (5% to 10% each).
• male predilection, and a bimodal pattern is noted with respect to the patient’s age
at diagnosis.
• One peak is observed between 15 and 35 years of age; another peak is seen after
the age of 50.
• The usual presenting sign is the identification by the patient of a persistently
enlarging, nontender, discrete mass or masses in one lymph node region.

20. • In the early stages, the involved lymph nodes are often rather movable; as the condition
progresses, the nodes become more matted and fixed to the surrounding tissues.
• If it is untreated, then the condition spreads to other lymph node groups and eventually
involves the spleen and other extralymphatic tissues, such as bone, liver, and lung. Oral
involvement has been reported, but it is rare.
• In about 30% to 40% of patients with Hodgkin disease, other systemic signs and symptoms may
be present, such as weight loss, fever, night sweats, and generalized pruritus (itching).
• The absence of these systemic signs and symptoms is considered to be better in terms of the
patient’s prognosis, and this information is used in staging the disease.

21. ORAL MANIFESTATIONS
• Primarily a disease of lymph node, seldom occurs as a disease primarily in
the oral cavity.
• Oral cavity could be involved secondarily.

22. ANN ARBOR STAGING OF HODGKIN LYMPHOMA
Stage I Stage II Stage III Stage IV
A: absence of B symptoms
B: fever, night sweats, weight loss

23. Histologic features
Based on the morphology and immunophenotype of the neoplastic cells and the background
cellular infiltrate, HL is subdivided into
 nodular lymphocyte–predominant Hodgkin lymphoma and
 classical Hodgkin lymphoma, the latter of which is divided into five subtypes.
1. Lymphocyte rich
2. Nodular sclerosis
3. Mixed cellularity
4. Lymphocyte depletion
5. Unclassifiable

24. • The common features include effacement of the normal nodal architecture by a diffuse, often
mixed, infiltrate of inflammatory cells that is interspersed with large, atypical neoplastic
lymphoid cells. In the case of classical Hodgkin lymphoma, this atypical cell is known as a
Reed-Sternberg cell.

25. Reed–Sternberg cell
• Characteristic malignant cells of Hodgkin’s diseases are large cells known as Reed–Sternberg (RS) cells
(typical and variant), 20–50 micrometers in diameter, abundant, amphophilic, finely
granular/homogeneous cytoplasm; two mirror-image nuclei (owl eyes) each with an eosinophilic
nucleolus and a thick nuclear membrane (chromatin is distributed at the cell periphery).
• One or two percent of these malignant cells are admixed within a reactive cell infiltrate composed of
variable proportions of lymphocytes, histiocytes, eosinophils, and plasma cells.
• The Reed–Sternberg cells are identified as large often
binucleated cells with prominent nucleoli and an
unusual CD15+, CD30+ immunophenotype.

26. • It was initially thought that H cells fused into terminally differentiated RS cells in a process
likened to monocytic giant cell formation, while the results of later studies suggested the
formation of RS cells from H cells through centrosome overduplication and disturbance of
cytokinesis.
• Immunophenotypically, classic HL cells express CD30 in all cases, CD15 in about 75% cases and
PAX5 in virtually all cases.
• Recent studies have shown that the neoplastic cells in virtually all cases of classic HL are
derived from germinal centre B cells with defective surface B-cell receptors, crippled
immunoglobulin transcripts, and lost B-cell programs due to epigenetic silencing.

28. Relationship of Hodgkin cells and Reed-sternberg cells
• A hallmark of cHL is the presence of mononuclear Hodgkin and bi- or multinuclear Reed Sternberg
cells.
• Recent time-lapse microscopy studies of HL cell lines showed that Hodgkin cells frequently undergo
incomplete cytokinesis and that Reed-Sternberg cells are generated by refusion of two sister cells
that are still connected by microtubuli bonds.
• Thus, it appears that a defect to complete an advanced cytokinesis is the main reason for the
generation of Reed-Sternberg cells from Hodgkin cells.
• These experiments as well as earlier studies also revealed that Reed-Sternberg cells have little
proliferative capacity, and that Hodgkin cells are the main proliferative compartment of the HRS
tumor clone.

29. RS cell and its variants
popcorn cell
lacunar cell
classic RS cell
(mixed cellularity) (nodular sclerosis) (lymphocyte
predominance)

31. • Nodular sclerosis (NS) Hodgkin’s disease comprises 60–80% of all cases.
• The morphology shows a nodular pattern.
• The broad bands of fibrosis divide the node into ‘nodules’. The capsule is
thickened.
• The characteristic cell is the lacunar-type RS cell, which has a
monolobated or multilobated nucleus and a small nucleolus with
abundant and pale cytoplasm.
• NS frequently is observed in adolescents and young adults and usually
involves the mediastinum and other supradiaphragmatic sites.

33. a. Typical nodule of NSHL confined by a sclerotic band (arrow heads)
and containing HRS and lacunar cells.
b. HRS cells in NSHL – so called lacunar cells

35. VARIOUS APPEARANCES OF LACUNAR CELLS IN NODULAR SCLEROSING HL

36. a. Expression of CD30 in HRS cells
b. Strong cytoplasmic CD15 expression in HRS cells (arrows,
NSHL, CD15-immunostaining, 400x).

37. • Mixed-cellularity Hodgkin’s disease comprises 15–30%.
• Histologically, the infiltrate is usually diffuse.
• RS cells are of the classic type (large, with bilobate, double or multiple
nuclei, and a large eosinophilic inclusion like nucleolus).
• It commonly affects the abdominal lymph nodes and spleen.
• Patients with this histology typically have advanced-stage disease with
systemic symptoms and immunodeficiency.

38. c. MCHL with a typical mixed reactive infiltrate consisting of
epithelioid cells, lymphocytes and eosinophils (HE, 400x). HRS cells
are marked with arrows.
d. MCHL in an immunocompromised patient with abundant
spindle cell shaped histiocytes

39. CD83 expression in HRS cells (arrow, MCHL,
CD83-immunostaining, 400x)

40. • Lymphocyte-depleted Hodgkin’s disease makes up less than 1%.
• The infiltrate in lymphocyte-depleted Hodgkin disease (LDHD) is
diffuse and often appears hypocellular.
• Large numbers of RS cells and bizarre sarcomatous variants are
present.
• It is associated with older age and HIV positivity.
• Patients usually present with advanced-stage disease.

42. • Lymphocyte-rich classic Hodgkin’s disease comprises 5%.
• In this type of HD, RS cells of the classic or lacunar type are
observed, with a background infiltrate of lymphocytes.
• It requires immunohistochemical diagnosis. Some cases
may have a nodular pattern.
• Clinically, the presentation and survival patterns are similar
to those for mixed cellularity Hodgkin’s disease.

43. HRS cells surrounded by small B cells in LRCHL (HE, 400x). HRS
cells are marked with arrows.

44. Typical weak PAX5 expression in a HRS cell in LRCHL (arrow).
Surrounding mantle zone B cells show a more prominent PAX5
expression (arrow heads, PAX5- immunostaining, 400x)

45. • Nodular lymphocyte-predominant Hodgkin’s disease constitutes 5%.
• In contrast to the other histological subtypes, the typical RS cells in
nodular lymphocytepredominant Hodgkin disease are not observed or
appear infrequently.
• Instead, a variant of RS cells, the lymphocytic and histiocytic cells (L&H), or
popcorn cells (their nuclei resemble an exploded kernel of corn), are seen
within a background of inflammatory cells, predominantly benign
lymphocytes.
• The L&H cells are positive for B-cell antigens, such as CD19 and CD20, but
generally are negative for CD15 and CD30.

46. • NLPHL most closely resembles LRCHL.
• NLPHL shows a strong predominance of the male gender and more
frequent relapses than LRCHL.
• The most important difference to LRCHL are the LP tumor cells, which
have a GC B cell phenotype and are usually negative for CD30 and CD15.

53. PD1-positive T cell rosettes surrounding LP cells in
NLPHL (arrows, PD1- immunostaining, 200x)

54. Treatment and Prognosis
• The treatment of Hodgkin lymphoma depends on the stage of involvement. In the past, patients who
had limited disease (stages I and II) often were managed by local radiation therapy alone.
• Patients with stage III or IV disease require chemotherapy; radiation therapy is used conjointly if
significant mediastinal involvement or residual disease is detected.
• regimen used to treat Hodgkin lymphoma MOPP (mechlorethamine, Oncovin, procarbazine,
prednisone) and ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine.
• The prognosis for this disease is fairly good today; the best treatment results occur in those who
present in the early stages.
• Patients with stage I and II disease often have an 80% to 90% relapse-free 10-year survival rate;
those with stage III and IV disease have a 55% to 75% 10-year survival rate.