LYMPHOMAS

Dr Leah Githinji Pediatrician/pulmonologist/allergy

Conceptualizing lymphoma
Neoplasms of lymphoid origin, typically causing lymphadenopathy Leukemia vs Lymphoma Lymphomas as clonal expansions of cells at certain developmental stages

ALL

CLL
nave

Lymphomas

MM

B-lymphocytes Plasma cells T-lymphocytes

Lymphoid progenitor

AML
Hematopoietic stem cell Myeloid progenitor

Myeloproliferative disorders
Neutrophils Eosinophils Basophils Monocytes Platelets

Red cells

Disease states correlate with stages in normal B-cell development

Diseases:

AML

Pro-B-ALL

Pre-B-ALL

B-ALL

-B-CLL -Multiple Myeloma -DLBCL -Plasmacytoma -FLL -BL -Hodgkins (?)

B-cell development
CLL
germinal center B-cell

stem cell lymphoid progenitor

progenitor-B

memory B-cell

mature naive B-cell

MM DLBCL, FL, HL

ALL
pre-B immature B-cell plasma cell

Lymphoma Classification
Nowhere in pathology has a chaos of names clouded clear concepts as in the subject of lymphoid tumors Willis R.A.: Pathology of tumors, Mosby 1948

Lymphoma classification (2001 WHO)

B-cell neoplasms
precursor mature
NonHodgkin Lymphomas

T-cell & NK-cell neoplasms

precursor mature

Hodgkin lymphoma

A practical way to think of Lymphoma

Category Survival of untreated patients Years Curability To treat or not to treat

NonHodgkin lymphoma

Indolent

Generally not curable

Generally defer Rx if asymptomatic

Aggressive

Months

Curable in some
Curable in some Curable in most

Treat

Very aggressive Hodgkin lymphoma All types

Weeks

Treat

Variable months to years

Treat

Mechanisms of Lymphomagenesis
Genetic alterations Infection Antigen stimulation Immunosuppression

Epidemiology of lymphomas
5th most frequently diagnosed cancer in both sexes Males > Females Incidence NHL increasing Hodgkin lymphoma stable

Incidence/100,000/annum
100 20 40 60 80 0

Age distribution of new NHL cases

Age (years)

0-1 1-4 5-9 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+

incidence/100,000/annum
0 1 2 3 4 5 6

Age distribution of new HL cases

Age (years)

0-1 1-4 5-9 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+

Risk factors for NHL

Immunosuppression or immunodeficiency Connective tissue disease Family history of lymphoma Infectious agents Ionizing radiation

Clinical manifestations
Lymph node swelling, often in the upper body area but it can be in almost any node or related organ. Node is usually PAINLESS as opposed to infected lymph nodes which are common and can be painful (HL, NHL) A lack of energy, general fatigue. (HL, NHL)

Clinical manifestations
Weight loss - usually at least 10% over a short time (HL, NHL) Fevers which can come and go. This can be accompanied by chills or temperature swings (HL, NHL) Night sweats - unexplained sweating at night, often drenching (more often HL than NHL)

Clinical manifestations
Itching - itching without an apparent cause or rash, sometimes on different parts of the body (more often HL than NHL) Less Often: Some people unexplained lower back pain (may be caused by expanding lymph nodes pressing on nerves). (HL, NHL) Lymph nodes are possibly painful after alcohol consumption. (HL)

Other complications of lymphoma

Bone marrow failure (infiltration) CNS infiltration Immune hemolysis or thrombocytopenia Compression of structures (eg spinal cord, ureters) Pleural/pericardial effusions, ascites

Diagnosis
Diagnosis should be biopsy-proven before treatment is initiated! Need enough tissue to assess cells and architecture
open biopsy (surgery) core needle biopsy FNA

Ann Arbor staging of lymphoma

Stage I Stage II Stage III Stage IV

A: absence of B symptoms B: fever, night sweats, weight loss

Staging (ctd)
Stage Definition
I Involvement of a single lymph node region (I) or of a single extralymphatic organ or site (IE)
Involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of an extralymphatic organ or site and one or more lymph node regions on the same side of the diaphragm (IIE) Involvement of lymph node regions on both sides of the diaphragm (III) which may be accompanied by involvement of the spleen (IIIS) or by localized involvement of an extralymphatic organ or site (IIIE) or both (IIISE) Diffuse or disseminated involvement of one or more extra lymphatic organs or tissues with or without associated lymph node involvement

II

III

IV

Extra Nodal Notations

Common lymphomas
Follicular lymphoma NHL Diffuse large B-cell lymphoma NHL Burkitts Lymphoma NHL Hodgkin lymphoma HL

Relative frequencies of different lymphomas

Non-Hodgkin Lymphomas (85%) Diffuse large B-cell Hodgkin Lymphoma (15%) NHL Follicular Other NHL
~85% of NHL are B-lineage

Hodgkin lymphoma

Thomas Hodgkin (1798-1866)

Classical Hodgkin Lymphoma

Hodgkin lymphoma
Cell of origin: germinal centre B-cell Reed-Sternberg cells (or RS variants) in the affected tissues Most cells in affected lymph node are polyclonal reactive lymphoid cells, not neoplastic cells

Reed-Sternberg cell

RS cell and variants

Classic RS cell Lacunar cell

(mixed cellularity) (nodular sclerosis)

Popcorn cell
(lymphocyte predominance)

A possible model of pathogenesis

transforming event(s) EBV? loss of apoptosis

cytokines

germinal centre B cell

RS cell inflammatory response

Hodgkin lymphoma Histologic subtypes

Classical Hodgkin lymphoma
Nodular sclerosis (most common subtype) Mixed cellularity Lymphocyte-rich Lymphocyte depleted

Epidemiology (HL)
Bimodal age distribution
first peak between 2nd - 3rd decade of life second peak between 5th - 6th decade of life

Male: Female 2:1 in kids, adults almost equal M:F Mixed cellularity (MC) Hodgkins Disease is more common at younger ages. More common in immune deficiency patients Less frequent than NHL

Hodgkins disease
Fatal disease with 90% of untreated patients dying within 2 to 3 years With chemotherapy, >80% of patients suffering from HD are cured. Pathogenesis of HD is still largely unknown. HD nearly always arises and disseminates in lymph nodes

Associated (etiological?) factors

EBV infection Smaller family size Higher socio-economic status Caucasian > non-caucasian Possible genetic predisposition Other: HIV? occupation? herbicides?

Clinical manifestations (HL)

Nontender lymph nodes enlargement (localized)
neck and supraclavicular area, mediastinal adenopathy other (abdominal, extranodal disease) NB: Extranodal sites relatively uncommon except in advanced disease

systemic symptoms (B symptoms)

fever (fever > 38C for three consecutive days) night sweats ( drenching night sweats) unexplained weight loss (10% or more in preceeding 6 months)

other symptoms
fatigue, weakness, pruritus cough , chest pain, shortness of breath, vena cava syndrome abdominal pain, bowel disturbances, ascites bone pain

Frequency of signs (HL)

SIGNS & SYMPTOMS % OF PATIENTS Lymphadenopathy 90 Mediastinal mass 60 B symptoms 30 Fever, weight loss, night sweats Hepatosplenomegaly 25 Most commonly involved lymph nodes are the cervical and supraclavicular in 75% Bone marrow is involved in 5% of patients

Treatments
Lymphomas are usually treated by a combination of chemotherapy, radiation, surgery, and/or bone marrow transplants. The cure rate varies greatly depending on the type of lymphoma and the progression of the disease.

Current up-front treatment regimens for aggressive lymphomas

Regimen CHOP BACOP M-BACOD ProMACE/MOP P MACOP-B Drugs Cyclophosphamide, Doxorubicin, Vincristine, Prednisone Bleomycin, Doxorubicin, Cyclophosphamide, Vincristine. Prednisone Methotrexate, Leucovorin, Bleomycin, Cyclophosphamide, Vincristine, Dexamethasone Prednisone, Methotrexate, Leucovin, Doxorubicin, Cyclophosphamide, Etoposide Methotrexate, Leucovorin, Doxorubicin, Cyclophosphamide, Vincristine, Bleomycin, Prednisone, Trimethoprim-sulfamethoxazole

(Used at various doses, with, or without radiation)

Treatments
With appropriate treatment about 85% of patients with Hodgkins disease are curable IA,B IIA IIB; IIIA,B; IVA,B Radiation Therapy Combination Chemo + Radiotherapy Combination Chemo (+/- radiotherapy)

Other treatments
Experimental therapies - CD20-specific antibodies (Rituximab, Bexxarr, Zevalin): Mechanism of action is unknown. Rarely used as up-front therapy. - Clonotypic antibodies to individual lymphomas: pioneered at Stanford. Current success rate is 1 patient in 15 years.

Prognostic factors (HL)

Unfavorable prognostic factors: - Stage IIIB, IV - B symptoms - Bulky disease - High ESR >50

Long term complications of Rx

Infertility
MOPP > ABVD; males > females sperm banking should be discussed premature menopause

Secondary malignancy
skin, AML, lung, NHL, thyroid, breast...

Cardiac disease Growth deficiency

NON HODGKINS LYMPHOMA

BURKITTS LYMPHOMA

Burkitts Lymphoma

BL
A tumor which first described in 1958 by Denis Burkitt, a surgeon working in Africa. A solid tumor of B Lymphocytes and a form of non-Hodgkin's lymphoma. BL not amenable to surgery; radiation therapy was not available, but chemoRx highly successful (90% cure rates in pediatric BL) First human tumor shown to be associated with a virus (EBV)

BL
Very aggressive Curable with standard-dose therapy but requires very extensive chemotherapy protocol Translocation t(8,14) Specific Histopathological finding
Starry night sky pattern

Burkitts Lymhoma Starry - night sky pattern

BL

BL
Geographic distribution of malaria and BL very similar BL has higher incidence in regions of intense malarial infection (some exceptions) ? Sickle cell trait protection against BL, (insufficient data) BL contains a specific chromosomal translocation t(8,14)

BL
HIV increases risk of BL 200-1000 fold: prior to major immunosuppression (but probably requires B cell hyperplasia) Only 30-40% of HIV+ BL in the USA is EBV+ (mechanism not the same as malaria)

BL in Africa almost invariably EBV associated: yet most B cells are not infected with EBV

BL
Males are three times more likely to suffer from this disorder as opposed to females

BL Signs and Symptoms

* Effects depend on the site of the tumor in the body: In African Burkitt's lymphoma the jaw is the commonest site (visible swelling of the cheek and loosening of the teeth). In non-African Burkitts lymphoma the tumor commonly arises in the abdomen (swelling and discomfort)

BL Rx Results

Complete Remission

BL Rx Results

3.5 weeks

Total cost of chemo ~ $200

COMPARING HL vs NHL

Comparing HL vs NHL
Hodgkin's Lymphoma VS
Age Average age is 27.7 with two age peaks, the major one between 15 and 24 with a lesser peak after age 55.

Non-Hodgkin's Lymphomas
Average age is about 67.

Chance of getting in all people over an entire lifetime

Men 0.23% Women 0.20%

Men 2.12% Women 1.79%

Occurrence

About 15% of all lymphomas

About 85% of all lymphomas

Comparing HL vs NHL
Hodgkin's Lymphoma VS
Location

Non-Hodgkin's Lymphoma
NHL is more likely to appear in the nodes in the abdomen (called the mesenteric nodes).

Most often in lymph nodes above the collar bone. In Hodgkin's it is also more likely to appear in the chest cavity between the lungs (the mediastinum), particularly in younger patients. Only about 15% to 20% of cases are found in areas below the diaphragm. Disease occurs outside the nodes in about 4% of cases.

Occurs in the chest cavity in less than 40% of patients. (An exception, lymphoblastic lymphoma, which is seen most often in young people, is likely to first appear in the chest.)
Disease occurs outside the nodes in about 23% of patients. Slow-growing lymphomas are common in the liver and bone marrow. B-Lymphocytes, T-Lymphocytes or Natural Killer (NK) Cells depending on the subtype

Affected Lymph Cells

B-Lymphocytes characterized by the Reed-Sternberg Cell

Comparing HL vs NHL
Hodgkin's lymphoma Vs
Symptoms
More likely than NHL (40%) to have systemic ("B") symptoms (such as fever and night sweats) at the time of diagnosis.
Less likely than NHL to be diagnosed in stage IV (10%). HL usually progresses in an orderly way from one lymph node region to the next. This process may be slow, particularly in younger people, or very aggressive. The disease typically spreads downward from the initial site. If it spreads below the diaphragm, it usually reaches the spleen first; If the disease starts in the nodes in the middle of the chest, it may spread outward to the chest wall and areas around the heart and lungs.

Non-Hodgkin's Lymphoma
Less likely than HL to have systemic ("B") symptoms (27%) at the time of diagnosis.

Progression

More likely than HD to be diagnosed in stage IV (36%) but this will vary by NHL subtype. The NHLs are less predictable in their course than HL and they are more apt to spread.

QUESTIONS

??