Lymphoma

The two broad categories of lymphoma: Hodgkin

disease (HD) and non-Hodgkin lymphoma (NHL)

Hodgkin disease (HD)
- is a malignant process of the lymphoreticular
system
- rare in children <10 yr of age.
- incidence of HD is bimodal with regard to age
- early peak occurs in the middle to late 20s, with
a second peak after 50 yr of age.

Reed-Sternberg cell
- is a large cell (1545 m in diameter) with
multiple or multilobulated nuclei.
- This cell type is considered the hallmark of HD
- arises from the germinal center B cells.

*** HD is characterized by a variable number of Reed-
Sternberg cells surrounded by an inflammatory infiltrate
of lymphocytes, plasma cells, and eosinophils in
different proportions

Rye classification system defines four major histologic
subtypes:
1. lymphocyte predominant (LP)
2. nodular sclerosing (NS)
3. mixed cellularity (MC)
4. lymphocyte depleted (LD)

Lymphocyte predominant (LP)
- affects 1015% of patients
- is more common among male and younger
patients
- usually presents as localized disease

Nodular sclerosing (NS)
- is the most common subtype, affecting 40% of
younger patients and 70% of adolescents with
HD.

Mixed cellularity (MC)
- is observed in 30% of patients
- is more common among children 10 yr of age
- often presents as advanced disease with
extranodal extension

Lymphocyte depleted (LD)
- is rare in children but is common in patients
with HIV infection patients.


Revised European-American Classification of Lymphoid
Neoplasms (REAL) classification system
- includes two modifications of the older Rye
system
- it defines lymphocyte predominance (LPHD)
but also anaplastic large cell lymphoma
Hodgkin-like

Lymphocyte predominance (LPHD)
- closely resembles a low-grade B-cell lymphoma
in clinical behavior and Reed-Sternberg cell
phenotype
- present with early disease and have an
excellent prognosis

Anaplastic large cell lymphoma Hodgkin-like
- has a poor response to conventional HD
chemotherapy and has been reported to
respond better to aggressive NHL therapy
regimens


CLINICAL MANIFESTATIONS.

Patients commonly present with painless, non-tender,
firm, rubbery, cervical or supraclavicular
lymphadenopathy

Most patients present with some degree of mediastinal
involvement

Depending on the extent and location of nodal and
extranodal disease, patients may present with
symptoms and signs of airway obstruction (dyspnea,
hypoxia, cough), pleural or pericardial effusion,
hepatocellular dysfunction, or bone marrow infiltration
(anemia, neutropenia, or thrombocytopenia).

Systemic symptoms, classified as B symptoms that are
considered important in staging, are:
- unexplained fever >39C
- weight loss >10% total body weight over 3 mos
- drenching night sweats

DIAGNOSIS.

Any patient with persistent, unexplained
lymphadenopathy unassociated with an obvious
underlying inflammatory or infectious process should
have a chest radiograph to identify the presence of a
mediastinal mass before undergoing node biopsy

Patients with persistently enlarged lymph nodes, even
after serologically proven infectious mononucleosis,
also should be considered for biopsy.

Formal excisional biopsy is preferred over needle
biopsy to ensure that adequate tissue is obtained, both
for light microscopy and for appropriate
immunocytochemical and molecular studies, culture,
and cytogenetic analysis if routine studies fail to provide
a firm diagnosis.

Once the diagnosis of HD is established, extent of
disease (stage) should be determined to select
appropriate therapy

Evaluation includes history, physical examination, and
imaging studies, including chest radiograph; CT scans of
the chest, abdomen and pelvis; gallium scan; and
positron emission tomography (PET) scan.

Laboratory studies include a complete blood cell count
(CBC) to identify abnormalities that might suggest
marrow involvement, erythrocyte sedimentation rate
(ESR), and serum copper and serum ferritin levels,
which are of some prognostic significance and, if
abnormal at diagnosis, serve as a baseline to evaluate
the effects of treatment.

Liver function tests, although not particularly sensitive
to the presence of liver involvement, can influence
treatment and treatment complications

A chest radiograph is particularly important for
measuring the size of the mediastinal mass in relation
to the maximal diameter of the thorax.

Chest CT more clearly defines the extent of a
mediastinal mass if present and identifies hilar nodes
and pulmonary parenchymal involvement, which may
not be evident on chest radiographs

Abdominal CT or MRI can identify gross
subdiaphragmatic involvement of nodes and
enlargement and defects in the liver and spleen.

Bone marrow aspiration and biopsy should be
performed in patients with advanced disease (stage III
or IV) or B symptoms (fever, weight loss, night sweats).

Bone scans are performed in patients with bone pain
and/or elevated alkaline phosphatase


Ann Arbor Staging Classification for Hodgkin Disease
STAGE DEFINITION
I

Involvement of a single lymph node (1)
or of a single extralymphatic organ or
site (IE)

II 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)
III 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)
IV Diffuse or disseminated involvement of one or
more extralymphatic organs or tissues with or
without associated lymph node involvement

The absence or presence of fever >38C for 3
consecutive days, drenching night sweats, or
unexplained loss of 10% of body weight in the 6
months preceding admission are to be denoted in all
cases by the suffix letters A or B, respectively.


TREATMENT.

Chemotherapy and radiation therapy are effective in
the treatment of HD

Current treatment of HD in pediatric patients involves
the use of combined chemotherapy with or without
low-dose involved field radiation therapy.

Treatment is determined largely by
- disease stage
- age at diagnosis
- presence or absence of B symptoms
- presence of hilar lymphadenopathy or bulky
nodal disease

The MOPP regimen (mechlorethamine [nitrogen
mustard], vincristine, procarbazine, and prednisone)
introduced in 1964 was the first combination
chemotherapy regimen used in the treatment of HD
and was a major milestone in the treatment of
advanced stage HD
- It resulted in a complete response rate of 70
80% and cure rate of 4050% at 10 yr in
patients with advanced stage disease
- significant acute and long-term toxicity

The combination chemotherapy regimens in current
use are based on
1. COPP (cyclophosphamide, vincristine [Oncovin],
procarbazine, and prednisone)
2. ABVD (doxorubicin [Adriamycin], bleomycin,
vinblastine, and dacarbazine)
3. with BEACOPP (bleomycin, etoposide,
doxorubicin, cyclophosphamide, vincristine,
procarbazine, prednisone) typically used for
patients with advanced stage disease

*** COPP/ABV (cyclophosphamide, vincristine,
procarbazine, prednisone/doxorubicin, bleomycin and
vinblastine) regimen is an example to reduce potential
toxicities


RELAPSE.

Most relapses occur within the first 3 yr from diagnosis
but relapses as late as 10 yr have been reported

Poor prognostic features include
- tumor bulk
- stage at diagnosis
- presence of B symptoms

Patients who never achieve remission or relapse <12
mo after initiation of therapy are candidates for
myeloablative chemotherapy and autologous stem cell
transplant with or without the addition of radiation
therapy.

Myeloablative allogeneic stem cell transplantation
reduces the relapse rate in patients with high-risk
relapsed or refractory HD.

Using current therapeutic regimens, patients with
favorable prognostic factors and early-stage disease
have an event-free survival (EFS) of 8590% and an
overall survival (OS) at 5 yr of 95%.

Long-term complications are related to radiation or
chemotherapy; these include secondary malignancy
(e.g., acute myelogenous leukemia, breast, lung,
thyroid, non-Hodgkin lymphoma), sepsis (e.g.,
splenectomy or splenic irradiation), sterility, short

stature, hypothyroidism, dental caries, subclinical
pulmonary dysfunction, and ischemic heart disease.


Non-Hodgkin Lymphoma (NHL)
- accounts for approximately 60% of all
lymphomas in children and adolescents
- >70% of patients present with advanced disease
at diagnosis, the prognosis has improved
dramatically, with survival rates of 9095% for
localized disease and 6090% with advanced
disease.

The four major pathological subtypes of childhood and
adolescent NHL are:
1. Burkitt lymphoma (BL): 40% of NHL
2. Lymphoblastic lymphoma (LL): 30%
3. Diffuse large B-cell lymphoma (DLBCL): 20%;
4. Anaplastic large cell lymphoma (ALCL): 10%

Almost all childhood and adolescent NHL is derived
from germinal center aberrations

Almost all forms of Burkitt lymphoma BL and Diffuse
large B-cell lymphoma DLBCL are of B cell origin

Cases of Lymphoblastic lymphoma are 80% T cell and
20% B cell

Cases of Anaplastic large cell lymphoma are 70% T cell,
20% null cell, and 10% B cell in origin.

Children with BL commonly have a t(8;14) translocation
(90%) or, less commonly, a t(2;8) or t(8;22)
translocation (10%).

Patients with ALCL commonly have a t(2;5)
translocation (5%).

NHLs are rapidly growing tumors and can cause
symptoms based on size and location

Burkitt lymphoma (BL) commonly presents with
abdominal (sporadic type) or head and neck (endemic
type) disease with involvement of the bone marrow or
CNS.

Lymphoblastic lymphoma (LL) commonly presents with
an intrathoracic or mediastinal supradiaphragmatic
mass, and also has a predilection for spreading to the
bone marrow and CNS

DLBCL commonly presents with either an abdominal or
mediastinal primary and, rarely, dissemination to the
bone marrow or CNS.

ALCL presents either with a primary cutaneous
manifestation (10%) or with systemic disease (fever,
weight loss) with dissemination to liver, spleen, lung,
mediastinum, or skin; spread to the bone marrow or
CNS is rare.

St. Jude Staging System for Childhood NHL
STAGE DESCRIPTION
I A single tumor (extranodal) or single anatomic
area (nodal), with the exclusion of mediastinum
or abdomen
II A single tumor (extranodal) with regional node
involvement
Two or more nodal areas on the same side of
the diaphragm
Two single (extranodal) tumors with or without
regional node involvement on the same side of
the diaphragm
A primary gastrointestinal tract tumor, usually
in the ileocecal area, with or without
involvement of associated mesenteric nodes
only, which must be grossly (>90%) resected
III Two single tumors (extranodal) on opposite
sides of the diaphragm
Two or more nodal areas above and below the
diaphragm
Any primary intrathoracic tumor (mediastinal,
pleural, or thymic)
Any extensive primary intra-abdominal disease
IV Any of the above, with initial involvement of
central nervous system or bone marrow at time
of diagnosis

Three clinical manifestations that require special
alternative treatment strategies include:
1. SVC syndrome secondary to a large
mediastinal mass obstructing various blood
flow or respiratory airways
2. Acute paraplegias secondary to spinal cord or
central nervous system compression from
neighboring localized NHL
3. Tumor lysis syndrome (TLS) secondary to
severe metabolic abnormalities, including
hyperuricemia, hyperphosphatemia,
hyperkalemia, and hypocalcemia from massive
tumor cell lysis.

TREATMENT.

The primary modality of treatment for childhood and
adolescent NHL is multiagent systemic chemotherapy
and intrathecal chemotherapy

Surgery is used mainly for diagnostic and/or biologic
specimens and staging but rarely is used for debulking
large masses.

Specific treatment for localized and advanced disease is
similar for BL and DLBCL.
- Localized BL and DLBCL require 6 wk to 6 mo of
multiagent chemotherapy.

COPAD (cyclophosphamide, vincristine, prednisone and
doxorubicin)

COMP (cyclophosphamide, vincristine, methotrexate, 6-
mercaptopurine and prednisone)

Intrathecal chemotherapy is administered to moderate
to advanced disease in all subtypes of childhood and
adolescent NHL and may include intrathecal
methotrexate, hydrocortisone, or Ara-C.

Some patients require G-CSF prophylaxis to prevent
fever and neutropenia following myelosuppressive
chemotherapy and prophylactic antibiotics to prevent
infections

Long-term complications may include:
- growth retardation
- cardiac toxicity
- gonadal toxicity with infertility
- secondary malignancies

The prognosis is excellent for most forms of childhood
and adolescent NHL
- localized disease have a 90100% chance of
survival
- advanced disease have a 6095% chance of
survival

Variation in survival depends on
- pathological subtype
- tumor burden at diagnosis as reflected in
serum LDH level
- presence or absence of CNS disease
- specific sites of metastatic spread