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MINISTRY OF PUBLIC HEALTH OF UKRAINE
KHARKOV NATINAL MEDICAL UNIVERSITY
МИНИСТЕРСТВО ЗДРАВООХРАНЕНИЯ УКРАИНЫ
ХАРЬКОВСКИЙ НАЦИОНАЛЬНЫЙ МЕДИЦИНСКИЙ
УНИВЕРСИТЕТ
Lymphomas
Лимфомы
Утверждено
ученым советом ХНМУ
Протокол № 4 от 19.01.2007 г.
Kharov KNMU- 2007
Харьков ХНМУ – 2007
Лимфомы: Метод. указ. к практ. занятиям для студентов V-VI курсов
медицинских вузов, обучающихся на английском языке / Сост. В.И.
Стариков, А.Н. Белый.– Харьков: ХНМУ, 2007.– 24 с.
Lung cancer is approved by the Scientific Committee of the Kharkov state
medical university and is recommended for V-th, VI-th year students of
medical faculty / Authors: V.I. Starikov, A.N. Bely.– Kharkov: KNMU.2007.
– 24 p.
Authors: Starikov V.I.
Bely A.N.
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Hodgkin Disease
Hodgkin disease (Hodgkin's lymphoma) is a potentially curable malignant lymphoma with
distinct histology, biologic behavior, and clinical characteristics. Thomas Hodgkin first described
Hodgkin disease (Hodgkin's lymphoma) in 1832. The disease is defined in terms of its microscopic
appearance (histology) and the expression of cell surface markers (immunophenotype).
Histology and classification
As classified by the World Health Organization (WHO), Hodgkin disease (Hodgkin's
lymphoma) exists in 5 types. Four of these, nodular sclerosis, mixed cellularity, lymphocyte
depleted, and lymphocyte rich, are referred to as classic Hodgkin disease (Hodgkin's
lymphoma). The fifth type, nodular lymphocyte predominant Hodgkin disease (NLPHD), is a
distinct entity with unique clinical features and a different treatment paradigm.
In classic Hodgkin disease (Hodgkin's lymphoma), the neoplastic cell is the Reed-Sternberg
(RS) cell. Reed-Sternberg cells compose only 1-2% of the total tumor cell mass. The remainder is
composed of a variety of reactive, mixed inflammatory cells consisting of lymphocytes, plasma
cells, neutrophils, eosinophils, and histiocytes. Most Reed-Sternberg cells are of B-cell origin,
derived from lymph node germinal centers but no longer able to express antibodies.
Some Hodgkin disease (Hodgkin's lymphoma) cases have been identified in which the ReedSternberg cell is of T-cell origin, but these are rare, accounting for 1-2% of classic Hodgkin disease
(Hodgkin's lymphoma). The Reed-Sternberg cells consistently express the CD30 (Ki-1) and CD15
(Leu-M1) antigens. CD30 is a marker of lymphocyte activation that is expressed by reactive and
malignant lymphoid cells and was originally identified as a cell surface antigen on Reed-Sternberg
cells. CD15 is a marker of late granulocytes, monocytes, and activated T cells that is not normally
expressed by B-lineage cells.
 Nodular sclerosis Hodgkin disease (NSHD) (60-80% of all cases): The morphology shows
a nodular pattern. Broad bands of fibrosis divide the node into nodules. The capsule is thickened.
The characteristic cell is the lacunar-type Reed-Sternberg cell, which has a monolobated or
multilobated nucleus, a small nucleolus, and abundant pale cytoplasm. NSHD is frequently observed
in adolescents and young adults and usually involves the mediastinum and other supradiaphragmatic
sites.
 Mixed-cellularity Hodgkin disease (MCHD) (15-30% of cases): Histologically, the
infiltrate is usually diffuse. Reed-Sternberg cells are of the classic type (large, with bilobate, double
or multiple nuclei, and a large, eosinophilic nucleolus). MCHD commonly affects the abdominal
lymph nodes and spleen. Patients with this histology typically have advanced-stage disease with
systemic symptoms. MCHD is the histologic type most commonly observed in patients with human
immunodeficiency virus (HIV) infection.
 Lymphocyte-depleted Hodgkin disease (LDHD) (less than 1% of cases): The infiltrate in
LDHD is diffuse and often appears hypocellular. Large numbers of Reed-Sternberg cells and bizarre
sarcomatous variants are present. It is associated with older age and HIV-positive status. Patients
usually present with advanced-stage disease. Epstein-Barr virus (EBV) proteins are expressed in
many of these tumors. Many cases of LDHD diagnosed in the past were actually were non-Hodgkin
lymphomas, often of the anaplastic large-cell type.
 Lymphocyte-rich classic Hodgkin disease (LRHD) (5% of cases): In this type of Hodgkin
disease (Hodgkin's lymphoma), Reed-Sternberg 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
MCHD.
 Nodular lymphocyte-predominant Hodgkin disease (NLPHD) (5% of cases): In contrast to
the other histologic subtypes, the typical Reed-Sternberg cells in NLPHD are either infrequent or
absent. Instead, lymphocytic and histiocytic (L&H) cells, or "popcorn cells" (their nuclei resemble
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an exploded kernel of corn), are seen within a background of inflammatory cells, which are
predominantly benign lymphocytes. Unlike Reed-Sternberg cells, L&H cells are positive for B-cell
antigens, such as CD19 and CD20, and are negative for CD15 and CD30. A diagnosis of NLPHD
needs to be supported by immunohistochemical studies, because it can appear similar to LRHD or
even some non-Hodgkin lymphomas.
Frequency
Hodgkin disease (Hodgkin's lymphoma) had a worldwide incidence of 62,000 cases in 2002.
Compared with North America and Europe, Hodgkin disease (Hodgkin's lymphoma) is relatively
rare in Japan (age-adjusted incidence of 0.3 per 100,000 males) and China (age-adjusted incidence
of 0.2 per 100,000 males). In developing countries, the incidence of the mixed-cellularity (MCHD)
and lymphocyte-depleted (LDHD) subtypes is higher. In contrast, the nodular-sclerosis (NSHD)
subtype is most frequent in developed countries.
Mortality/Morbidity
The 5-year disease-specific survival for patients with stages I and II Hodgkin disease
(Hodgkin's lymphoma) is 90%; III, 84%; and IV, 65%.
Race
Hodgkin disease (Hodgkin's lymphoma) incidence rates in the United States vary by race
and sex. The incidence in cases per 100,000 individuals is 3.3 for white males, 2.7 for white females,
2.9 for black males, 2.3 for black females, 1.4 for Asian/Pacific Islander males, and 1.0 for
Asian/Pacific Islander females.
Sex
Overall, Hodgkin disease (Hodgkin's lymphoma) is somewhat more common in males than
in females. The observed male predominance is particularly evident in children, in whom 85% of the
cases are in males.
Age
Age-specific incidence rates of Hodgkin disease (Hodgkin's lymphoma) have a bimodal
distribution in both sexes, peaking in young adults (aged 15-34 y) and older individuals (>55 y). In
the United States, young adults typically have NSHD, whereas children (aged 0-14 y) and older
individuals more commonly have the MCHD subtype.
Clinical
History
Clinical history features of Hodgkin disease (Hodgkin's lymphoma)
 Asymptomatic lymphadenopathy may be present (above the diaphragm in 80% of
patients).
 Constitutional symptoms (eg, unexplained weight loss, fever, night sweats) are present in
40% of patients. Collectively, these are known as "B symptoms."
 Intermittent fever is observed in approximately 35% of cases. Infrequently, the classic PelEbstein fever is observed (high fever for 1-2 wk followed by an afebrile period of 1-2 wk).
 Chest pain, cough, shortness of breath, or a combination of these things may be present
due to a large mediastinal mass or lung involvement. Rarely, hemoptysis is observed.
 Patients may present with pruritus.
 Alcohol-induced pain at sites of nodal disease is specific for Hodgkin disease (Hodgkin's
lymphoma) and occurs in less than 10% of patients.
 Back or bone pain occurs rarely.
Physical
Physical examination findings in Hodgkin disease (Hodgkin's lymphoma)
 Palpable painless lymphadenopathy occurs in the cervical area (60-80%), axilla (6-20%),
and, less commonly, in the inguinal area (6-20%). It is described as rubbery adenopathy.
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 Involvement of the Waldeyer ring or occipital or epitrochlear areas is infrequently
observed.
 Splenomegaly may be present.
 Patients may have hepatomegaly.
 Superior vena cava syndrome resulting from massive mediastinal lymphadenopathy can
also be seen.
 Central nervous system (CNS) symptoms or signs may be due to paraneoplastic
syndromes, including cerebellar degeneration, neuropathy, Guillain-Barre syndrome, or multifocal
leukoencephalopathy.
Causes
The etiology of Hodgkin disease (Hodgkin's lymphoma) is unknown.
 Infectious agents, particularly EBV, may be involved in the pathogenesis of Hodgkin
disease (Hodgkin's lymphoma).
 In as many as 50% of Hodgkin disease (Hodgkin's lymphoma) cases, the tumor cells are
EBV-positive; EBV positivity is higher with MCHD (60-70%) than with NSHD (15-30%). Almost
100% of HIV-associated Hodgkin disease (Hodgkin's lymphoma) cases are EBV-positive.
 An epidemiologic study from Denmark and Sweden showed an increased risk of EBVpositive Hodgkin disease (Hodgkin's lymphoma) in patients with a self-reported history of infectious
mononucleosis (IM) in adolescence.6 The average incubation time from IM to symptoms of Hodgkin
disease (Hodgkin's lymphoma) was 2.9 years.
 Patients with HIV infection have a higher incidence of Hodgkin disease (Hodgkin's
lymphoma) compared with the population without HIV infection. However, Hodgkin disease
(Hodgkin's lymphoma) is not considered an acquired immunodeficiency syndrome (AIDS)-defining
neoplasm.
 Genetic predisposition may play a role in the pathogenesis of Hodgkin disease (Hodgkin's
lymphoma). Approximately 1% of patients with Hodgkin disease (Hodgkin's lymphoma) have a
family history of the disease. Siblings of an affected individual have a 3- to 7-fold increased risk for
developing Hodgkin disease (Hodgkin's lymphoma). This risk is higher in monozygotic twins.
 Human leukocyte antigen (HLA)-DP alleles are more common in Hodgkin disease
(Hodgkin's lymphoma).
Workup
Laboratory Studies
 Erythrocyte sedimentation rate (ESR) (a general marker of inflammation) measurements
may be elevated in Hodgkin disease (Hodgkin's lymphoma). An elevated ESR has been associated
with worse prognosis. However, the ESR is a nonspecific test that should not be used for Hodgkin
disease (Hodgkin's lymphoma) screening.
 Lactate dehydrogenase (LDH) may be increased. LDH may correlate with the bulk of
disease.
 Complete blood cell (CBC) count studies (for anemia, lymphopenia, neutrophilia, or
eosinophilia) should be performed. Hodgkin disease (Hodgkin's lymphoma)–associated anemia is
most commonly the anemia of chronic disease. However, it may result from bone marrow
involvement by tumor or from the presence of an autoantibody (positive findings on a warm Coombs
test). Cytopenias are common in advanced Hodgkin disease (Hodgkin's lymphoma) disease. Platelet
counts may be increased or decreased.
 Serum creatinine in Hodgkin disease (Hodgkin's lymphoma) has a rare association with
nephrotic syndrome.
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 Alkaline phosphatase (ALP) may be increased due to the presence of liver or bone
involvement. Other uncommon laboratory findings include hypercalcemia, hypernatremia, and
hypoglycemia (due to the presence of insulin autoantibodies).
 An HIV test is important in the workup of Hodgkin disease (Hodgkin's lymphoma) and
non-Hodgkin lymphomas, because antiviral therapies can improve disease outcomes in HIV-positive
patients.8
 Serum levels of cytokines (interleukin [IL]-6, IL-10) and soluble CD25 (IL-2 receptor)
correlate with tumor burden, systemic symptoms, and prognosis, but these studies are generally
obtained only in special situations or in the context of a clinical trial.
Imaging Studies
Imaging studies for Hodgkin disease (Hodgkin's lymphoma)
 Computed tomography (CT) scans of the chest, abdomen, and pelvis
o Possible abnormal findings include enlarged lymph nodes, hepatomegaly and/or
splenomegaly (with or without focal parenchymal abnormalities), lung nodules or infiltrates, and
pleural effusions.
o A mediastinal mass, representing mediastinal lymphadenopathy, is a very common finding
in classic Hodgkin disease (Hodgkin's lymphoma), although it is uncommon in NLPHD.
 Positron emission tomography (PET) scanning is now considered to be essential to the
initial staging of Hodgkin disease (Hodgkin's lymphoma).9
Other Tests
Sampling of a pleural effusion by thoracentesis and examination of the cells obtained may be
useful in the evaluation of Hodgkin disease (Hodgkin's lymphoma). The pleural fluid may be an
exudate
or
transudate,
or
it
may
be
chylous.
CNS evaluation by lumbar puncture and magnetic resonance imaging (MRI) should be performed if
symptoms or signs of CNS involvement are present. CNS involvement with Hodgkin disease
(Hodgkin's lymphoma) is exceedingly rare, but it has been reported.
Procedures
 A histologic diagnosis of Hodgkin disease (Hodgkin's lymphoma) is always required.
o An excisional lymph node biopsy is recommended, because the lymph node architecture is
important for histologic classification.
o When a patient presents with neck lymphadenopathy that may be due to a head and neck
cancer, a fine-needle aspiration (FNA) is usually advised as the initial diagnostic step, followed by
excisional biopsy if squamous cell histology is excluded.
 Bone marrow biopsies
o Because Hodgkin disease (Hodgkin's lymphoma) in the bone marrow is often patchy,
bilateral bone marrow biopsies are advised to improve the identification of advanced disease (stage
IV).
o Bone marrow involvement is more common in elderly individuals, in patients with
advanced-stage disease, in the presence of systemic symptoms, and in patients with a high-risk
histology.
o A bone marrow biopsy can be omitted in patients with stage I Hodgkin disease (Hodgkin's
lymphoma) and some patients with stage II disease without hematologic abnormalities.
 A staging laparotomy is a surgical procedure that includes splenectomy with biopsies of
the liver and lymph nodes in the para-aortic, mesenteric, portal, and splenic hilar regions. At
present, a staging laparotomy procedure is very rarely indicated, because even early-stage Hodgkin
disease (Hodgkin's lymphoma) is most often treated with combination chemotherapy. The procedure
can be helpful in rare cases in which radiation therapy is under consideration as the sole treatment of
early-stage Hodgkin disease (Hodgkin's lymphoma).
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Staging
The Ann Arbor classification (1971) is used most often for cases of Hodgkin disease
(Hodgkin's lymphoma). Clinical staging involves assessment of disease extent by clinical
examination, history, and imaging techniques. When staging laparotomies are used as part of
staging, the disease extent is designated as pathologic staging.
 Stage I denotes a single lymph node area or single extranodal site.
 Stage II denotes 2 or more lymph node areas on the same side of the diaphragm.
 Stage III denotes lymph node areas on both sides of the diaphragm.
 Stage IV denotes disseminated or multiple involvement of the extranodal organs.
Involvement of the liver or the bone marrow is considered stage IV disease. For staging
classifications, the spleen is considered to be a lymph node area. Involvement of the spleen is
denoted with the S suffix (ie, IIBS).
 A or B designations denote the absence or presence of B symptoms.
o A "B" designation includes the presence of 1 or more of the following:
 Fever (temperature >38°C)
 Drenching night sweats
 Unexplained loss of more than 10% of body weight within the preceding 6 months
o An "A" designation is the absence of the above.
o An "X" designation is sometimes used to indicate the presence of bulky disease.
 Approximately one third of new patients have splenic involvement based on laparotomy
data. However, this depends on the histologic subtype. Two thirds of patients with the mixed
cellularity subtype have splenic involvement, compared with only one third of patients with the
lymphocyte-depleted or nodular sclerosis histology. When liver or bone marrow involvement is
present, the spleen is likely to be involved.
 Spread of Hodgkin disease (Hodgkin's lymphoma) takes place via the lymphatics,
hematogenous routes, and direct extension.
 Contiguous involvement of extranodal sites (eg, involvement of the lung parenchyma due
to direct extension of large mediastinal lymphadenopathy) is not considered stage IV disease.
Rather, it is designated with the E suffix (ie, IIBE).
Unfavorable factors in limited-stage Hodgkin disease (Hodgkin's lymphoma)
Many factors that can be assessed at the time of the disease diagnosis can help to determine
whether a patient's Hodgkin disease (Hodgkin's lymphoma) has a high or low risk of proving
resistant to therapy. Such an estimate is important for treatment planning. In addition, it can help
identify patients who would potentially benefit from participating in clinical trials that seek to either
minimize therapy in low-risk patients or intensify therapy in high-risk patients.
In patients with stage I or II disease, the following factors are considered unfavorable and, if
present, will increase the intensity of the recommended initial therapy:
 Bulky disease, defined as a mediastinal mass greater than one third of the intrathoracic
diameter (on a chest radiograph) or greater than 35% of the thoracic diameter at vertebral level T5-6.
Hodgkin disease (Hodgkin's lymphoma) also qualifies as bulky disease if it is greater than 10 cm in
diameter on a CT scan.
 An ESR result (a general marker of inflammation) 50 mm/h or higher, if the patient is
otherwise asymptomatic
 More than 3 sites of disease involvement
 The presence of B symptoms
 The presence of extranodal disease
The International Prognostic Factors Project (IPFP) score for advanced Hodgkin
disease (Hodgkin's lymphoma)
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The IPFP was a survey of the characteristics at diagnosis and outcomes of 5,141 patients
with Hodgkin disease (Hodgkin's lymphoma) with either advanced disease, defined as either stage
III or IV disease, or earlier stage disease with systemic symptoms or bulky features. The following
characteristics were determined to each contribute independently to an increased relative risk for
Hodgkin disease (Hodgkin's lymphoma) progression despite therapy:
 Serum albumin less than 4 g/dL
 Hemoglobin less than 10.5 g/dL
 Male sex
 Stage IV disease
 Age 45 years or older
 White blood cell (WBC) count greater than 15,000/mm3
 Lymphocyte count less than 600/mm3 or less than 8% of the total WBC count
The International Prognostic Score (IPS) is considered to be the number of features that are
present at diagnosis for Hodgkin disease (Hodgkin's lymphoma).The IPS correlates with the rate of
freedom from disease progression and overall survival. Patients with 0-1 of these factors would be
predicted to have a 90% overall survival. In contrast, patients with 4 or more of these factors may
have an overall survival rate of only 59%. One limitation of this scoring method is that it was unable
to clearly identify the highest risk subgroup of patients with Hodgkin disease (Hodgkin's
lymphoma), that is, those who may benefit from up-front high-dose therapy. Analysis of cytokines
and other serum markers may help to identify these patients in the future.
Medical Care
Principles of therapy for Hodgkin disease (Hodgkin's lymphoma)
 Published guidelines from the National Comprehensive Cancer Network (NCCN), 12 the
European Society of Medical Oncology (ESMO), and the International Harmonization Project
provide consensus opinions from leading experts on evidence-based approaches to the diagnosis and
treatment of Hodgkin disease (Hodgkin's lymphoma).
 Hodgkin disease (Hodgkin's lymphoma) is considered to be a curable malignancy, but
therapies for this disease can have significant long-term toxicity. Therefore, advances in treatment
protocols have sought to (1) minimize the treatment given to patients with early stage, low-risk
disease and (2) safely maximize the treatment given to patients with disease that is likely to be
refractory to standard therapies.
 Combined-modality therapy (radiation therapy [XRT] and chemotherapy) is frequently the
preferred approach in for most patients. In early stage disease, combined-modality therapy provides
a synergistic effect while limiting the total exposure to any particular agent. In patients with
advanced Hodgkin disease (Hodgkin's lymphoma), involved-field XRT can be used for sites of
persistent disease following chemotherapy. XRT to sites of disease that were bulky at diagnosis is a
standard feature of the Stanford V regimen (see Chemotherapy, Stanford V regimen, below).
 The high sensitivity of positron emission tomography (PET) scanning for classic Hodgkin
disease (Hodgkin's lymphoma) has this imaging modality a prominent role in the assessment of
treatment response in affected patients. A positive PET scan following therapy correlates strongly
with a high risk of relapse. An early attainment of a negative PET scan during therapy is a positive
prognostic indicator, but studies have not yet provided information on whether a course of therapy
can be safely shortened in this situation.
o PET/CT scans should be obtained at least 3 weeks, and preferably 6-8 weeks following the
last therapy in order to lessen the risk of false-positive scans resulting from nonmalignant
inflammatory responses.
o Biopsies of PET-positive lesions are typically done in order to test for persistent Hodgkin
disease (Hodgkin's lymphoma).
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 The goal of therapy is to induce a complete remission (CR), which is defined as the
"disappearance of all evidence of disease," as evaluated by PET/CT scanning, physical examination,
and bone marrow examination (if appropriate). A partial remission (PR) is defined as "regression of
measurable disease and no new sites" of disease.
 Despite the high rate of cure for this disease, many cases Hodgkin disease (Hodgkin's
lymphoma) do relapse. In most of these cases, salvage chemotherapy followed by high-dose
chemotherapy (HDC) with autologous hematopoietic stem cell support is indicated.
 The role of allogeneic hematopoietic stem cell transplantation for Hodgkin disease
(Hodgkin's lymphoma) is being explored. It is possible that a graft-vs-lymphoma effect may
contribute to favorable outcomes in affected patients, but mortality directly resulting from the
transplant procedure has been unacceptably high. Newer transplant protocols that use less-intensive
conditioning regimens (chemotherapy) offer the potential for long-term disease-free survival (DFS)
with less transplant-related mortality. Allogeneic hematopoietic stem cell transplantation should
ideally be pursued only in the context of a clinical trial.
 Because of the limited number of patients with Hodgkin disease (Hodgkin's lymphoma)
and the importance of the clinical questions that remain about optimal disease management, patient
involvement in clinical trials is strongly encouraged.
 NLPHD is clinically distinct from classic Hodgkin disease (Hodgkin's lymphoma) in that it
generally presents as early stage disease that can be treated with local measures (surgery, radiation)
or followed expectantly. Some cases of NLPHD can transform to aggressive non-Hodgkin
lymphomas that are treated using standard paradigms.
XRT
For treatment of classic Hodgkin disease (Hodgkin's lymphoma), XRT is generally
administered in combination with chemotherapy. Radiation fields and doses are selected to
minimizing the potential side effects of therapy, while maximizing the potential for long-term DFS.
Involved-field therapy encompasses only the areas of observed disease. Regional-field therapy
extends the involved field to include adjacent lymph regions.
Other fields that have been used historically and may be used in exceptional clinical
circumstances include the mantle field, covering the mediastinal, cervical, and axillary nodes, and
the inverted Y field, covering the para-aortic, pelvic, and inguinal nodes. Subtotal nodal irradiation
involves the mantle field plus the para-aortic nodes. The mantle field is shaped in order to reduce
radiation exposure to the heart and lungs. Careful avoidance of the spinal cord can reduce the risk of
myelitis. Shielding the testes and oophoropexy (temporary surgical suspension of the ovaries [eg,
outside of a radiation field]) are important during the reproductive years.
The dose of radiation to be administered is tailored to the specific clinical scenario. Doses
used in combined modality therapy are 30-36 Gy for bulky disease sites and 20-30 Gy for nonbulky
disease sites. When used alone, doses may range from 30-44 Gy.
In the NLPHD subtype of Hodgkin disease (Hodgkin's lymphoma), involved-field XRT may
be recommended for stage IA and IIA disease.
Chemotherapy
Induction regimens are those given as initial treatment for Hodgkin disease (Hodgkin's
lymphoma).
 MOPP regimen (mechlorethamine, vincristine, procarbazine, prednisone) was the first
effective combination chemotherapy developed for Hodgkin disease (Hodgkin's lymphoma). It is a
4-drug regimen developed by Vincent DeVita and colleagues at the NCI in the mid 1960s and is
primarily of historical importance.
 The ABVD regimen (Adriamycin, bleomycin, vinblastine, dacarbazine) was designed in
Italy by Gianni Bonadonna and his colleagues in the early 1970s. This combination has now become
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the standard chemotherapy regimen for Hodgkin disease (Hodgkin's lymphoma). ABVD is superior
to MOPP in terms of DFS and has a lower incidence of sterility and secondary leukemia.
 The Stanford V regimen (doxorubicin, vinblastine, mustard, bleomycin, vincristine,
etoposide, prednisone) is a multidrug regimen created at Stanford University by Sandra Horning and
colleagues. The drugs are administered weekly, alternating myelosuppressive and
nonmyelosuppressive agents, for 12 weeks. Involved-field XRT at the conclusion of the 12-week
regimen is an important part of this regimen. A potential advantage of the Stanford V regimen is that
its use of a broad spectrum of chemotherapy drugs can limit the exposure (and potential side-effects)
of any single drug.
 The BEACOPP regimen (bleomycin, etoposide, doxorubicin, cyclophosphamide,
vincristine, procarbazine, prednisone) was developed in Germany by Volker Diehl and colleagues. A
dose-intensified version of BEACOPP (escalated BEACOPP), with higher doses of etoposide,
Adriamycin, and cyclophosphamide and the addition of granulocyte colony-stimulating factor (GCSF) for neutrophil support, has also been developed, which may be useful for unfavorable,
advanced-stage Hodgkin disease (Hodgkin's lymphoma). However, escalated BEACOPP is
associated with greater hematologic toxicity and a higher incidence of secondary malignancies,
including acute myelogenous leukemia (AML). Engert et al reported on the 10-year follow-up of the
German Hodgkin Study Group HD9 trial. The study compared 2 doses (baseline and escalated) of
BEACOPP with COPP alternating with doxorubicin, bleomycin, vinblastine, and dacarbazine
(ABVD). BEACOPP escalated significantly improved freedom from treatment failure (82% vs 70%;
P < 0.0001) and overall survival (86% vs 80%; P = 0.0053) compared with BEACOPP baseline (P <
0.001) and overall survival. COPP/ABVD has been the standard of care for this patient population,
but freedom from treatment failure was only 64% and overall survival was only 75% in this group.
Ongoing clinical trials will directly compare the ABVD regimen to the Stanford V and
escalated BEACOPP regimens.
 Salvage chemotherapy: For patients whose disease has failed induction chemotherapy,
salvage chemotherapy is generally given. Salvage regimens incorporate drugs that are
complementary to those that failed during induction therapy. Commonly used salvage regimens
include ICE (ifosfamide, carboplatin, etoposide), DHAP (cisplatin, cytarabine, prednisone), and
ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin).
 HDC with bone marrow transplantation: HDC at doses that ablate the bone marrow is
feasible with reinfusion of the patient's previously collected hematopoietic stem cells (autologous
transplantation) or infusion of stem cells from a donor source (allogeneic transplantation).
Historically, hematopoietic stem cells have been obtained from bone marrow, but they are now
typically obtained by pheresis of peripheral blood lymphocytes. A validated and relatively safe
conditioning regimen for autologous transplantation is the BEAM regimen (carmustine [BCNU],
etoposide, cytarabine, melphalan).
Specific regimens
Each of the medications in all of the regimens described in the article are given
intravenously, except for prednisone and procarbazine, which are given orally.
Induction (for initial disease treatment)
 MOPP regimen: Every 28 days for 6 or more cycles.
o Mechlorethamine: 6 mg/m2, days 1 and 8
o Vincristine: 1.4 mg/m2, days 1 and 8
o Procarbazine: 100 mg/m2, days 1-14
o Prednisone: 40 mg/m2, days 1-14, cycles 1 and 4 only
 ABVD regimen: Every 28 days for 6 or more cycles.
o Adriamycin: 25 mg/m2, days 1, 15
o Bleomycin: 10 mg/m2, days 1, 15
o Vinblastine: 6 mg/m2, days 1, 15
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o Dacarbazine: 375 mg/m2, days 1, 15
 Stanford V regimen: XRT is administered to bulky sites 2-4 weeks following the end of
chemotherapy.
o Vinblastine: 6 mg/m2, weeks 1, 3, 5, 7, 9, 11
o Doxorubicin: 25 mg/m2, weeks 1, 3, 5, 9, 11
o Vincristine: 1.4 mg/m2, weeks 2, 4, 6, 8, 10, 12
o Bleomycin: 5 units/m2, weeks 2, 4, 8, 10, 12
o Mechlorethamine: 6 mg/m2, weeks 1, 5, 9
o Etoposide: 60 mg/m2 twice daily, weeks 3, 7, 11
o Prednisone: 40 mg/m2, every other day, weeks 1-10, tapered weeks 11, 12
 Escalated BEACOPP regimen: Every 3 weeks for 8 cycles.
o Bleomycin: 10 mg/m2, day 8
o Etoposide: 200 mg/m2, days 1-3
o Doxorubicin: 35 mg/m2, day 1
o Cyclophosphamide: 1,250 mg/m2, day 1
o Vincristine: 1.4 mg/m2, day 8
o Procarbazine: 100 mg/m2, days 1-7
o Prednisone: 40 mg/m2, days 1-14
Salvage therapy (for primary refractory or relapsed disease)
 ICE regimen
o Ifosfamide: 5 g/m2, day 2
o Mesna: 5 g/m2, day 2
o Carboplatin: AUC 5, day 2
o Etoposide: 100 mg/m2, days 1-3
 DHAP regimen
o Cisplatin: 100 mg/m2, day 1
o Cytarabine: 2 g/m2, given twice on day 2
o Dexamethasone: 40 mg, days 1-4
 EPOCH regimen – In this regimen, etoposide, vincristine, and doxorubicin are given
together over a total of 96 hours in a continuous intravenous infusion.
o Etoposide: 50 mg/m2, days 1-4
o Vincristine: 0.4 mg/m2, days 1-4
o Doxorubicin: 10 mg/m2, days 1-4
o Cyclophosphamide: 750 mg/m2, day 5
o Prednisone: 60 mg/m2, days 1-6
Myeloablative regimens (high-dose therapy requires hematopoietic stem cell support
for recovery)
 BEAM regimen: Different schedules for BEAM exist that vary primarily in the dose of
etoposide administered. This is the version used by Schmitz et al in a key randomized, prospective
clinical trial.19 Following this chemotherapy, autologous hematopoietic stem cells are administered
on day 0.
o BCNU 300 mg/m2, day –7
o Etoposide 150 mg/m2, every 12 hours, total of 8 doses, days –7 to –4
o Cytarabine 200 mg/m2, every 12 hours, total of 8 doses, days –7 to –4
o Melphalan 140 mg/m2, day –3
Targeted therapies
Targeted immunotherapeutic agents are currently being evaluated for potential use in
Hodgkin disease (Hodgkin's lymphoma). The CD30 cell surface antigen, which is expressed at high
levels on Reed-Sternberg cells, is a target of 2 monoclonal antibodies, SGN-30 and MDX-60. Each
11
has shown modest activity when administered to patients with refractory or recurrent Hodgkin
disease (Hodgkin's lymphoma).
 Specifics of treatment by stage and clinical presentation
o Treatment of Hodgkin disease (Hodgkin's lymphoma) is tailored to disease type, disease
stage, and an assessment of the risk of resistant disease. Two sets of consensus guidelines currently
help guide the standard of care for Hodgkin disease (Hodgkin's lymphoma), written by the NCCN
and the ESMO.
o The guidelines are very similar, but the NCCN guidelines have more specific
recommendations for response evaluation and follow-up. In addition, a set of revised response
criteria for malignant lymphoma, including Hodgkin disease (Hodgkin's lymphoma), and
recommendations for using PET scanning to monitor Hodgkin disease (Hodgkin's lymphoma) were
published by the International Harmonization Project. Together, these provide specific guidance for
evaluating the response of disease therapy.
 Goals of therapy: The primary goal of therapy is to induce a CR, which is defined as the
"disappearance of all evidence of disease," as evaluated by PET/CT scanning, physical examination,
and bone marrow examination (if appropriate). PET/CT scanning should be obtained at least 3 weeks
and preferably 6-8 weeks following the last therapy in order to lessen the risk of false-positive scans
resulting from nonmalignant inflammatory responses. A PR is defined as "regression of measurable
disease and no new sites" of disease. A failure to achieve a CR with initial therapy or a relapse after
having attained a CR is an indication for additional HDC and/or XRT, often with autologous
hematopoietic stem cell support.
 Early stage, low-risk disease: This group is defined as patients with clinical stages IA or
IIA classic Hodgkin disease (Hodgkin's lymphoma) who do not have unfavorable factors (bulky
disease, elevated ESR, >3 sites of involvement, B symptoms, extranodal disease). These patients
generally should receive 4 cycles of the ABVD regimen or 8 weeks of the Stanford V regimen,
followed by involved-field XRT. Radiation alone has been shown to be inferior to the combined
modality approach in early stage, low-risk disease. If XRT is contraindicated or not possible, then
chemotherapy should continue for 2 additional cycles following the attainment of a CR.
 In a multicenter, randomized trial, Engert et al determined that 2 cycles of ABVD followed
by 20 Gy of involved-field radiation is as effective as 4 cycles of ABVD followed by 30 Gy of
involved-field radiation in patients with early-stage Hodgkin's disease and a favorable prognosis.
Toxic effects and adverse events were more common in the group who received the 4 cycles of
ABVD and higher dose level of radiation.
 Early stage disease with unfavorable factors: This group is defined as patients with clinical
stages I or II with bulky disease, with or without unfavorable factors (elevated ESR, >3 sites of
involvement, B symptoms, extranodal disease). These patients are candidates for 4-6 cycles of the
ABVD regimen or 12 weeks of the Stanford V regimen, followed by involved-field XRT.
 Advanced and/or high-risk disease
o These patients have stage I or II disease with B symptoms (IB, IIB), or stages III or IV.
The NCCN recommends either 4 cycles of the ABVD regimen or 12 weeks of the Stanford V
regimen, followed by restaging with PET/CT scanning. If a patient has positive results on PET scans
following the ABVD regimen, an additional 2 cycles are administered. Once a CR has been
achieved, involved-field XRT is given. If, after 12 weeks of the Stanford V regimen, a patient is in a
CR or PR has been attained, then involved-field XRT is standard.
o EMSO recommends that patients with this category of disease receive either 8 cycles of
the ABVD regimen or the standard-dose BEACOPP regimen, with involved-field XRT applied only
to tumors initially more than 7.5 cm or to sites of residual disease following chemotherapy. For
patients with advanced-stage disease, the use of the escalated BEACOPP regimen has support in the
literature.
12
 NLPHD
o Early-stage NLPHD can be treated with local excision, involved-field XRT, or expectant
management (close observation).33 Advanced-stage disease may represent histologic transformation
to T-cell rich B-cell lymphoma (TCR-BCL) or diffuse large cell B-cell lymphoma (DLCBL). These
are types of non-Hodgkin lymphoma that should be treated with a typical non-Hodgkin regimen,
such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone).
o Rituximab is a humanized monoclonal antibody that is specific for CD20, a cell-surface
antigen expressed by the malignant L&H cells in NLPHD. It has shown activity as a single agent in
NLPHD. The German Hodgkin Lymphoma Study Group (GHSG) published long-term follow-up
data on the use of rituximab in patients with relapsed/refractory NLPHD. 34 The investigators
observed a 94% overall response rate, with 8 complete remissions from their population of 15
patients.34 Therefore, rituximab is a promising agent for advanced NLPHD, although the use of
rituximab in NLPHD, especially in early-stage disease, should ideally be pursued in the context of a
clinical trial.
 Hodgkin disease (Hodgkin's lymphoma) with concomitant HIV infection: In patients with
advanced Hodgkin disease (Hodgkin's lymphoma) and HIV, the results with standard chemotherapy
(eg, ABVD, BEACOPP) can be dramatically improved by simultaneous treatment with highly active
antiretroviral therapy (HAART). Such therapy generally involves 3 drugs: 2 nucleoside reverse
transcriptase inhibitors combined with either a protease inhibitor, a nonnucleoside reverse
transcriptase inhibitor, or a viral fusion inhibitor.
 Relapsed or primary refractory disease
o Hodgkin disease (Hodgkin's lymphoma) that has never entered a CR or that has relapsed
after the attainment of a CR is associated with a very poor prognosis when treated with standard
chemotherapy and radiation. Therefore, for patients with relapsed or refractory disease, HDC with
autologous stem cell transplantation is recommended.35 In this procedure, salvage chemotherapy is
first administered to help reduce the size of the persistent disease and obtain a CR, if possible. The
number of cycles to be administered depends on how well the disease is responding to therapy. An
optimal situation is one in which the disease enters a CR with negative PET scan findings, although
one study demonstrated that patients may achieve long-term DFS, even if their condition has little or
no response.36
o Following one of the cycles of salvage chemotherapy, hematopoietic stem cells are
collected from the peripheral blood by leukapheresis and are stored frozen. Following the
administration of myeloablative chemotherapy (eg, BEAM), the stored hematopoietic stem cells are
thawed and reinfused into the patient to facilitate hematopoietic recovery. HDC with autologous
stem cell transplantation can provide better than 50% long-term, progression-free survival for
patients with relapses, although specific predicted outcomes vary widely depending on patientspecific risk factors.
o Many questions relating to salvage and HDC therapy for patients with Hodgkin disease
(Hodgkin's lymphoma) need to be addressed and are the subject of ongoing clinical trials. These
include (1) the optimal salvage regimen or regimens, (2) the ideal conditioning regimen or regimens,
(3) the potential benefits of twin transplants compared with single transplants, and (4) how to
prospectively identify those patients who are unlikely to benefit from HDC and how to best manage
their disease.
o In some cases in which HDC fails, allogeneic stem cell transplantation may be a viable
option. In this method, myeloablative therapy (chemotherapy and sometimes XRT) is followed by
the infusion of hematopoietic stem cells from a genetically matched donor. 20 This offers the potential
for an immunologic antitumor effect from T cells provided by the hematopoietic stem cell donor,
which may improve the chances for cure of the disease.
o Historically, allogeneic stem cell transplantation for Hodgkin disease (Hodgkin's
lymphoma) has been considered too high risk for most patients due a high transplant-related
13
mortality. However, new transplant protocols use less toxic conditioning regimens and may be safer
and more effective for patients with refractory Hodgkin disease (Hodgkin's lymphoma). 21
Follow-up
Further Outpatient Care
Follow-up for the patient in complete remission
NCCN and ESMO both provide recommendations for the long-term follow-up of treated
patients with Hodgkin disease (Hodgkin's lymphoma).
 Most relapses occur in the first 3 years after therapy. Follow-up visits are recommended
every 2-4 months for the first 1-2 years and every 3-6 months for the next 3-5 years.
 Follow-up examinations include the following:
o History and physical examination
o CBC counts and chemistry panel, including LDH, ESR, glucose, and lipid levels
o Thyroid-stimulating hormone (TSH) levels (at least annually if the patient has had neck
XRT)
o Chest x-ray or CT scans of the chest every 6-12 months in the first 2-5 years. Abdominal
and pelvic CT scans may be added every 6-12 months in the first 2-3 years, especially if the disease
had originally occurred below the diaphragm.
o PET scans obtained for surveillance following CR is specifically not encouraged by the
NCCN due to the possibility that false-positive results may occur.
o Spiral chest CT scans may be appropriate annually, starting 5 years after therapy to screen
patients at increased risk for lung cancer.
 Female patients with a history of chest irradiation should be screened annually with
mammography, starting at age 40 years or 5-8 years following the XRT.
 Vaccinations against pneumococcus (especially in patients who have had splenectomy),
Haemophilus influenzae, meningococcus, and influenza (annually, especially in patients who have
received bleomycin or chest XRT), should be maintained.
Complications
Late complications of therapy in Hodgkin disease (Hodgkin's lymphoma) survivors
Survivors of Hodgkin disease (Hodgkin's lymphoma) may have long-term sequelae from
their therapy.37 With the current widespread use of nonleukemogenic chemotherapy (ABVD) and the
use of smaller radiation fields and doses, the rate of treatment-related deaths is expected to decrease.
 Cardiac disease
o Mantle radiotherapy increases the risk the risk of coronary artery disease, chronic
pericarditis, pancarditis, valvular heart disease, and defects in the conduction system.
o Patients with history of mediastinal radiation have a 3-fold increase in their risk of cardiac
death.
o A study of patients who had previously undergone mediastinal irradiation for Hodgkin
disease (Hodgkin's lymphoma) but who had no clinical evidence of heart disease demonstrated a
significant incidence of silent coronary artery obstruction and previous ventricular damage. Based on
these results, it is reasonable to initiate functional screening 5 years after XRT in patients with
Hodgkin disease (Hodgkin's lymphoma).
 Pulmonary disease
o The ABVD regimen contains bleomycin, a drug associated with dose-related pulmonary
toxicity, mainly interstitial pneumonitis, which may lead to fibrosis.
o The addition of mantle irradiation enhances lung injury. Pulmonary symptomatology, such
as cough or dyspnea upon exertion, is observed in 50% of patients, and declining pulmonary
function parameters are observed in approximately one third of patients during ABVD
chemotherapy, with or without XRT. This may lead to dose reductions or even discontinuation of
bleomycin.
14
o Baseline tests and follow-up evaluation with pulmonary function tests are recommended.
The best parameter to follow is the carbon monoxide diffusion capacity.
o Although acute toxicity is common, the incidence of severe long-term pulmonary toxicity
is low. Fatal pulmonary toxicity has been reported in up to 2-3% of patients treated with the ABVD
regimen.
 Secondary cancers – Secondary leukemias and solid tumors are significant causes of
morbidity and mortality for patients who have received early therapies, including the MOPP regimen
and mantle XRT. With modern therapies that emphasize the widespread use of the ABVD and
Stanford V regimens and the application of radiation to involved fields only, the incidence of
secondary cancers is expected to be much lower.
o Myelodysplastic syndromes (MDS)/acute leukemia
 In the Stanford case series, the projected risk for developing MDS or acute leukemia over
a follow-up period of 35 years was 2%, and the relative risk compared with matched controls was
38%. The MOPP regimen is associated with an approximately 5% incidence of MDS/leukemia.
With the ABVD regimen, such risk is lower, less than 1%.
 MDS/AML is usually seen in the first 3-8 years following treatment for Hodgkin disease
(Hodgkin's lymphoma); subsequently, the risk appears to decline. These findings are consistent with
the biology of secondary leukemias following alkylator therapy.
 MDS/AML usually develops in the context of an MDS with cytogenetic abnormalities in
chromosomes 5 and/or 7. Exposure to alkylating agents (eg, the mechlorethamine used in the MOPP
regimen) has been implicated.
 Exposure to epipodophyllotoxins (etoposide and teniposide) may also result in AML,
which generally develops within 3 years and is associated with chromosomal abnormalities at band
11q23.
o Breast cancer
 Patients treated with mantle XRT when they are younger than 30 years are 19 times more
likely to develop breast cancer. If women are exposed to chest XRT when they are younger than 15
years, this relative risk increases to 136.
 MOPP chemotherapy also produces an increased risk for breast cancer when combined
with XRT.
o Other solid tumors
 The most common secondary malignancy following treatment for Hodgkin disease
(Hodgkin's lymphoma) is lung cancer. Both chemotherapy with alkylating agents and irradiation are
associated with a 10-fold increased relative risk of lung cancer. Smoking can further increase the
risk.
 Patients in the Stanford case series were also found to have increased risks of developing
melanoma, non-Hodgkin lymphoma, soft-tissue sarcoma, salivary gland cancers, pancreatic cancers,
and thyroid cancers.
 Infertility
o MOPP chemotherapy causes permanent infertility in at least 80% of males and
approximately 50% of females. Young females may maintain their ovarian function, and some
studies suggest that this may be improved by the use of oral contraceptives. The escalated
BEACOPP regimen is also likely to impair fertility.
o The ABVD and Stanford V regimens pose a lower risk of permanent sterility than
regimens that contain an alkylating agent (eg, MOPP chemotherapy).The EORTC Lymphoma Group
reported an 82% rate of recovery of fertility in male patients who were treated without alkylating
agents. Male patients who are considering bearing children may consider sperm banking before
initiating therapy.
 Infectious complications
15
o Patients who have undergone splenectomy are predisposed to bacterial sepsis secondary to
encapsulated microorganisms (especially Streptococcus pneumoniae). Empiric antibiotic therapy
should be instituted promptly in patients who have undergone splenectomy and present with fever.
Pneumococcal vaccination before splenectomy and every 5-7 years thereafter is also recommended.
o Influenza vaccination annually may help to reduce the incidence and/or complications of
influenza in patients who have received bleomycin or chest XRT.
o Herpes zoster usually appears in previously irradiated dermatomes, but this condition may
also occur in patients who have not been irradiated.
 Hypothyroidism – Elevation of thyroid stimulating hormone (TSH) occurs in one third of
adult patients after neck/mediastinal XRT.
 Lhermitte syndrome – Patients with this syndrome describe an electric shock sensation that
radiates along the back and legs upon flexion of the neck. It can occur in approximately 15% of
patients after mantle irradiation. Lhermitte syndrome is not associated with the development of
radiation myelitis, and it does not require treatment. This syndrome may last for many months, but
eventually, it resolves without long-term sequelae.
 Psychosocial sequelae – Survivors of Hodgkin disease (Hodgkin's lymphoma) have an
increased incidence of fatigue, psychiatric distress (anxiety, depression), employment problems,
family issues, and sexual functioning problems, as compared with individuals without this disease or
relative to survivors of acute leukemia.
Medicolegal Pitfalls
 Because Hodgkin disease (Hodgkin's lymphoma) is considered to be a curable malignancy,
medicolegal problems may arise from failure to diagnose the disease in a timely manner, possibly
attributable to the following factors:
o The misinterpretation of B symptoms
o A lack of follow-up for abnormal chest radiographs or physical examination findings
o A missed pathologic diagnosis because a needle biopsy was obtained rather than an
excisional lymph node biopsy
 Treatment for Hodgkin disease (Hodgkin's lymphoma) seeks to balance the risk of
treatment failure with the risk of treatment side effects. Medicolegal liability may therefore result
from overtreatment of low-risk disease or undertreatment of high-risk disease.
 Patients with refractory or relapsed Hodgkin disease (Hodgkin's lymphoma) should be
promptly referred to centers capable of HDC with hematopoietic stem cell support.
 In the case of survivors of Hodgkin disease (Hodgkin's lymphoma), problems may arise in
the following scenarios:
o Failure to identify secondary cancers in a timely manner
o Failure to consider sepsis as a possible cause for fever in a splenectomized patient
o Failure to diagnose and treat predictable complications of Hodgkin disease (Hodgkin's
lymphoma) treatment, such as coronary artery, pulmonary, or thyroid disease
 Failure to warn patients about potential complications of Hodgkin disease (Hodgkin's
lymphoma) therapy, including the risk of cardiac disease, lung toxicity, and secondary
cancers. Patients should also be apprised of the potential loss of fertility that may arise from MOPP
chemotherapy, escalated BEACOPP chemotherapy, pelvic irradiation, or HDC, so that they may
explore fertility-preserving options such as sperm banking, oral contraceptive use, or oophoropexy.
16
Lymphoma, Non-Hodgkin
The term lymphoma describes a heterogenous group of malignancies with different biology
and prognosis. In general lymphomas are divided into 2 large groups of neoplasms, namely nonHodgkin lymphoma (NHL) and Hodgkin disease. About 85% of all malignant lymphomas are
NHLs. The median age at diagnosis is the sixth decade of life, with some exceptions. (Burkitt
lymphoma and lymphoblastic lymphoma occur in younger patients.) NHL includes many
clinicopathologic subtypes, each with distinct epidemiologies; etiologies; morphologic,
immunophenotypic, genetic, and clinical features; and responses to therapy.
Currently, several NHL classification schemas exist, reflecting the growing understanding of
the complex diversity of the NHL subtypes. The Working Formulation, originally proposed in 1982,
classified and grouped lymphomas by morphology and clinical behavior (ie, low, intermediate, or
high grade). In the 1990s, the Revised European-American Lymphoma (REAL) classification
attempted to apply immunophenotypic and genetic features in identifying distinct clinicopathologic
NHL entities. The World Health Organization (WHO) classification further elaborates upon the
REAL approach. This classification divides NHL into those of B-cell origin and those of T-cell and
NK-cell origin. For clinical oncologists, the most practical way of sorting the currently recognized
types of NHL is according to their predicted clinical behavior; each classification schema contributes
to a greater understanding of the disease, which dictates prognosis and treatment.
NHLs are tumors originating from lymphoid tissues, mainly of lymph nodes. Various
neoplastic tumor cell lines correspond to each of the cellular components of antigen-stimulated
lymphoid follicles.
NHL represents a progressive clonal expansion of B cells or T cells and/or natural killer
(NK) cells arising from the accumulation of genetic lesions that affect proto-oncogenes or tumor
suppressor genes, resulting in cell immortalization. These oncogenes can be activated by
chromosomal translocations (ie, the genetic hallmark of lymphoid malignancies), or tumor
suppressor loci can be inactivated by chromosomal deletion or mutation. In addition, the genome of
certain lymphoma subtypes can be altered with the introduction of exogenous genes by various
oncogenic viruses. Several cytogenetic lesions are associated with specific NHLs, reflecting the
presence of specific markers of diagnostic significance in subclassifying various NHL subtypes.
Most NHLs are of B-cell origin (almost 85%); only 15% are derived from T/NK cells, and
the small remainder stem from macrophages. These tumors are characterized by the level of
differentiation, the size of the cell of origin, the origin cell's rate of proliferation, and the histologic
pattern of growth. For many of the B-cell NHL subtypes, the pattern of growth and cell size may be
important determinants of tumor aggressiveness. Tumors that grow in a nodular pattern, which
vaguely recapitulate normal B-cell lymphoid follicular structures, are generally less aggressive than
lymphomas that proliferate in a diffuse pattern. Lymphomas of small lymphocytes generally have a
more indolent course than those of large lymphocytes, which may have intermediate-grade or highgrade aggressiveness. However, some subtypes of high-grade lymphomas are characterized by small
cell morphology.
Frequency
NHL is the most prevalent hematopoietic neoplasm, representing approximately 4% of all
cancer diagnoses and ranking seventh in frequency among all cancers. NHL is more than 5 times as
common as Hodgkin disease.
Mortality/Morbidity
 Of the estimated 63,190 new cases of NHL in the United States in 2007, approximately
18,660 people are expected to die from the disease. The 5-year relative survival rate of patients with
NHL is approximately 63%. Of interest, the survival rate for patients with Non-Hodgkin lymphomas
has steadily improved over the last 2 decades. The improvement in medical and nursing care,
development of novel therapeutic strategies (ie, monoclonal antibodies), validation of biomarkers of
17
response, and the implementation of tailored treatment are some of the factors that have modified the
life expectancy of patients with NHL.
 The potential for cure varies among the different histological subtypes and directly relates
to the stage at presentation and patient response to initial therapy.
 In general, low-grade lymphomas are indolent tumors associated with a predicted median
survival time of 5-10 years. Intermediate-grade and high-grade lymphomas are more aggressive but
are more responsive to chemotherapy. They are associated with a predicted median survival time of
2-5 years and less than 2 years (unless cure is achieved), respectively.
Race
Incidence varies with race; white people have a higher risk than black and Asian American
people.
Sex
In general, incidence is slightly higher in men than in women, with a male-to-female ratio of
approximately 1.4:1, but the ratio may vary depending on the subtype of NHL; for example primary
mediastinal diffuse large B-cell lymphoma occurs more frequently in females than in males.
Age
 The median age at presentation for all subtypes of NHL is older than 50 years, except for
patients with high-grade lymphoblastic and small noncleaved lymphomas, which are the most
common types of NHL observed in children and young adults.
 At diagnosis, low-grade lymphomas account for 37% of NHLs in patients aged 35-64
years but account for only 16% of cases in patients younger than 35 years. Low-grade lymphomas
are extremely rare in children.
Clinical
History
In general, the clinical manifestations of patients with NHL depend on various factors such
as the location of the lymphomatous process, the rate of tumor growth, and the function of the organ
being compromised or displaced by the malignant process.
The Working Formulation classification groups the subtypes of non-Hodgkin lymphoma
(NHL) by clinical behavior, that is, low-grade, intermediate-grade, and high-grade. Because the
Working Formulation is limited to classification based upon morphology, it cannot encompass the
complex spectrum of NHL disease, excluding important subtypes such as mantle cell lymphoma or
T/NK lymphomas. However, it continues to serve as a basis for understanding the clinical behavior
of groups of NHLs.
 Low-grade lymphomas
o Peripheral adenopathy that is painless and slowly progressive is the most common clinical
presentation in these patients.
o Spontaneous regression of enlarged lymph nodes can occur in low-grade lymphoma,
potentially causing confusion with an infectious condition.
o Primary extranodal involvement and B symptoms (ie, temperature >38°C, night sweats,
weight loss >10% from baseline within 6 mo) are not common at presentation, but they are common
in patients with advanced, malignant transformation (ie, evolution from a low-grade to an
intermediate- or high-grade lymphoma) or end-stage disease.
o Bone marrow is frequently involved and may be associated with cytopenia or cytopenias.
o Fatigue and weakness are more common in patients with advanced-stage disease.
 Intermediate- and high-grade lymphomas
o These types of lymphomas cause a more varied clinical presentation.
o Most patients present with adenopathy.
o More than one third of patients present with extranodal involvement; the most common
sites are the GI tract (including the Waldeyer ring), skin, bone marrow, sinuses, genitourinary (GU)
tract, thyroid, and CNS.
18
o B-symptoms are more common, occurring in approximately 30-40% of patients.
o Lymphoblastic lymphoma, a high-grade lymphoma, often manifests with an anteriorsuperior mediastinal mass, superior vena cava (SVC) syndrome, and leptomeningeal disease with
cranial nerve palsies.
o Patients with Burkitt lymphoma (occurring in the United States) often present with a large
abdominal mass and symptoms of bowel obstruction.
o Obstructive hydronephrosis secondary to bulky retroperitoneal lymphadenopathy
obstructing the ureters can also be observed in these patients.
o Primary CNS lymphomas are high-grade neoplasms of B-cell origin. Most lymphomas
originating in the CNS are large cell lymphomas or immunoblastomas, and they account for 1% of
all intracranial neoplasms. These lymphomas are more commonly observed in patients who are
immunodeficient because of conditions such as Wiskott-Aldrich syndrome, transplantation, or
AIDS.
Physical
 Low-grade lymphomas
o Peripheral adenopathy
o Splenomegaly: Splenomegaly is observed in approximately 40% of patients; the spleen is
rarely the only involved site at presentation.
o Hepatomegaly
 Intermediate- and high-grade lymphomas
o Rapidly growing and bulky lymphadenopathy
o Splenomegaly
o Hepatomegaly
o Large abdominal mass: This usually occurs in Burkitt lymphoma.
o Testicular mass
o Skin lesions: Lesions are associated with cutaneous T-cell lymphoma (mycosis fungoides),
anaplastic large-cell lymphoma, and angioimmunoblastic lymphoma.
o Chest radiograph: The chest radiograph may demonstrate a bulky mediastinal mass, which
is associated with primary mediastinal large B-cell lymphoma or lymphoblastic lymphoma.
Causes
 Chromosomal translocations and molecular rearrangements play an important role in the
pathogenesis of many lymphomas and correlate with histology and immunophenotype.
o t(14;18)(q32;q21): This translocation is the most common chromosomal abnormality
associated with NHL. This translocation occurs in 85% of follicular lymphomas and 28% of highergrade NHLs. This translocation results in the juxtaposition of the bcl -2 apoptotic inhibitor oncogene
at chromosome band 18q21 to the heavy chain region of the immunoglobulin (Ig) locus within
chromosome band 14q32.
o t(11;14)(q13;q32): This translocation has a diagnostic nonrandom association with mantle
cell lymphoma. This translocation results in the overexpression of bcl -1 (cyclin D1/PRAD 1), a cellcycle regulator on chromosome band 11q13.
o 8q24 translocations: The 8q24 translocations lead to c-myc dysregulation. This is
frequently observed in high-grade small noncleaved lymphomas (Burkitt and non-Burkitt types),
including those associated with HIV infection.
o t(2;5)(p23;q35): This translocation between the nucleophosmin (NPM) gene and the
anaplastic lymphoma kinase (ALK1) gene results in the expression of an aberrant fusion protein
found in a majority of anaplastic large cell lymphomas.
o t(11;18)(q21;q21) and t(1;14)(p22;132): Two chromosomal translocations are associated
with mucosa-associated lymphoid tissue (MALT) lymphomas. The more common (ie,
t[11;18][q21;q21]) translocates the apoptosis inhibitor AP12 gene with the MALT1 gene, resulting in
19
the expression of an aberrant fusion protein. The other translocation, t(1;14)(p22;132), involves the
translocation of the bcl -10 gene to the immunoglobulin gene enhancer region.
 Some viruses are implicated in the pathogenesis of NHL, probably because of their ability
to induce chronic antigenic stimulation and cytokine dysregulation, which leads to uncontrolled Bor T-cell stimulation, proliferation, and lymphomagenesis. These viruses include the following:
o Epstein-Barr virus (EBV) is a DNA virus that is associated with Burkitt lymphoma
(especially the endemic form in Africa), Hodgkin disease, lymphomas in immunocompromised
patients (eg, from HIV infection,2 organ transplantation), and sinonasal lymphoma.
o Human T-cell leukemia virus type 1 (HTLV-1) causes a latent infection via reverse
transcription in activated T-helper cells. This virus is endemic in certain areas of Japan and the
Caribbean islands, and approximately 5% of carriers develop adult T-cell leukemia or lymphoma.
o Hepatitis C virus (HCV) is associated with the development of clonal B-cell expansions
and certain subtypes of NHL (ie, lymphoplasmacytic lymphoma, Waldenström macroglobulinemia),
especially in the setting of essential (type II) mixed cryoglobulinemia.
o Kaposi sarcoma–associated herpesvirus (KSHV) is associated with body cavity–based
lymphomas in patients with HIV infection and in patients with multicentric Castleman disease.
 Environmental factors linked to the development of NHL include chemicals (eg,
pesticides, herbicides, solvents, organic chemicals, wood preservatives, dusts, hair dye),
chemotherapy, and radiation exposure.
 Congenital immunodeficiency states (eg, severe combined immunodeficiency disease
[SCID], Wiskott-Aldrich syndrome), acquired immunodeficiency states (eg, AIDS), and induced
immunodeficiency states (eg, immunosuppression) are associated with increased incidence of NHL
and are characterized by a relatively high incidence of extranodal involvement, particularly of the GI
tract, and with aggressive histology. Primary CNS lymphomas can be observed in about 6% of
patients with AIDS.
 The chronic inflammation observed in patients with autoimmune disorders, such as
Sjögren syndrome and Hashimoto thyroiditis, promotes the development of MALT and predisposes
patients to subsequent lymphoid malignancies. Hashimoto thyroiditis, which occurs in 16-23% of
middle-aged and elderly females, is a preexisting condition in 23-56% of primary thyroid
lymphomas.
 Helicobacter pylori infection is associated with the development of primary GI
lymphomas, particularly gastric MALT lymphomas.
Workup
Laboratory Studies
 CBC count with differential and platelet count in patients with non-Hodgkin lymphoma
(NHL) may show the following:
o Counts within the reference range in the early stage of disease
o Anemia secondary to bone marrow infiltration, autoimmune hemolysis (particularly
associated with small lymphocytic lymphoma [SLL]/chronic lymphocytic leukemia [CLL]),
bleeding, anemia of chronic disease
o Thrombocytopenia, leukopenia, or pancytopenia secondary to bone marrow infiltration or
autoimmune cytopenias
o Lymphocytosis with circulating malignant cells (common in patients with low-grade
lymphomas)
o Thrombocytosis (paraneoplastic syndrome associated with lymphomas or reactive
secondary to blood loss)
 Chemistries may show the following:
o Elevated lactate dehydrogenase (LDH) - Poor prognostic factor, correlation with increased
tumor burden
20
o Abnormal liver function test (LFT) results - Secondary to hepatic involvement,
hypermetabolic tumor growth, chronic inflammation
o Hypercalcemia - In patients with acute form of adult T-cell lymphoma-leukemia (ATLL)
 Beta2-microglobulin may be elevated and correlates with a poor prognosis.
 Occasionally, NHL is associated with monoclonal gammopathy, positive Coombs test
result (especially SLL/CLL), and hypogammaglobulinemia.
 HIV serology should be obtained, especially in patients with diffuse large cell
immunoblastic or small noncleaved histologies.
 HTLV-1 serology should be obtained in patients with ATLL.
Imaging Studies
 CT scan of the neck, chest, abdomen, and pelvis is used to detect enlarged lymph nodes,
hepatosplenomegaly, or filling defects in the liver and spleen. Currently, it is the most widely used
test for initial staging, assessing treatment response, and conducting follow-up care.
 A chest radiograph yields positive information in approximately one fourth of patients
with NHLs, including identification of hilar or mediastinal adenopathy, pleural or pericardial
effusions, and parenchymal involvement.
 Bone scan is only ordered in patients with bone pain, elevated alkaline phosphatase, or
both. Bone lesions are particularly associated with the acute form of ATLL and diffuse large B-cell
lymphomas.
 Gallium scans (optional, selected cases) can detect initial sites of disease, reflect therapy
response, and detect early recurrences. This scan is positive in nearly all patients with aggressive and
highly aggressive lymphomas and in approximately 50% of patients with indolent lymphomas at
diagnosis.
 Whole body F-18 2-deoxyglucose (FDG) positron emission tomography (PET) scan can be
used for the initial evaluation of patients with NHL; however, this scan is more useful for
posttreatment evaluation to differentiate early recurrences or residual disease from fibrosis or
necrosis. This PET scan has a higher predictive value for relapse than classic CT scan imaging.
 Obtain an upper GI series with small bowel follow-through in patients with head and neck
involvement (eg, tonsil, base of tongue, nasopharynx, Waldeyer ring) and those with a GI primary
lesion.
 Obtain an ultrasound of opposite testis in male patients with a testicular primary lesion.
 Multiple gated acquisition (MUGA) scan should be performed to evaluate the left
ventricular ejection fraction (LVEF) of patients who are being considered for treatment with
anthracyclines. In general, anthracyclines should not be administered to those patients with LVEF of
less than 50%.
 Obtain MRI of the brain and spinal cord of patients who are suspected to have primary
CNS lymphoma, lymphomatous meningitis, paraspinal lymphoma, or vertebral body involvement by
lymphoma. It can also be performed to identify focal areas of marrow involvement in those patients
suspected to have bone marrow involvement but in whom random bone marrow biopsy findings
have been negative.
Other Tests
 Immunophenotypic analysis of lymph node, bone marrow, peripheral blood (if positive for
neoplastic cells), or a combination of these
o This study compliments and confirms the results of routine tissue section and may be
useful in resolving a diagnostic dilemma in patients with an atypical morphology.
o Immunophenotypic analysis helps to distinguish reactive from neoplastic lymphoid
infiltrates, lymphoid from nonlymphoid malignancies, and specific lymphoid neoplasms. Although
bcl -2 expression distinguishes follicular lymphoma from reactive follicular hyperplasia, bcl -1
21
expression strongly favors a diagnosis of mantle cell lymphoma. CD30 expression is important for
the recognition of anaplastic large cell lymphoma, and it can also be found in the majority of
Hodgkin lymphomas.
o This analysis provides information about lineage and clonality, which are complimentary
to the histology of a given case.
o Analysis is also useful for subclassifying certain lymphoma subtypes, which has
therapeutic and prognostic importance.
 Cytogenetic studies
o These studies have contributed to the understanding of the biology and prognosis of
lymphoma.
o Cytogenetic studies are critical to the discovery of oncogene abnormalities that now are
known to be intimately involved in the pathogenesis of NHL.
Procedures
 Biopsy of peripheral (or most accessible) lymphadenopathy
o Excisional lymph node biopsy is required because lymphoma diagnosis relies heavily on
careful assessment of altered nodal architecture accompanying lymphomatous infiltrates.
o Fine-needle aspiration (FNA) is insufficient for establishing a diagnosis; needle-core
biopsies have a limited role in establishing a diagnosis of NHL.
o A well-processed hematoxylin and eosin (H&E)–stained section of an excised lymph node
is the mainstay of pathologic diagnosis.
 Bone marrow aspirate and biopsy
o Perform this procedure for staging rather than diagnostic purposes.
o Bilateral bone marrow aspirate and biopsy should be performed because bone marrow
involvement is usually patchy. In bone marrow sections, the neoplastic cells may infiltrate in a focal
(ie, paratrabecular or nonparatrabecular, depending on the type of lymphoma), interstitial, or diffuse
pattern.
 Biopsy of extranodal sites
o In approximately 30-35% of adult patients with NHL, the extranodal sites are the primary
presenting sites, and the most common site is the GI tract.
o Processing extranodal biopsy material for lymphoma protocol studies is important
whenever suspicion of a hematolymphoid neoplasm exists.
 Lumbar puncture for cerebrospinal fluid (CSF) examination should be performed in
patients with the following conditions:
o Diffuse aggressive NHL with bone marrow, epidural, testicular, paranasal sinus,
nasopharyngeal involvement, or patient with two or more extranodal sites of disease.
o High-grade lymphoblastic lymphoma
o High-grade small noncleaved cell lymphomas (eg, Burkitt and non-Burkitt types)
o HIV-related lymphoma
o Primary CNS lymphoma
o Patients with neurologic signs and symptoms
Histologic Findings
NHLs are a heterogenous group of lymphoproliferative malignancies with varying
morphologic features depending on the specific type of this disorder. The abnormal lymphocytes in
the lymph node, bone marrow, or extranodal sites can be small cleaved or noncleaved, intermediate,
or large cell and can have a follicular or diffuse pattern. In contrast with reactive follicular
hyperplasia, lymphomas usually alter the lymph node architecture, and the capsule is usually
involved.
Staging
Staging is important in selecting a treatment and also for prognosis. CT scans of the neck,
chest, abdomen, and pelvis, as well as bilateral bone marrow aspirate and biopsy, are necessary to
22
stage the lymphoma. Noncontiguous lymph node involvement, uncommon in Hodgkin disease, is
more common among patients with NHL.
 The Ann Arbor staging system is the most commonly used staging system for patients with
NHL.
o Stage I NHL involves a single lymph node region (I) or localized involvement of a single
extralymphatic organ or site (IE).
o Stage II NHL involves 2 or more lymph node regions on the same side of the diaphragm
(II) or localized involvement of a single associated extralymphatic organ in addition to criteria for
stage II (IIE).
o Stage III involves lymph node regions on both sides of the diaphragm (III) that also may
be accompanied by localized involvement of an extralymphatic organ or site (IIIE), spleen (IIIS), or
both (IIISE).
o Stage IV represents disseminated or multifocal involvement of one or more extralymphatic
sites with or without associated lymph node involvement or isolated extralymphatic organ
involvement with distant (nonregional) nodal involvement.
o Subscript letters designate involvement of extralymphatic organs, as follows: L, lung; H,
liver; P, pleura; O, bone; M, bone marrow; and D, skin. The designation E is used when extranodal
lymphoid malignancies arise in tissues that are separate from but near the major lymphatic
aggregates.
o In this system, stages I-IV can be appended by A or B designations. Patients with A
disease do not have systemic symptoms. The B designation is applied in patients with any of the
following symptoms: unexplained loss of more than 10% of body weight in the preceding 6 months
before diagnosis, unexplained fever with temperature above 38°C, and drenching night sweats.
IPI and FLIPI score
In addition to staging, risk stratification is important in patients with NHL. Several scoring
systems had been developed and validated prospectively in patients with diffuse large B-cell
lymphoma (International Prognostic Index, IPI) or follicular B-cell lymphomas (Follicular
Lymphoma International Prognostic Index, FLIPI) that can be used to predict the prognosis of
patients with B-cell malignancies.
Treatment
Medical Care
The treatment of non-Hodgkin lymphomas (NHLs) varies greatly depending on tumor stage,
phenotype (B-, T- or NK/null-cell), histology (ie, whether low-, intermediate-, or high-grade),
symptoms, performance status, patient's age, and comorbidities.
Indolent NHL
Follicular lymphoma (grade I-IIIa) comprises 70% of this group. Other entities in this group
include small lymphocytic lymphoma (SLL), lymphoplasmacytoid lymphoma, and marginal zone
lymphomas (MZL, nodal or extranodal).
Indolent stage I and contiguous stage II NHL
Standard management consists of radiotherapy alone. Forty percent of patients with limitedstage disease remained disease-free at 10 years after radiation in a study done by Mac Manus and
Hoppe. No randomized study has shown combined chemotherapy and radiation to be better than
radiation alone. Radiation therapy (2500-4000 cGy) produces a 10-year failure-free survival (FFS)
rate of 50-60%, with an overall survival (OS) rate of 60-80%. Offering adjuvant chemotherapy to
selected patients with stage I-II NHL who have unfavorable prognostic factors (eg, B symptoms, >2
nodal sites), and to those with follicular mixed histology is not unreasonable. Early treatment in
asymptomatic patients has not been shown to improve survival.
Indolent noncontiguous stage II, III, and IV NHL
The treatment of indolent B-cell lymphomas continues to evolve as newer therapies are
becoming available with potent antitumor activity and limited toxicity. Monoclonal antibodies are
23
changing the treatment paradigm of patients with B-cell lymphomas. However, controversies persist
regarding the best treatment strategy and also the best time to initiate treatment.
The disease course of indolent lymphomas is characterized by a continuous decrease in the
quality and the duration of response with each subsequent treatment or treatments. This effect is
primarily due to the acquisition of chemotherapy resistance. Advanced indolent lymphomas have
been accepted to be not curable with currently available therapies. However, sustained complete
remissions can be achieved with various treatment modalities. The use of rituximab, a monoclonal
antibody targeting CD20 antigen present in benign and malignant B-cells, in combination with
systemic chemotherapy, has resulted in an improved duration of remission and survival for patients
with indolent B-cell lymphomas when compared to chemotherapy. Prospective studies and 2 metaanalyses suggest that the rituximab-chemotherapy, also known as chemo-immunotherapy, may be
changing the natural progression of indolent lymphomas.
Asymptomatic patients, especially older patients and patients with concomitant medical
problems, deferred therapy with careful observation is an option. Early intervention in asymptomatic
patients does not appear to prolong survival. The median time to progression is 4-6 years, and OS is
6-10 years.
The treatment of symptomatic patients with indolent lymphomas should be focused on
achieving the best possible quality of response without producing excessive toxicity. Single-agent
treatment with chlorambucil or cyclophosphamide (with or without prednisone) is useful in elderly
patients with significant comorbidities. However, only a few achieve remission; most achieve
palliation.
Combination chemotherapies are used in younger patients with the goal of achieving a
complete remission. Frequently used combination regimens are CHOP (cyclophosphamide,
hydroxydaunomycin, Oncovin-vincristine, and prednisone), CVP (cyclophosphamide, vincristine,
and prednisone), and fludarabine alone or in combination (cyclophosphamide, mitoxantrone).
Combination agents are useful in bulky and rapidly progressive disease and have increased response
rates as compared to single agents, but there is no improvement in overall survival.
Longer duration of remission, with more patients achieving a complete response and/or
complete molecular response, has become possible with newer biological agents like rituximab.
Czuczman et al reported a 95% overall response rate and increase in time to progression with
addition of rituximab to CHOP chemotherapy. When used in combination with chemotherapy,
rituximab has shown higher response rates, longer time to progression and longer survival than
chemotherapy. Randomized trials have shown better responses when rituximab was combined with
chemotherapy regimens (CHOP, CVP). Rituximab as a single agent is also useful in patients who are
unable to tolerate chemotherapy or those patients who elect to undergo treatment in the absence of
high tumor burden.
Bone marrow transplant may have a role in patients with relapsed high-risk disease.
Allogenic transplant has lower relapse rates but an increase in transplant-related mortality as
compared to autologous transplant. The precise role of transplantation in indolent lymphomas is still
being investigated.
Aggressive NHL
Diffuse large B-cell lymphoma is the most common type of NHL. Other distinct entities in
this group include immunoblastic, anaplastic, lymphoblastic, large-cell, Burkitt, and Burkitt-like
lymphomas (high-grade lymphomas). Mantle-cell lymphomas also behave aggressively.
Aggressive stage I and contiguous stage II (nonbulky or <10 cm) NHL
Based on 2 large randomized trials (ie, Southwest Oncology Group [SWOG], Eastern
Cooperative Oncology Group [ECOG]), the preferred treatment option for patients with
intermediate-grade NHL is combination chemotherapy (3 cycles of CHOP) plus involved-field
radiation therapy. According to SWOG data, patients who are treated with chemotherapy and
involved-field radiation therapy have significantly better progression-free survival rates (ie, 77%
versus 66%) and 5-year OS rates (ie, 82% versus 72%) compared to patients surviving 8 cycles of
24
chemotherapy (ie, CHOP) alone. Patients with high-grade disease should be strongly considered for
treatment with more aggressive regimens beyond CHOP.
Aggressive noncontiguous stage II, III, and IV NHL
Approximately 40-50% are cured with standard therapy, approximately 35-40% will respond
but ultimately progress or relapse and the remainder will be primarily refractory. Scoring systems
such the IPI score have been developed and validated to estimate the response rate or survival rate of
a given patient with aggressive lymphomas.
For many years, the treatment of aggressive lymphomas consisted of chemotherapy
regimens using multiple drugs. Initial clinical studies were focused on investigating the use of more
toxic regimens (higher doses or more drugs). A prospective randomized trial of 4 regimens (ie, [1]
CHOP versus [2] prednisone, methotrexate, leucovorin, doxorubicin, cyclophosphamide, and
etoposide [ProMACE]–cyclophosphamide, etoposide, Adriamycin, cytarabine, bleomycin, Oncovin,
methotrexate, leucovorin, and prednisone [CytaBOM] versus [3] methotrexate, bleomycin,
Adriamycin, cyclophosphamide, Oncovin, and dexamethasone [m-BACOD] versus [4]
methotrexate-leucovorin, Adriamycin, cyclophosphamide, Oncovin, prednisone, and bleomycin
[MACOP-B]) for patients with diffuse large cell lymphoma showed no difference in response rate
(RR), OS, or time to treatment failure (TTF) at 3 years. The other 3 regimens were more toxic than
CHOP therapy. However, non-CHOP regimens such as MACOP-B are used as first-line therapies in
somesubtypes of NHL such as primary mediastinal large B-cell NHL.
After more than 2 decades of scientific investigations, the treatment of aggressive
lymphomas switched by the clinical development of rituximab. Currently, 6-8 cycles of CHOP
chemotherapy in combination with rituximab is the standard of care in patients with advanced
disease.
The GELA (Groupe d'Etude des Lymphomas de l'Adulte) study was the first phase III trial
to investigate the efficacy of combining rituximab with standard doses of CHOP chemotherapy for
elderly (those older than 60 y) patients with diffuse large B-cell lymphoma. In this landmark study,
patients were randomized to receive either CHOP plus rituximab or CHOP alone. At 5-year followup, rituximab and CHOP improved OS from 46% to 58% compared with CHOP alone. The results
of this study were further validated by other international randomized studies favoring the use of
rituximab and chemotherapy in elderly patients with aggressive B-cell lymphomas.
Similar results were observed in younger patients, where the combination of rituximab and
CHOP chemotherapy resulted in an improved survival. A large international study, the MabThera
International Trial (MINT) addressed the role of rituximab-chemotherapy in young patients with
aggressive B-cell lymphomas. The study, which has been presented only in an abstract form, was a
phase III trial in which 823 diffuse large B-cell, CD20+, non-Hodgkin lymphoma (DLBCL) patients
(ages 18-60 y) were randomized to receive either rituximab plus a standard anthracycline-containing
chemotherapy regimen (standard chemotherapy) or standard chemotherapy alone as induction
therapy. The rituximab plus standard chemotherapy regimens increased 2-year overall survival (OS)
from 86% to 95% compared with standard chemotherapy alone and resulted in significant
improvement in time to treatment failure and projected overall survival.
Ongoing research is being focused on identifying patients at risk for treatment failure and
developing tailored treatment for patients with aggressive lymphoma based on clinical scores (IPI
score) or gene profiles.
Patients at high risk of relapse (IPI intermediate or poor risk groups) might have an
improved 5-year event-free survival/overall survival from autologous and allogeneic bone marrow or
peripheral stem cell transplantation following chemotherapy.
CNS prophylaxis, usually with 4-6 injections of methotrexate intrathecally, is recommended
for patients with paranasal sinus or testicular involvement, diffuse small noncleaved cell or Burkitt
lymphoma, or lymphoblastic lymphoma. CNS prophylaxis for bone marrow involvement is
controversial.
25
PET scanning is more sensitive than CT scan or gallium scan for staging and response
assessment. Early PET negativity with 2-4 cycles correlates with durable remission and vice versa.
After remission is achieved, patients are monitored with CT scans every 6 months for the first 2-3
years, as most recurrences occur in the first 3 years.
Treatment of acute lymphoblastic lymphoma, a very aggressive form of NHL, is usually
patterned after acute lymphoblastic leukemia (ALL) therapy. Other subtypes of high-grade
lymphomas are usually treated with more aggressive variations of CHOP chemotherapy, including
the addition of high-dose methotrexate or other chemotherapy drugs and higher doses of
cyclophosphamide.
Indolent recurrent NHL
In general, treatment with standard agents rarely produces a cure in patients who have
relapsed. Sustained remissions after relapse can often be obtained in patients with indolent
lymphomas, but relapse usually ensues. Favorable survival after relapse has been associated with age
younger than 60 years, prior complete remission rather than partial remission, and duration of
response longer than 1 year. For relapse that remains low grade, the following are possible treatment
options:
 Single alkylating agents
 Combination chemotherapy - CVP, CHOP, and others
 Purine analogues - Fludarabine, 2-CDA
 Rituximab (results in a 40-50% RR in patients with relapsed/refractory indolent B-cell
lymphomas) in standard or extended schedules of administration.
 Radioimmunotherapy -131 I-rituximab radioimmunotherapy of relapsed or refractory
indolent NHL achieves high overall response rates and complete response rates with minimal
toxicity. Tositumomab (131 I murine IgG2a lambda monoclonal antibody directed against CD20
antigen). Ibritumomab (90 Y) also has been approved for use in relapsed indolent lymphoma. They
typically are used only in patients with less than 25% bone marrow involvement with lymphoma and
in patients refractory to rituximab.
 Local relapse can be treated with radiotherapy.
 High-dose chemotherapy plus stem cell transplantation is being investigated to determine
whether it can produce significantly better survival rates compared with conventional chemotherapy.
Aggressive recurrent adult NHL
High-dose chemotherapy plus stem-cell transplantation is the treatment of choice for patients
who have recurrent aggressive lymphomas. Preliminary studies indicate that approximately 20-40%
of patients have a long-term disease-free status, but the precise percentage depends on patient
selection and specific treatment used.
Second-line chemotherapy regimens such as ICE (ifosfamide, carboplatin, etoposide),
DHAP (dexamethasone, high-dose cytarabine, cisplatin), or EPOCH (etoposide, vincristine,
doxorubicin, cyclophosphamide, prednisone) are usually used with rituximab if CD20 positive.
Gemcitabine and Navelbine is also being attempted in these relapsed patients. Chemotherapy
is usually followed by stem-cell transplantation.
In the Parma trial, the patients with relapse who were randomized to autologous bone
marrow transplantation followed by involved-field radiation therapy did better than those
randomized to conventional chemotherapy and involved-field radiation therapy. After a 5-year
median follow-up study, the event-free survival (EFS) rate was significantly better with
transplantation (ie, 46% versus 12%), and the OS rate was also better (ie, 53% versus 32%). In
general, patients who respond to initial therapy and who respond to conventional salvage therapy
prior to bone marrow transplantation have better survival outcomes. Patients who relapse late (>12
mo after diagnosis) have better OS than patients who relapse earlier. Patients who are not candidates
26
for transplantation can be treated with chemotherapy with or without monoclonal antibodies. If
possible, these patients should be enrolled into clinical trials.
 Tumor vaccines are still being investigated for use in patients with lymphoma.
 Novel biological agents are currently under study in these settings.
Surgical Care
The role of surgery in the treatment of patients with NHL is limited. Surgery is useful in
selected situations (eg, GI lymphoma), particularly if the disease is localized or if risk of perforation,
obstruction, and massive bleeding is present. Orchiectomy is part of the initial management of
testicular lymphoma.
Consultations
 A hematologist-oncologist should treat patients with NHL.
 Consult a radiation oncologist for treatment of patients with localized or limited-stage lowgrade lymphoma and for palliative radiation therapy (eg, for treatment of SVC syndrome, treatment
of painful metastases [especially in the bones], as an adjunctive treatment for CNS lymphomas).
 Consult an infectious disease specialist for the management of patients with neutropenic
fever who are not responding to the usual broad-spectrum antibiotics.
 Surgical consultation is needed for lymph node biopsy, palliative procedures, or placement
of a venous access device (eg, Port-a-Cath, Hickman catheter) for blood drawing and chemotherapy
access.
Diet
 Usually, a regular diet is adequate, except when the patient is neutropenic. Patients with
neutropenia should not eat raw fruits or vegetables.
 Transplant patients who have severe mucositis, decreasing albumin levels, or both may be
administered total parenteral nutrition (TPN) until they can tolerate oral feedings.
Activity
The following restrictions apply to patients who are neutropenic, thrombocytopenic, or both:
 Avoid exposure to or contact with other patients with communicable or infectious diseases.
Ideally, patients with neutropenia should be admitted directly to a private room and should not stay
long in the emergency department for evaluation. All persons should wash hands before and after
examining these patients.
 Use a soft toothbrush during episodes of neutropenia and thrombocytopenia.
 Patients should not shave with a razor.
Medication
Multiple chemotherapeutic agents are active against non-Hodgkin lymphoma (NHL) and can
be used alone or in combination, depending on the histology and stage of the disease and whether
the patient can tolerate chemotherapy. Also, several biological therapies are currently available for
these patients, including interferons, rituximab, and radiolabeled antibodies (the newest biological
therapy).
Alkylating agents impair cell function by forming covalent bonds with DNA, ribonucleic
acid (RNA), and proteins. These agents are not cell cycle phase–specific and are used for
hematologic and nonhematologic malignancies.
Anthracycline antibiotics bind to nucleic acids by intercalation with base pairs of the DNA
double helix, interfering with the DNA synthesis. They cause inhibition of DNA topoisomerases I
and II.
Vinca alkaloids inhibit microtubule assembly, causing metaphase arrest in dividing cells.
Vinca alkaloids are also cell cycle phase–specific at the M and S phase.
Glucocorticoids cause lysis of lymphoid cells, which led to their use against ALL, multiple
myeloma, and NHL. These agents are also used as adjunctive antiemetic agents, to decrease
27
vasogenic edema associated with tumors, and as prophylactic medication to prevent hypersensitivity
reactions associated with some chemotherapeutic drugs.
Antimetabolites cause tumor cell death by inhibiting enzymes that are important in DNA
synthesis.
Biological response modulators control the response of the patient's immune system to tumor
cells, infecting organisms, or both.
Follow-up
Further Inpatient Care
 Further inpatient care depends on the patient's active problem, tumor type and stage, and
overall prognosis.
 Admit patients with non-Hodgkin lymphoma (NHL) for complications of disease
progression (eg, pain control for intractable pain) or adverse effects from chemotherapy (eg,
neutropenic fever, dehydration secondary to diarrhea, vomiting requiring IV hydration, severe
mucositis).
 Admit patients for infusional chemotherapy or high-dose chemotherapy followed by stem
cell transplantation.
Further Outpatient Care
 Treatment and follow-up care of patients with NHL are usually performed on an outpatient
basis.
 Monitoring the patient's blood cell count while receiving chemotherapy (eg, prior to each
treatment cycle and 10-14 d after each treatment cycle) is important.
 Monitor adverse effects of chemotherapy with a detailed patient history, an examination, a
CBC count, and chemistries (especially LFTs, electrolytes, LDH, BUN/creatinine).
 Treat symptomatic adverse effects such as nausea, vomiting, diarrhea, mucositis, anorexia,
pain, and fatigue.
 Administer packed red blood cell (PRBC) transfusions for patients with symptomatic
anemia and provide platelet transfusions for patients with a platelet count less than 10-20 k/CU mm.
 Provide growth factor (eg, granulocyte colony-stimulating factor [GCSF], granulocytemacrophage colony-stimulating factor [GM-CSF], erythropoietin) support as necessary.
 Perform a disease and response to treatment evaluation by obtaining patient history,
physical examination (at intervals q2-3mo), and imaging studies (eg, CT scans at intervals q412mo).
 Provide psychosocial support for the patient and family.
Inpatient & Outpatient Medications
 Most of the chemotherapy, whether combination chemotherapy (eg, CHOP) or single-drug
(eg, fludarabine) therapy, can be administered in an outpatient setting in the infusion clinic. In the
infusion clinic, specially trained oncology nurses, who are supervised by oncologists, administer the
chemotherapy.
 Growth factor support (eg, GCSF, GM-CSF, erythropoietin) is administered in an
outpatient treatment setting.
 Infusional chemotherapy (eg, infusional cyclophosphamide, doxorubicin, and etoposide
[CDE], which should be administered continuously for 4 d) should be administered as inpatient
treatment.
 For the initial treatment of patients with intermediate- or high-grade lymphoma and
patients with bulky disease, an inpatient setting is recommended in order to monitor for tumor lysis
syndrome and to manage appropriately.
 Patients with fever during neutropenia should be admitted for broad-spectrum antibiotic
therapy.
28
 High-dose chemotherapy and bone marrow and/or stem cell transplant treatment are
administered in an inpatient setting of a transplant-approved center.
Transfer
Patients with NHLs who are being treated in community hospitals and need high-dose
chemotherapy with stem-cell support should be transferred to tertiary hospitals with approved
transplant centers.
Deterrence/Prevention
Currently, no proven prevention techniques are known for NHL. Avoiding long-term
immunosuppression and other possible causes of NHLs possibly may help.
Complications
 Disease-related complications
o Cytopenias (ie, neutropenia, anemia, thrombocytopenia) secondary to bone marrow
infiltration: Anemia could also be secondary to autoimmune hemolytic anemia, which is observed in
some types of NHL (eg, SLL/CLL).
o Bleeding secondary to thrombocytopenia, disseminated intravascular coagulation (DIC), or
vascular invasion by the tumor
o Infection secondary to leukopenia, especially neutropenia
o Cardiac problems secondary to large pericardial effusion or arrhythmias secondary to
cardiac metastases
o Respiratory problems secondary to pleural effusion and/or parenchymal lesions
o SVC syndrome secondary to a large mediastinal tumor
o Spinal cord compression secondary to vertebral metastases
o Neurologic problems secondary to primary CNS lymphoma or lymphomatous meningitis
o GI obstruction, perforation, and bleeding in a patient with GI lymphoma (may also be
caused by chemotherapy)
o Pain secondary to tumor invasion
o Leukocytosis (lymphocytosis) in leukemic phase of disease
 Chemotherapy and other treatment-related complications
o Cytopenias (ie, neutropenia, anemia, thrombocytopenia)
o Nausea or vomiting
o Infection
o Fatigue
o Neuropathy
o Dehydration after diarrhea or vomiting
o Cardiac toxicity from doxorubicin
o Catheter-related sepsis
o Catheter-related thrombosis
o Secondary malignancies
o Tumor lysis syndrome: Characterized by hyperuricemia, hyperkalemia,
hyperphosphatemia, hypocalcemia, and renal failure, this syndrome commonly occurs after
treatment of high-grade bulky NHLs because of their exquisite sensitivity to therapy, which is
caused by their high proliferative capacity. Death from cardiac asystole can occur from
hyperkalemia. Measures to prevent this complication include aggressive hydration, allopurinol
administration, and urine alkalinization. Frequent monitoring of input and output, electrolytes, uric
acid, and creatinine is necessary. Dialysis is sometimes required.
o Atherosclerosis: In a 3-year study, Bilora et al found evidence that patients receiving
radiotherapy and chemotherapy for either Hodgkin or non-Hodgkin lymphoma are predisposed to
early development of atherosclerosis.12 In 96 patients, the investigators found increased thickness of
the intima media at 1-year follow-up and decreased thickness at 3-year follow-up. Even with this
29
change, over the course of the follow-up, however, the reduction in flow-mediated
dilatation measured in the patients at 1 year had not improved by the second examination.12
Prognosis
 Patient's response to treatment and prognosis depends on tumor histology (based on
Working Formulation classification), tumor stage, patient's age, tumor bulk, performance status,
serum LDH, beta2-microglobulin, and presence of extranodal disease. In general, these clinical
characteristics are thought to reflect the following host or tumor characteristics:
o Tumor growth and invasive potential (eg, LDH, stage, tumor size, beta2-microglobulin,
number of nodal and extranodal sites, bone marrow involvement)
o Patient's response to tumor (eg, performance status, B symptoms)
o Patient's tolerance of intensive therapy (eg, performance status, patient age, bone marrow
involvement)
 Prognostic score for aggressive lymphomas: The International Prognostic Index (IPI),
which was originally designed as a prognostic factor model for aggressive NHL, also appears to be
useful for predicting the outcome of patients with low-grade lymphoma and mantle cell lymphoma.
This index is also used to identify patients at high risk of relapse based on specific sites of
involvement, including bone marrow, CNS, liver, testis, lung, and spleen. These patients may be
considered for clinical trials that aim at improving the current treatment standard. An age-adjusted
model for patients younger than 60 years has been proposed. In younger patients, stage III or IV,
high LDH levels and nonambulatory performance status are independently associated with decreased
survival rates. Clinical features included in the IPI that are independently predictive of survival
include the following:
o Age - Younger than 60 years versus older than 60 years
o LDH level - Within the reference range versus elevated
o Performance status - ECOG 0-1 versus 2-4
o Ann Arbor stage - Stage I-II versus III-IV
o Number of extranodal sites - 0-1 versus more than 1
o Patients with 0-1, 2-3, and 4-5 risk factors have 75%, 50%, and 25% chance, respectively,
of having a relapse-free and OS at 5 years.
 Prognostic score for follicular lymphomas: The FLIPI score was created by a collection of
characteristics at diagnosis from 4167 patients with follicular lymphoma (FL) diagnosed between
1985 and 1992 from Solal-C é ligny et al.13 Univariate and multivariate analyses were used to
propose the prognostic index (PI). This index was then tested on 919 patients. Five adverse
prognostic factors were selected: age (>60 y), Ann Arbor stage (III-IV), hemoglobin level (<12
g/dL), number of nodal areas (>4) and serum LDH level (above normal). Three risk groups were
defined: low risk (0-1 adverse factor), intermediate risk (2 factors), and poor risk (3 or more adverse
factors). FLIPI appeared more discriminant than the International Prognostic Index. FLIPI may be
used for improving treatment choices, comparing clinical trials, and designing studies to evaluate
new treatments.
 Biomarkers in tumor cells such as the expression of bcl- 2 or bcl- 6 proteins, and cDNA
microarray provide useful prognostic information.
 Concomitant immunodeficiencies: Patients with congenital or acquired immunodeficiency
have an increased risk of lymphoma and respond poorly to therapy.
 Other prognostic factors
o Time to achieve CR and response duration: Patients who do not achieve complete
remission by the third cycle of CHOP chemotherapy have a worse prognosis than those who achieve
rapid CR.
o Immunophenotype: Patients with aggressive T- or NK-cell lymphomas generally have
worse prognoses than those with B-cell lymphomas, except the Ki-1 anaplastic large T- or null-cell
lymphomas.
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o Cytogenetic abnormalities and oncogene expression: Patients with lymphomas with 1, 7,
and 17 chromosomal abnormalities have worse prognoses than those with lymphomas without these
changes.
 Low-grade lymphomas have indolent clinical behavior, are associated with a
comparatively prolonged survival rate (median survival is 6-10 y), but have little potential for cure
when the disease manifests in more advanced stages. They also have the tendency to transform to
high-grade lymphomas.
 Approximately 70% of all patients with intermediate- and high-grade NHL relapse or
never respond to initial therapy. Most recurrences are within the first 2 years after therapy
completion.
 Patients with relapsed or resistant NHL have a very poor prognosis (<5-10% are alive at 2
y with conventional salvage chemotherapy regimens).
Miscellaneous
Medicolegal Pitfalls
 Ensure that the patient has a correct diagnosis before administering treatment. NonHodgkin lymphoma (NHL) should be distinguished from reactive lymph node hyperplasia, which
only requires careful follow-up and supportive care and does not require chemotherapy, radiation
therapy, or both.
 Determine the stage and specific subtype of NHL, ie, whether it is low-, intermediate-, or
high-grade, because the type of treatment strongly depends on these 2 important parameters.
 NHL should also be distinguished from Hodgkin disease because the treatment strategy is
different in these 2 neoplastic lymph node diseases.
 If NHL diagnosis is doubtful, acquire a second or third opinion from an expert
hematopathologist before instituting therapy. Flow cytometry and cytogenetics should also be
performed and can be especially helpful in difficult situations.
 Ensure that patients understand their diagnosis, treatment options, prognosis, and
complications of therapy, which, in rare occasions, may result in a fatal event (eg, death secondary
to severe infection in a patient with severe neutropenia who is unresponsive to antimicrobial
therapy). Start the treatment only after the patient has signed an informed consent form.
Special Concerns
 Pediatric patients with NHL are best treated by pediatric oncologists.
 Pregnancy
o NHL during pregnancy is uncommon; however, if diagnosed, this presents an ethical
dilemma. Remission may be obtained with chemotherapy, but chemotherapy has potentially harmful
effects to the fetus. Consider fetus exposure to transplacental chemotherapy when evaluating therapy
options and carefully evaluate the timing of delivery.
o For patients diagnosed with NHL during the second or third trimester of pregnancy, few
literature reports suggest that they can be treated with chemotherapy without significant toxicity to
the fetus. If possible, alkylating agents should be avoided. If the fetus can be delivered safely prior to
administration of chemotherapy and a short wait will not affect the treatment outcome and prognosis
of the patient, starting the treatment after the birth of the baby is better.
o If the patient has high-grade NHL (eg, Burkitt or lymphoblastic lymphoma) diagnosed
during the first trimester of pregnancy, immediate therapy institution is necessary; otherwise, the
condition could be fatal. Discuss at length with the patient and family that chemotherapy treatment
at this period of pregnancy is very risky for the fetus, and whether therapeutic termination of
pregnancy should be performed before the patient is treated should be decided. Consultation with the
ethical committee of the hospital should be obtained in these very difficult situations.
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