HODGKIN

High-dose chemotherapy at doses that ablate the bone marrow is feasible with reinfusion of the
patient's previously collected hematopoietic stem cells or infusion of stem cells from a donor
source. 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). [7]

Toxicities associated with treatment regimens include the following:

 Hematologic toxicity: Anemia (need for transfusion), thrombocytopenia, increased risk of
infection (febrile neutropenia); myelodyplasia or acute leukemia
 Pulmonary toxicity, particularly if bleomycin or thoracic radiation are used; increased risk
of lung cancer or fibrotic lung disease, particularly in smokers
 Cardiac toxicity from anthracycline therapy; congestive heart failure from treatment;
increased risk of coronary artery disease
 Infectious: Long-term increased risk of infection from splenectomy (rarely done in current
practice), long-term immunodeficiency from treatment effects
 Cancer: Increased risk of secondary cancers, particularly breast cancer in young women
treated with mediastinal radiation; increased risk of sarcomas in radiation fields
 Neurologic: Chemotherapy-induced neuropathy, muscular atrophy
 Psychiatric: Depression and anxiety related to diagnosis and complications from treatment

https://emedicine.medscape.com/article/222040-clinical
https://www.webmd.com/a-to-z-guides/epstein-barr-virus#1
https://www.alodokter.com/mononukleosis
NON
https://emedicine.medscape.com/article/203399-overview#a1
ractice Essentials
Non-Hodgkin lymphomas (NHLs) are tumors originating from lymphoid tissues, mainly of
lymph nodes. These tumors may result from chromosomal translocations, infections,
environmental factors, immunodeficiency states, and chronic inflammation. See the image
below.
This 28-year-old man was being evaluated for fever of unknown origin. Gallium-67 study shows
extensive uptake in the mediastinal lymph nodes due to non-Hodgkin lymphoma (NHL).
View Media Gallery
Signs and symptoms
The clinical manifestations of NHL vary with such factors 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.
Signs and symptoms of low-grade lymphomas include the following:
  Peripheral adenopathy: Painless and slowly progressive; can spontaneously regress
 Primary extranodal involvement and B symptoms: Uncommon at presentation; however,
common with advanced, malignant transformation or end-stage disease
 Bone marrow: Frequent involvement; may be associated with cytopenias(s) [1] ;
fatigue/weakness more common in advanced-stage disease
Intermediate- and high-grade lymphomas have a more varied clinical presentation, including the
following:
 Adenopathy: Most patients
 Extranodal involvement: More than one third of patients; most common sites are GI/GU
tracts (including Waldeyer ring), skin, bone marrow, sinuses, thyroid, CNS
 B symptoms: Temperature >38°C, night sweats, weight loss >10% from baseline within 6
months; in approximately 30-40% of patients
See Clinical Presentation for more detail.
Diagnosis
Examination in patients with low-grade lymphomas may demonstrate peripheral adenopathy,
splenomegaly, and hepatomegaly.
Intermediate- and high-grade lymphomas may result in the following examination findings:
 Rapidly growing and bulky lymphadenopathy
 Splenomegaly
 Hepatomegaly
 Large abdominal mass: Usually in Burkitt lymphoma
 Testicular mass
 Skin lesions: Associated with cutaneous T-cell lymphoma (mycosis fungoides), anaplastic
large-cell lymphoma, and angioimmunoblastic lymphoma [2]
Testing
Laboratory studies in a patient with suspected NHL should include the following:
 CBC count: May be normal in early-stage disease; in more advanced stages, may
demonstrate anemia, thrombocytopenia/leukopenia/pancytopenia, lymphocytosis,
thrombocytosis
 Serum chemistry studies: May show elevated LDH and calcium levels, abnormal liver
function tests
 Serum beta2-microglobulin level: May be elevated
 HIV serology: Especially in patients with diffuse large cell immunoblastic or small
noncleaved histologies
 Human T-cell lymphotropic virus-1 serology: For patients with adult T-cell
leukemia/lymphoma
 Hepatitis B testing: In patients in whom rituximab therapy is planned because reactivation
has been reported
Other tests that may be helpful in evaluating suspected NHL include the following:
 Immunophenotypic analysis of lymph node, bone marrow, peripheral blood
 Cytogenetic studies: NHL occasionally associated with monoclonal gammopathy; possible
positive Coombs test; maybe hypogammaglobulinemia
Imaging tests
The following imaging studies should be obtained in a patient suspected of having NHL:
 Chest radiography
  Upper GI series with small bowel follow-through: In patients with head and neck
involvement and those with a GI primary lesion
 CT scanning of the neck, chest, abdomen, and pelvis
 PET scanning
 Bone scanning: Only in patients with bone pain, elevated alkaline phosphatase, or both
 Testicular ultrasonography: For opposite testis in male patients with a testicular primary
lesion
 Multiple gated acquisition (MUGA) scanning: For patients being considered for treatment
with anthracyclines
 MRI of brain/spinal cord: For suspected primary CNS lymphoma, lymphomatous
meningitis, paraspinal lymphoma, or vertebral body involvement by lymphoma
Procedures
The diagnosis of NHL relies on pathologic confirmation following appropriate tissue biopsy. The
following are procedures in cases of suspected NHL:
 Bone marrow aspiration and biopsy: For staging rather than diagnostic purposes
 Excisional lymph node biopsy (extranodal biopsy): For lymphoma protocol studies
Perform lumbar puncture for CSF analysis in patients with the following conditions:
 Diffuse aggressive NHL with bone marrow, epidural, testicular, paranasal sinus, or
nasopharyngeal involvement, or 2 or more extranodal sites of disease
 High-grade lymphoblastic lymphoma
 High-grade small noncleaved cell lymphomas
 HIV-related lymphoma
 Primary CNS lymphoma
 Neurologic signs and symptoms
See Workup for more detail.
Management
The treatment of NHL varies greatly, depending on various factors. Common therapies include
the following:
Chemotherapy: Most common; usually combination regimens
 Radiation therapy
 Rituximab administration
 Bone marrow transplantation: Possible role in relapsed high-risk disease
 Radioimmunotherapy
 Transfusions of blood products
 Antibiotics
Pharmacotherapy
Medications used in the management of NHL include the following:
 Cytotoxic agents (eg, chlorambucil, cyclophosphamide, doxorubicin, vincristine,
fludarabine, pralatrexate, nelarabine, etoposide, mitoxantrone, cytarabine, bendamustine,
carboplatin, cisplatin, gemcitabine, denileukin diftitox, bleomycin)
 Histone deacetylase inhibitors (eg, vorinostat, romidepsin, belinostat)
 Colony-stimulating factor growth factors (eg, epoetin alfa, darbepoetin alfa, filgrastim,
pegfilgrastim)
 Monoclonal antibodies (eg, rituximab, ibritumomab tiuxetan, tositumomab and I131,
alemtuzumab, ofatumumab, obinutuzumab)
  mTOR (mammalian target of rapamycin) kinase inhibitors (eg, temsirolimus)
 Proteasome inhibitors (eg, bortezomib)
 Immunomodulators (eg, interferon alfa-2a or alfa-2b)
 Corticosteroids (eg, dexamethasone, prednisone)
Surgery
Surgical intervention in NHL is limited but can be useful in selected situations (eg, GI
lymphoma), particularly in localized disease or in the presence of risk of perforation, obstruction,
and massive bleeding. Orchiectomy is part of the initial management of testicular lymphoma.
See Treatment and Medication for more detail.
Background
The term lymphoma describes a heterogeneous group of malignancies with different biology and
prognosis. In general, lymphomas are divided into 2 large groups of neoplasms, namely non-
Hodgkin lymphoma (NHL) and Hodgkin disease. About 85% of all malignant lymphomas are
NHLs. The median age at diagnosis is the sixth decade of life, although 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. With
respect to prognosis, NHLs can be divided into two groups, indolent and aggressive. [3]
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 natural killer (NK)–cell origin.
A study by Shustik et al found that within the WHO classification, the subdivisions of grade 3A
and 3B had no difference in outcome or curability with anthracycline-based therapy. [4]
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.
Although a variety of laboratory and imaging studies are used in the evaluation and staging of
suspected NHL (see Workup), a well-processed hematoxylin and eosin (H&E)–stained section of
an excised lymph node is the mainstay of pathologic diagnosis. The treatment of non-Hodgkin
lymphoma (NHL) varies greatly, depending on tumor stage, grade, and type and various patient
factors (eg, symptoms, age, performance status; see Treatment and Management).
For discussion of individual subtypes of NHL, see the following:
 Anaplastic Large Cell Lymphoma
 Follicular Lymphoma
 B Cell Lymphoma
 Diffuse Large Cell Lymphoma
 Diffuse Mixed Lymphoma
 Lymphoblastic Lymphoma
 Mantle Cell Lymphoma
 Mycosis Fungoides
 Primary CNS Lymphoma
  Cutaneous T-Cell Lymphoma
Pathophysiology
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 NK cells arising from
an accumulation of lesions affecting 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.
Almost 85% of NHLs are of B-cell origin; 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 high-grade aggressiveness. However, some subtypes of high-grade lymphomas are
characterized by small cell morphology.
Etiology
NHLs may result from chromosomal translocations, infections, environmental factors,
immunodeficiency states, and chronic inflammation.
Chromosomal translocations
Chromosomal translocations and molecular rearrangements play an important role in the
pathogenesis of many lymphomas and correlate with histology and immunophenotype.
The t(14;18)(q32;q21) translocation is the most common chromosomal abnormality associated
with NHL. This translocation occurs in 85% of follicular lymphomas and 28% of higher-grade
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.
The t(11;14)(q13;q32 translocation has a diagnostic nonrandom association with mantle cell
lymphoma. This translocation results in the overexpression of bcl -1 (cyclin D1/PRAD 1), a cell-
cycle regulator on chromosome band 11q13.
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.
The t(2;5)(p23;q35) translocation occurs between the nucleophosmin (NPM) gene and the
anaplastic lymphoma kinase (ALK1) gene. It results in the expression of an aberrant fusion
protein found in a majority of anaplastic large cell lymphomas.
Two chromosomal translocations, t(11;18)(q21;q21) and t(1;14)(p22;132), 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 MALT1gene, resulting
in 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.
Infection
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 B-
or T-cell stimulation, proliferation, and lymphomagenesis. 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, [5] organ
transplantation), and sinonasal lymphoma.
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.
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.
Kaposi sarcoma–associated herpesvirus (KSHV) is associated with body cavity–based
lymphomas in patients with HIV infection and in patients with multicentric Castleman disease.
Helicobacter pylori infection is associated with the development of primary gastrointestinal (GI)
lymphomas, particularly gastric mucosa-associated lymphoid tissue (MALT) lymphomas.
Environmental factors
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. A study by Antonopoulos et al found that maternal smoking during
pregnancy may have a modest increase in the risk for childhood NHL but not HL. [6]
Immunodeficiency states
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.
Celiac disease has been associated with an increased risk of malignant lymphomas. The risk of
lymphoproliferative malignancy in individuals with celiac disease depends on small intestinal
histopathology; no increased risk is observed in those with latent celiac disease. [7]
Chronic inflammation
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 is a preexisting condition
in 23-56% of patients with primary thyroid lymphomas.
Epidemiology
The American Cancer Society estimated that approximately 72,240 new cases of NHL will be
diagnosed in 2017. [8] Since the early 1970s, the incidence rates of NHL have nearly doubled.
Although some of this increase may be attributable to earlier detection (resulting from improved
diagnostic techniques and access to medical care), or possibly to HIV-associated lymphomas, for
the most part the rise is unexplained.
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. [9]
Overall, NHL is most often diagnosed in people aged 65-74; median age at diagnosis is 67
years. [9] The exceptions are 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.
Prognosis
The 5-year relative survival rate of patients with NHL is 71%. [9] The survival rate has steadily
improved over the last 2 decades, thanks to improvements in medical and nursing care, the
advent of novel therapeutic strategies (ie, monoclonal antibodies), validation of biomarkers of
response, and the implementation of tailored treatment.
The prognosis for patients with NHL depends on the following factors:
 Tumor histology (based on Working Formulation classification)
 Tumor stage
 Patient age
 Tumor bulk
 Performance status
 Serum lactate dehydrogenase (LDH) level
 Beta2-microglobulin level
 Presence or absence of extranodal disease
In general, these clinical characteristics are thought to reflect the following host or tumor
characteristics:
 Tumor growth and invasive potential (eg, LDH, stage, tumor size, beta2-microglobulin
level, number of nodal and extranodal sites, bone marrow involvement)
 Patient's response to tumor (eg, performance status, B symptoms)
 Patient's tolerance of intensive therapy (eg, performance status, patient age, bone marrow
involvement)
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 disease, high LDH levels, and nonambulatory performance status are
independently associated with decreased survival rates.
Pediatric and adolescent patients have better outcome than adults with CNS lymphoma. [10] An
ECOG performance status score of 0-1 is associated with improved survival. Higher dose
methotrexate is associated with slightly better response.
Clinical features included in the IPI that are independently predictive of survival include the
following:
 Age - Younger than 60 years versus older than 60 years
 LDH level - Within the reference range versus elevated
 Performance status - Eastern Cooperative Oncology Group ( ECOG) grade 0-1 versus 2-4
 Ann Arbor stage - Stage I-II versus III-IV
 Number of extranodal sites - Zero to 1 versus more than 1
With this model, relapse-free and overall survival rates at 5 years are as follows:
 0-1 risk factors - 75%
 2-3 risk factors - 50%
 4-5 risk factors - 25%
For patients with follicular lymphoma—the second most common subtype of NHL—the
Follicular Lymphoma International Prognostic Index (FLIPI) score appears to be more
discriminating than the IPI. [11] The FLIPI score is calculated on the basis of 5 adverse prognostic
factors, as follows:
 Age (>60 y)
 Ann Arbor stage (III-IV)
 Hemoglobin level (< 12 g/dL)
 Number of nodal areas (>4)
 Serum LDH level (above normal)
Three risk groups are defined: low risk (0-1 adverse factor), intermediate risk (2 factors), and
poor risk (3 or more adverse factors).
Biomarkers in tumor cells such as the expression of bcl- 2 or bcl- 6 proteins and cDNA
microarray provide useful prognostic information.
Patients with congenital or acquired immunodeficiency have an increased risk of lymphoma and
respond poorly to therapy.
Time to achieve complete remission (CR) and response duration has prognostic significance.
Patients who do not achieve CR by the third cycle of chemotherapy have a worse prognosis than
those who achieve rapid CR.
Immunophenotype is also a factor. 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.
Cytogenetic abnormalities and oncogene expression affect prognosis. 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 and are associated with a comparatively
prolonged survival (median survival is 6-10 y), but they 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 years
with conventional salvage chemotherapy regimens).
Drake et al found that low levels of vitamin D were associated with a decrease in clinical end
points (event-free survival and overall survival) in subsets of patients with aggressive B-cell
lymphoma (ie, diffuse large B-cell lymphoma or T-cell lymphoma). [12] Although the results of
this study suggest an association between vitamin D levels and its metabolism with the biology
of some aggressive lymphomas, further studies are needed before conclusions can be drawn.
A study by Change et al also found a protective effect associated with vitamin D and also
concluded that routine residential UV radiation exposure may have a protective effect against
lymphomagenesis through mechanisms possibly independent of vitamin D. [13]
Survivors of NHL are at risk for development of a second primary malignancy. A review of
Surveillance, Epidemiology, and End Results data from 1992-2008 found hazard ratios for a
second cancer to be 2.70 for men and 2.88 for women. [14]
Patient Education
Patients should receive a clear and detailed explanation of all the available treatment options,
prognosis, and adverse effects of chemotherapy. Advise patients to call their oncologists as
necessary and educate patients about oncologic emergencies that require an immediate
emergency department visit. Suggest psychosocial counseling.
For patient education information, see the Blood and Lymphatic System Center, as well
as Lymphoma.