Non-Hodgkin Lymphoma Guidelines
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Non-Hodgkin lymphoma (NHL) represents a heterogeneous group of malignancies of different biology and prognosis. NHL includes many subtypes, each with distinct epidemiologies; etiologies; morphologic, immunophenotypic, genetic, and clinical features; and responses to therapy.
The National Comprehensive Cancer Network (NCCN) guidelines for NHL provide general recommendations on classification, differential diagnosis and supportive care, as well as specific guidance for the management of the most common subtypes. [30, 31]
The European Society for Medical Oncology (ESMO) has published separate guidelines for the management and treatment of the following subtypes:
Follicular lymphoma
Mantle cell lymphoma
Diffuse large B cell lymphoma
Primary cutaneous lymphoma
Gastric marginal zone lymphoma of the mucosa-associated lymphatic tissue (MALT) type
The three most commonly used classification schemas for non-Hodgkin lymphoma (NHL) are as follows:
National Cancer Institute’s Working Formulation (IWF) [2]
Revised European-American Classification of Lymphoid Neoplasms (REAL) [3]
World Health Organization (WHO) classification [4, 32]
The Working Formulation, originally proposed in 1982, classified and grouped lymphomas by morphology and clinical behavior (ie, low, intermediate, or high grade) with 10 subgroups labeled A to J. [1] In 1994, the Revised European-American Lymphoma (REAL) classification attempted to apply immunophenotypic and genetic features in identifying distinct clinicopathologic NHL entities. [3]
The World Health Organization (WHO) classification, first introduced in 2001 and updated in 2008 and 2016, further elaborates upon the REAL approach. This classification divides NHL into two groups: those of B-cell origin and those of T-cell/natural killer (NK)–cell origin. [4]
National Cancer Institute’s Working Formulation (IWF)
Although considered obsolete, the IWF classification is still used, mainly for historical data comparisons. [2]
Low-grade NHL subtypes in the IWF classification are as follows:
Small lymphocytic, consistent with chronic lymphocytic leukemia
Follicular, predominantly small-cleaved cell
Follicular, mixed small-cleaved, and large cell
Intermediate-grade NHL subtypes in the IWF classification are as follows:
D. Follicular, predominantly large cell
E. Diffuse, small-cleaved cell
F. Diffuse mixed, small and large cell
G. Diffuse, large cell, cleaved, or noncleaved cell
High-grade NHL subtypes in the IWF classification are as follows:
H. Immunoblastic, large cell
I. Lymphoblastic, convoluted, or nonconvoluted cell
J. Small noncleaved-cell, Burkitt, or non-Burkitt
World Health Organization classification
The WHO modification of the REAL classification of NHL is based on morphology and cell lineage. Within the B-cell and T-cell categories, two subdivisions are recognized: precursor neoplasms, which correspond to the earliest stages of differentiation, and more mature differentiated neoplasms. [4]
The WHO classification subtypes for NHL precursors are as follows:
Precursor B–lymphoblastic leukemia/lymphoma
Precursor T–lymphoblastic lymphoma/leukemia
The WHO classification subtypes for peripheral B-cell neoplasms are as follows:
B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma
B-cell prolymphocytic leukemia
Lymphoplasmacytic lymphoma/immunocytoma
Mantle cell lymphoma
Follicular lymphoma
Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphatic tissue (MALT) type
Nodal marginal zone B-cell lymphoma (± monocytoid B cells)
Splenic marginal zone lymphoma (± villous lymphocytes)
Hairy cell leukemia
Plasmacytoma/plasma cell myeloma
Diffuse large B-cell lymphoma (DLBCL)
Burkitt lymphoma
The WHO classification subtypes for peripheral T-cell and NK-cell neoplasms are as follows:
T-cell chronic lymphocytic leukemia/prolymphocytic leukemia
T-cell granular lymphocytic leukemia
Mycosis fungoides/Sézary syndrome
Peripheral T-cell lymphoma, not otherwise characterized
Hepatosplenic gamma/delta T-cell lymphoma
Subcutaneous panniculitis-like T-cell lymphoma
Angioimmunoblastic T-cell lymphoma
Extranodal T-/NK-cell lymphoma, nasal type
Enteropathy-type intestinal T-cell lymphoma
Adult T-cell lymphoma/leukemia (human T-lymphotrophic virus [HTLV] 1+)
Anaplastic large cell lymphoma, primary systemic type
Anaplastic large cell lymphoma, primary cutaneous type
Aggressive NK-cell leukemia
The National Comprehensive Cancer Network (NCCN) recommendations for the diagnostic evaluation of non-Hodgkin lymphomas are as follows [30, 31] :
Excisional or incisional biopsy is required
Fine needle aspiration (FNA) biopsy alone is not generally suitable for the initial diagnosis of lymphoma
A core needle biopsy is not optimal but can be used under certain circumstances
In certain circumstances, when a lymph node is not easily accessible for excisional or incisional biopsy, a combination of core biopsy and FNA biopsies in conjunction with appropriate ancillary techniques for the differential diagnosis (immunohistochemistry, flow cytometry, PCR for IGHV and TCR gene rearrangements, karyotype, and fluorescence in situ hybridization [FISH] for major translocations) may be sufficient for diagnosis.
• Histologic grading cannot be performed on an FNA.
• Hematopathology review of all slides with at least one paraffin block representative of the tumor should be performed
Rebiopsy if consult material is nondiagnostic
The NCCN guidelines list the following immunophenotype studies as essential for diagnosis of non-Hodgkin lymphoma:
In 2014, the International Conference on Malignant Lymphomas (a multidisciplinary team of researchers representing major lymphoma clinical trial groups and cancer centers from North America, Europe, Japan, and Australasia) published guidelines for the evaluation, staging, and response assessment of patients with malignant lymphomas. This staging system is known as the Lugano Modification of the Ann Arbor staging system. [5] In 2015, the National Comprehensive Cancer Network (NCCN) adopted this system. [30, 31] The revised recommendations for staging include the following [5] :
Positron emission tomography–computed tomography (PET-CT) is preferred for fluorodeoxyglucose (FDG)-avid lymphomas; CT is indicated for non-avid lymphomas
PET-CT is preferred for pretreatment assessment and routine staging
Contrast-enhanced CT is more accurate for measurement of nodal size and is also preferred for radiation planning
PET-CT is preferred for determining splenic involvement, with cutoff for splenomegaly of more than 13 cm
Bone marrow biopsy is usually not required if the PET-CT scan indicates bone or marrow involvement but if the scan is negative, a bone marrow biopsy is indicated to identify involvement by discordant histology, if clinically relevant
Liver size is not a reliable measure; liver involvement is suggested by diffusely increased or focal uptake, with or without focal or disseminated nodules
Prior Ann Arbor staging divided patients according to absence (A) or presence (B) of disease-related symptoms (B symptoms include weight loss >10%, fever, drenching night sweats); these are not required in NHL staging since they are not prognostic
In addition, these guidelines offered consensus on further modifications to the Ann Arbor staging classification, as shown in Table 1, below [5, 30, 31] :
Table 1. Non-Hodgkin lymphoma staging. (Open Table in a new window)
Stage
Area of Involvement
Extranodal (E) Status
I
Single node or adjacent group of nodes
Single extranodal lesions without nodal involvement
II
Multiple lymph node groups on same side of diaphragm
Stage I or II by nodal extent with limited contiguous extranodal involvement
II bulky*
Multiple lymph node groups on same side of diaphragm with “bulky disease”
N/A
III
Multiple lymph node groups on both sides of diaphragm; nodes above the diaphragm with spleen involvement
N/A
IV
Multiple noncontiguous extranodal sites
N/A
*Stage II bulky disease is considered limited or advanced; this distinction is made on the basis of histology and a number of prognostic factors.
Suffixes A and B are not required. X for bulky disease replaced with documenting of largest tumor diameter. Definition of “bulky” disease varies, depending on lymphoma histology.
The International Prognostic Index (IPI), which was originally designed as a prognostic factor model for aggressive non-Hodgkin lymphoma, also appears to be useful for predicting the outcome of patients with low-grade lymphoma. This index is also used to identify patients at high risk of relapse, based on specific sites of involvement, including bone marrow, central nervous system, liver, testis, lung, and spleen. [6] Separate indices have been developed for follicular and mantle cell lymphoma. [7, 8, 9]
The IPI includes the following risk factors [6] :
Each factor is worth 1 point. Based on the IPI score, patients can be categorized as follows [6] :
Low risk (0-1 point)
Low-intermediate risk (2 points)
High-intermediate risk (3 points)
High risk (4-5 points)
With this model, relapse-free and overall survival rates at 5 years are as follows:
In 2001, the WHO classification called for grading of follicular lymphoma (FL) from grades 1-3 based on the number of centroblasts per high-power field (hpf). However, the 2008 update consolidated cases with few centroblasts as FL grade 1-2 (low grade) and divided FL grade 3 into 3A (presence) and 3B (absence) of centrocytes. National Comprehensive Cancer Network (NCCN) 2015 guidelines suggest that grade 3B should be treated as diffuse large B-cell lymphoma (DLBCL), whereas 3A can be treated as either FL or DLBCL. [4, 10]
Prior to 2008, primary cutaneous follicle center lymphoma (PCFCL) was classified as a variant of FL. In the 2008 update, its classification was changed to that of a distinct entity. PCFCL may contain a high proportion of large B cells, including large centrocytes and centroblasts. Dissemination beyond the skin is rare.
In addition to its general guidance on diagnosis of lymphoma, the NCCN recommends the following studies to establish a diagnosis of FL [30] :
Immunohistochemistry panel: CD20, CD3, CD5, CD10, BCL2, BCL6, cyclin D1, CD21, or CD23
Cell surface marker analysis by flow cytometry: kappa/lambda, CD19, CD20, CD5, CD23, CD10
European Society for Medical Oncology (ESMO) guidelines are in agreement with the NCCN that diagnosis follows the WHO classification and excisional biopsy is preferred. Core biopsy is considered only in cases where lymph nodes are not easily accessible. Fine-needle aspiration is not recommended. [11]
The Groupe d’Etude des Lymphomes Folliculaires (GELF) recommends the following criteria for identifying patients in whom immediate therapy is necessary [12] :
Three nodes in three distinct areas, with each node ≥3 cm in diameter
A tumor ≥7 cm in diameter
Presence of systemic symptoms
Symptomatic spleen enlargement
Ascites or pleural effusion
Cytopenias (leukocytes < 1.0 x 109/L and/or platelets < 100 x 109/L)
Leukemia (>5.0 x 109/L malignant cells)
The NCCN recommends both the GELF criteria and the 2004 Follicular Lymphoma International Prognostic Index (FLIPI) for risk stratification. The FLIPI includes the following risk factors [8] :
Age >60 y
Ann Arbor Stage III-IV
Lactate dehydrogenase (LDH) level above the upper limit of normal
Hemoglobin level < 12 g/dL
Four or more nodal sites of disease
For each factor, the patient receives 1 point. Based on the FLIPI score, patients can be categorized as follows [8] :
Low risk (0 or 1 point)
Intermediate risk (2 points)
High risk (≥3 points)
In 2009, the International Follicular Lymphoma Prognostic Factor Project published an updated score, FLIPI2. The FLIPI2 includes the following risk factors (as with FLIPI1, each factor is worth 1 point) [7] :
Age >60y
β2-microglobulin (B2M) above the upper limit of normal
Bone marrow involvement
Hemoglobin level < 12 g/dL
Longest diameter of the largest involved node >6 cm
Based on the FLIPI2 score, patients can be categorized as follows [7] :
Low risk (0 or 1 point)
Intermediate risk (2 points)
High risk (≥3 points)
With this model, relapse-free and overall survival rates at 5 years are as follows [7] :
0-1 risk factors – 79%
Two risk factors – 51%
Three or more risk factors – 20%
FLIPI1 and FLIPI2 are used to predict prognosis but are not used to select treatment options.
The NCCN and ESMO offer similar treatment recommendations, as follows [30, 11] :
Involved-site radiation therapy (ISRT), 24-30 Gy, is the preferred treatment option for stage I or II
If significant toxicity is expected from radiotherapy, initial observation may be more appropriate
Other first-line treatment options include rituximab, alone or in combination with other agents, and radioimmunotherapy
Combination treatment with involved-field radiation therapy (IFRT) and chemotherapy (see below) and/or radioimmunotherapy is recommended for more advanced stages
In asymptomatic patients with advanced-stage, low tumor burden disease, initiate treatment when the patients become symptomatic, as there is no survival advantage with immediate treatment versus a watch-and-wait approach
The NCCN lists the following regimens as preferred first-line therapy for FL [30] :
Bendamustine plus obinutuzumab
Bendamustine plus rituximab
R-CHOP (rituximab, cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine [Oncovin], prednisone)
RCVP (rituximab, cyclophosphamide, vincristine, prednisone)
For elderly or infirm patients who are unlikely to tolerate those regimens, the NCCN recommends the following as first-line regimens:
In addition to its general guidance on diagnosis of lymphoma, the National Comprehensive Cancer Network (NCCN) recommends the following studies to establish a diagnosis of gastric mucosa-associated lymphoid tissue (MALT) lymphoma [30] :
Immunohistochemistry panel: CD20, CD3, CD5, CD10, BCL2, kappa/lambda, CD21 or CD23, BCL6, cyclin D1
Cell surface marker analysis by flow cytometry: kappa/lambda, CD19, CD20, CD5, CD23, CD10
Helicobacter pylori testing; if positive, fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR) for detection of t(11;18), to identify patients who are unlikely to respond to antibiotic therapy
European Society for Medical Oncology (ESMO) guidelines for clinical management of marginal zone lymphomas of MALT type provide similar recommendations. [13]
The following two systems are currently used for staging gastric marginal zone lymphoma:
Lugano staging system (1994) [14]
Paris staging system (2003) [15]
The Lugano system is a modification of the Ann Arbor staging system, and the Paris system corresponds to the tumor-node-metastasis (TNM) system for staging gastric cancer, which presents more accurately the depth of gastric wall involvement, a factor in the response to H pylori eradication. See Table 2, below.
Table 2. Comparison of Lugano and Paris staging systems (Open Table in a new window)
Lugano Staging System
Paris Staging System
Stage
Area of Involvement
TNM
Tumor extension
IE1
Confined to GI tract—mucosa, submucosa
T1m N0 M0
T1sm N0 M0
Mucosa
Submucosa
IE2
Confined to GI tract—muscularis propria, serosa
T2 N0 M0
T3 N0 M0
Muscularis propria
Serosa
IIE1
Extending into abdomen—local nodal involvement
T1-3 N1 M0
Perigastric lymph nodes
IIE2
Extending into abdomen—distant nodal involvement
T1-3 N2 M0
More distant regional nodes
IIE
Penetration of serosa to involve adjacent organs or tissues
T4 N0 M0
Invasion of adjacent structures
IV
T1-4 N3 M0
T1-4 N0-3 M1
Lymph nodes on both sides of the diaphragm/distant metastases (eg, bone marrow or additional extranodal sites)
Table. (Open Table in a new window)
Disseminated extranodal involvement or concomitant supra-diaphragmatic nodal involvement
Both the NCCN and ESMO recommend that early staging procedures include gastroduodenal endoscopy, with multiple biopsies taken from each region of the stomach, duodenum, gastroesophageal junction, and any abnormal-appearing site. Endoscopic ultrasound is recommended to evaluate regional lymph nodes and gastric wall infiltration. Attention to other MALT sites and autoimmune diseases is necessary. As in other lymphomas, staging procedures should include CT scanning, laboratory studies, and bone marrow examination. [30, 13]
Both the NCCN and ESMO recommend antibiotic eradication of Helicobacter pylori as first-line treatment for H pylori–positive patients, including t(11;18)-positive patients. However, patients with t(11;18) are unlikely to respond to antibiotic therapy, or to alkylating agents as a sole treatment; they should be treated with involved-site radiation therapy (ISRT) or rituximab. In H pylori–negative patients, ISRT, 30 Gy, is the preferred treatment option. Rituximab is an option if radiation therapy is contraindicated. [30, 13]
Mantle cell lymphoma (MCL) is diagnosed in accordance with the World Health Organization criteria for hematological neoplasms and detection of cyclin D1 expression or the t(11;14) translocation along with mature B-cell proliferation. The National Comprehensive Cancer Network (NCCN) recommends the following studies to establish a diagnosis of MCL [30] :
Immunohistochemistry panel: CD20, CD3, CD5, CD10, BCL2, BCL6, cyclin D1, CD21, CD23, Ki-67
Cell surface marker analysis by flow cytometry: kappa/lambda, CD19, CD20, CD5, CD23, CD10
Molecular analysis for detection of antigen receptor gene rearrangements; CCND1 rearrangements.
Fluorescence in situ hybridization (FISH) or cytogenetics for detection of t(11;14), t(14;18).
Immunohistochemistry for SOX 11, which is expressed in approximately 90% of MCLs but is negative in all other B-cell lymphoid neoplasms except Burkitt lymphomas and lymphoblastic lymphomas
The European Society for Medical Oncology (ESMO) recommends the 2008 MCL International Prognostic Index (MIPI) for risk stratification. [16] The MIPI includes the following risk factors [9] :
Age: 50-59 (1 point); 60-69 (2 points); ≥70 (3 points)
Eastern Cooperative Oncology Group (ECOG) performance status ≥2 (2 points)
Lactate dehydrogenase level (ratio to upper limit of normal): 0.67-0.99 (1 point); 1.00-1.49 (2 points); ≥1.50 (3 points)
White blood cell count (× 109/L): 6700-9999 (1 point); 10,000-14,999 (2 points); ≥15,000 (3 points)
Based on the MIPI score, patients can be categorized as follows [9] :
Low risk (0-3 points)
Intermediate risk (4-5 points)
High risk (≥6 points)
In addition, both the NCCN and ESMO recommend assaying Ki-67 proliferative antigen to evaluate cell proliferation. Low Ki-67 (< 30%) is associated with a more favorable prognosis; however, it is not used to guide treatment decisions. [16, 30]
The NCCN and ESMO offer similar treatment recommendations, as follows [30, 16] :
Chemotherapy followed by involved-site radiation therapy (ISRT), 30-36 Gy, is the preferred treatment option for limited stage I or II (non-bulky) disease, although this presentation is rare
For advanced-stage disease in younger patients and selected elderly fit patients, the recommended approach is aggressive induction therapy with a regimen such as RDHAP (rituximab, dexamethasone, cytarabine, cisplatin), RDHAX (rituximab, dexamethasone, cytarabine, oxaliplatin) , or hyperCVAD (cyclophosphamide, vincristine, doxorubicin [Adriamycin], dexamethasone alternating with high-dose methotrexate and cytarabine) + rituximab, followed by consolidation therapy consisting of high-dose therapy with autologous stem cell rescue
Prophylaxis and monitoring for tumor lysis syndrome should be strongly considered during the induction therapy.
In elderly fit patients, less-aggressive treatment regimens, such as R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by rituximab maintenance is recommended by both NCCN and ESMO
For elderly patients who are not candidates for any of the above chemotherapy regimens, palliative chemotherapy should be considered, using milder chemo-immunotherapy regimens (eg, bendamustine plus rituximab)
In addition to its general guidance on diagnosis of lymphoma, the National Comprehensive Cancer Network (NCCN) recommends the following studies to establish a diagnosis of diffuse large B-cell lymphoma (DLBCL) [30] :
Immunohistochemistry (IHC) panel: CD20, CD3, CD5, CD10, CD45, BCL2, BCL6, Ki-67, IRF4/MUM1, MYC
Cell surface marker analysis by flow cytometry: kappa/lambda, CD45, CD3, CD5, CD19, CD10, CD20
Additional IHC panel for subtyping: Cyclin D1, kappa/lambda, CD30, CD138, EBER-ISH, ALK, HHV8
Fluorescence in situ hybridization (FISH) or cytogenetics for detection of t(14;18), t(3;v), t(8;14), t(8;v)
IHC should include adequate markers to differentiate the two subtypes of DLBCL: activated B-cell type (ABC) and germinal center B-cell type (GCB). The subtypes are genetically different diseases, and survival in patients with the ABC subtype is worse than in those with GCB. [17]
The NCCN and the European Society for Medical Oncology (ESMO) recommend use of the International prognostic index (IPI) for all patients. Age-adjusted International Prognostic Index (aa-IPI) should be used for risk stratification of patients aged 60 years and younger. [30, 18]
The IPI includes the following risk factors:
Age >60 years
Elevated serum lactate dehydrogenase (LDH) level
Eastern Cooperative Oncology Group (ECOG) performance status ≥2
Stage III or IV disease
Extranodal involvement >1 site
Each risk factor is worth 1 point. On the basis of the IPI score, patients can be categorized as follows:
Low risk (0-1 point)
Low-intermediate risk (2 points)
High-intermediate risk (3 points)
High risk (4-5 points)
The aa-IPI includes the following risk factors (1 point is allotted for each factor) [6] :
Based on the aa-IPI score, patients can be categorized as follows [6] :
Low risk (0 points)
Low-intermediate risk (1 point)
High-intermediate risk (2 points)
High risk (3 points)
National Comprehensive Cancer Network recommendations
NCCN treatment recommendations for stage I/II (nonbulky) disease are as follows [30] :
R-CHOP (rituximab, cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine [Oncovin], prednisone) for three cycles, followed by involved-field radiation therapy (IFRT)
R-CHOP for six cycles with or without IFRT is an acceptable alternative
Patients who are not candidates for chemotherapy should receive involved-site radiation therapy (ISRT)
For stage II bulky disease, NCCN recommends R-CHOP for six cycles, with or without radiation therapy.
For stage III/IV (advanced-stage) disease, NCCN treatment recommendations are as follows [30] :
R-CHOP every 21 days for six cycles is preferred
Consider radiation therapy for bulky sites
Other regimens that may be considered include dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) plus rituximab or dose-dense R-CHOP-14
In patients at increased risk for central nervous system relapse (eg, disease involving the paranasal sinus, testis, epidural, bone marrow, HIV lymphoma, kidney or adrenal involvement or >2 extranodal sites, elevated LDH or concomitant expression of BCL2 and MYC protein), four to eight doses of intrathecal methotrexate and/or cytarabine, or 3-3.5 g/m2 of systemic methotrexate for prophylaxis is recommended
For relapse or refractory disease, high-dose chemotherapy (HDC) and autologous stem cell rescue (ASCR) is the treatment of choice. Before or after HDC and ASCRA, IFRT is given to previous disease sites. Second-line regimens for HDC include the following, which may be given with or without rituximab :
DHAP (dexamethasone, cytarabine [high-dose Ara C], cisplatin)
ESHAP (methylprednisolone, etoposide, cytarabine, cisplatin)
GDP (gemcitabine, dexamethasone, cisplatin)
GemOx (gemcitabine and oxaliplatin)
ICE (ifosfamide, carboplatin, etoposide)
MINE (mitoxantrone, ifosfamide, mesna, etoposide)
Patients with relapsed disease who are not eligible for HDC and ASCR should be enrolled in a clinical trial. If one is not available, they should receive palliative chemotherapy.
European Society for Medical Oncology recommendations
The ESMO guidelines contain specific recommendations for patients < 60 years old based on aaIPI risk. [18]
For aa-IPI=0 without bulky disease, treatment recommendations are as follows:
R-CHOP every 21 d for six cycles is preferred
Radiation therapy has no proven benefit
For aa-IPI=0 with bulky disease or aa-IPI=1, treatment recommendations are as follows:
R-CHOP every 21 d for six cycles with IFRT, or
R-ACVBP (rituximab, doxorubicin, vindesine, cyclophosphamide, bleomycin, prednisolone) and sequential consolidation
For aa-IPI≥2, ESMO notes that no standard of care has been established; enrollment in a clinical trial is preferred. R-CHOP every 21 days for eight cycles is one possible regimen.
A PET-CT scan should be performed to confirm complete remission (CR). Patients in CR should receive clinical follow up with a history and physical examination and laboratory studies (eg, complete blood cell count, comprehensive metabolic panel, lactate dehydrogenase level) every 3-6 months for 5 years and then yearly or as clinically indicated. Imaging studies (CT scan) should be performed no more often than every 6 mo for 2 years after the completion of treatment, and then only as clinically indicated. [30]
The 2008 World Health Organization classification identifies the following three clinical variants of Burkitt lymphoma (BL) [4] :
Endemic (eBL) – The most common form of childhood malignancy in equatorial Africa, associated with Epstein-Barr virus (EBV) infection
Sporadic (sBL) – The majority of cases are in the United States and Europe; up to 30% are associated with EBV
Immunodeficiency associated – Occurs in patients with HIV infection, post-transplantation immunosuppression, and congenital immunodeficiency
In addition to its general guidance on diagnosis of lymphoma, the National Comprehensive Cancer Network (NCCN) recommends the following studies to establish a diagnosis of Burkitt lymphoma [30] :
Immunohistochemistry panel: CD45(LCA), CD20, CD3, BCL2, BCL6, Ki-67, TdT or
Cell surface marker analysis by flow cytometry: kappa/lambda, CD45, CD20, CD3, CD5, CD19, CD10, TdT
Fluorescence in situ hybridization (FISH) or cytogenetics for detection of t(8;14), MYC.
Epstein-Barr encoding region in situ hybridization (EBER-ISH) can be used to identify EBV
A prognostic scoring system was developed in 2013 using the Surveillance, Epidemiology, and End Results (SEER) database. Risk factors and points assigned are as follows [19] :
Age 40-59 years or black race/ethnicity: 1 point
Age 60-79 years or stage III/IV disease: 2 points
Age 80 years and older: 4 points
The four risk groups based on the scoring system are as follows:
Low risk (0-1 point)
Low-intermediate risk (2 points)
High-intermediate risk (3 points)
High risk (≥4 points)
With this model, relative survival rates at 5 years are as follows:
Low risk – 71%
Low-intermediate – 55%
High-intermediate – 41%
High-risk – 29%
Because of the complexity of the disease, NCCN guidelines recommend that treatment of Burkitt lymphoma be given at centers with expertise in the management of the disease. Recommended chemotherapy regimens for low-risk disease include the following:
CODOX-M (original or modified) (cyclophosphamide, doxorubicin, vincristine with intrathecal methotrexate and cytarabine followed by high-dose systemic methotrexate) ± rituximab (three cycles)
Dose-adjusted EPOCH (etoposide, prednisone, vincristine [Oncovin], cyclophosphamide, doxorubicin [hydroxydaunorubicin]) + rituximab (minimum three cycles with one additional cycle beyond complete remission (regimen includes intrathecal methotrexate)
HyperCVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) alternating with high-dose methotrexate and cytarabine + rituximab (regimen includes intrathecal therapy)
Recommended combination regimens for high-risk disease include the following:
Other treatment recommendations are as follows [30] :
Enrollment in available clinical trials for all patients
CHOP is not considered adequate therapy
Central nervous system prophylaxis with systemic and/or intrathecal chemotherapy with methotrexate and/or cytarabine
Prophylaxis for tumor lysis syndrome is mandatory
The NCCN recommends follow up every 2-3 months for the first year after complete response, then every 3 months for the next year, and every 6 months thereafter. Relapse is rare after 2 years. [30]
In addition to the National Comprehensive Cancer Network (NCCN), the European Organization for Research and Treatment of Cancer (EORTC) and the International Society for Cutaneous Lymphoma (ISCL) published guidelines for the management of primary cutaneous B-cell lymphomas (CBCL). [20]
The NCCN and EORTC/ISCL guidelines recommend use of the WHO-EORTC classification for cutaneous B-cell lymphomas (CBCL), which distinguishes the following three main types [21] :
Primary cutaneous marginal zone lymphoma (PC-MZL)
Primary cutaneous follicle center cell lymphoma (PC-FCL)
Primary cutaneous diffuse large B-cell, leg type (PC-DLBCL, LT)
Of note, a germinal (or follicle) center phenotype and large cells in a skin lesion is not equivalent to diffuse large B-cell lymphoma (DLBCL) but is consistent with primary cutaneous germinal/follicle center lymphoma.
In addition to its general guidance on diagnosis of lymphoma, the NCCN recommends the following studies to establish a diagnosis of CBCL [33] :
Immunohistochemistry (IHC) panel: CD20, CD3, CD5, CD10, BCL2, BCL6, IRF4/MUM1
Additional IHC panel for subtyping: Ki-67, CD43, CD21, CD23, Cyclin D1, kappa/lambda
Assessment of IgM and IgD expression to distinguish between PC-FCL and PC-DLBCL, leg type
Fluorescence in situ hybridization (FISH) or cytogenetics for detection of t(14;18)
Bone marrow biopsy in PC-FCL, optional for PC-MZL
The 2007 TNM classification system of the ISCL/EORTC is used for staging, as shown in Table 3, below. [22]
Table 3. International Society for Cutaneous Lymphoma/European Organization for Research and Treatment of Cancer tumor-node-metastasis classification for cutaneous B-cell lymphoma (Open Table in a new window)
Tumor
Involvement
Node
Involvement
Metastatic Spread
Involvement
T1
Solitary skin involvement
T1a: ≤5 cm diameter
T1b: >5 cm diameter
N0
No lymph node involvement
M0
No evidence of extracutaneous non-lymph node disease
T2
Multiple lesions limited to one body region or two contiguous body regions
T2a: all-disease in a < 15-cm diameter
T2b: all-disease in a >15- and < 30-cm diameter
T2c: all-disease in a >30-cm diameter
N1
Involvement of one peripheral lymph node region
M1
Evidence of extracutaneous non-lymph node disease
T3
Generalized skin involvement
T3a: multiple lesions involving two noncontiguous body regions
T3b: multiple lesions involving three body regions
N2
Involvement of two or more peripheral lymph node regions or involvement of any lymph node region that does not drain an area of current or prior skin involvement
N3
Central lymph nodes involvement
PC-FCL and PC-MZL
Both the NCCN and EORTC/ISCL guidelines recommend local radiation therapy or excision for T1-2 PC-FCL and PC-MZL. [33, 20] The NCCN recommends intralesional steroids or topical therapy including steroids, imiquimod, nitrogen mustard, and bexarotene as alternative treatment options. [33]
For T3 disease, the NCCN recommends radiation therapy; chlorambucil; or cyclophosphamide, vincristine, and prednisone (CVP) with or without rituximab. Extracutaneous disease should be managed using the treatment guidelines for follicular lymphoma. [33]
EORTC/ISCL guidelines recommend systemic rituximab as the first choice of treatment for patients with extensive skin lesions. Combination chemotherapy (eg, R-COP, R-CHOP) should be considered only in exceptional cases, such as in patients with progressive disease not responding to rituximab or patients developing extracutaneous disease. [20]
PC-DBCL, LT
Both guidelines caution that radiation therapy is less effective in PC-DBCL, LT. R-CHOP with local radiation therapy is recommended as first line of treatment for all stages of DBCL, LT. [33, 20] . Because of the lack of studies on relapsed disease, EORTC/ISCL recommend that treatment protocols for relapsed DBCL be followed. [20] .
The World Health Organization–European Organization for Research and Treatment of Cancer (WHO-EORTC) classification of cutaneous T-cell lymphoma (CTCL) is divided into CTCLs with indolent clinical behavior and those with aggressive subtypes. CTCLs with indolent clinical behavior include the following [21] :
Mycosis fungoides
Mycosis fungoides variants and subtypes (eg, folliculotropic mycosis fungoides, pagetoid reticulosis, granulomatous slack skin)
Primary cutaneous CD30+ lymphoproliferative disorder (eg, primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis)
Subcutaneous panniculitis-like T-cell lymphoma (provisional)
Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma (provisional)
CTCLs with aggressive clinical behavior include the following [31] :
Sézary syndrome
Adult T-cell leukemia/lymphoma
Extranodal NK/T-cell lymphoma, nasal type
Primary cutaneous peripheral T-cell lymphoma, unspecified
Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma (provisional)
Cutaneous gamma/delta-positive T-cell lymphoma (provisional)
In addition to the NCCN guidelines, the European Organization for Research and Treatment of Cancer (EORTC) published consensus recommendations for the treatment of mycosis fungoides/Sezary syndrome (MF/SS) in 2006. [23] In 2013, the European Society for Medical Oncology (ESMO) included treatment recommendations in its guidelines for primary cutaneous lymphoma. [24]
The NCCN recommends the following studies to establish a diagnosis of MF/SS [31] :
Immunohistochemistry panel of skin biopsy: CD2, CD3, CD4, CD5, CD7, CD8, CD20, CD30, CD25, CD56, T1A1, granzyme B, βF1, TCR-CyM1
Molecular analysis of skin biopsy: TCR gene rearrangements by polymerase chain reaction (PCR)
Assessment of peripheral blood for Sezary cells
Biopsy of suspicious lymph nodes (in absence of definitive skin diagnosis)
Assessment of HTLV-1 serology in at-risk populations
In 2007, the ISCL/EORTC released a revised tumor-node-metastasis-blood (TNMB) classification of MF/SS based on particular skin findings and extracutaneous disease. [25] See Table 4, below.
Table 4. International Society for Cutaneous Lymphoma/European Organization for Research and Treatment of Cancer tumor-node-metastasis-blood revised classification for mycosis fungoides and Sezary syndrome (Open Table in a new window)
Skin
Involvement
Node
Involvement
Viscera
Involvement
T1
Patchy or plaquelike skin disease involving ≤10% of the skin surface area
N0
No abnormal lymph nodes
M0
No visceral organ involvement
T2
Patchy or plaquelike skin disease involving ≥10% of the skin surface area
N1
Histopathology Dutch Gr 1 or NCI LN 0-2
M1
Visceral organ involvement
T3
Tumors are present ≥1 cm in diameter
N2
Histopathology Dutch Gr 2 or NCI LN 3
MX
Abnormal visceral site; no histologic confirmation
T4
Erythroderma ≥80% of body area
N3
Histopathology Dutch Gr 3-4 or NCI LN 4
Blood
Involvement
Nx
Abnormal lymph nodes; no histologic confirmation
B0
≤5% of peripheral blood lymphocytes are Sezary cells
B1
>5% of peripheral blood lymphocytes are Sezary cells but do met B2 criteria
B2
≥1000/mcL Sezary cells or CD4/CD8 ≥10 or ≥40% CD4+/CD7- or ≥30% CD4+/CD26- cells
The ISCL/EORTC system was further modified to update clinical staging classifications. [25] See Table 5, below.
Table 5. Staging classifications for mycosis fungoides and Sezary syndrome (Open Table in a new window)
Clinical Stage
5-Year Survival [23]
TNM (B) Stage
IA
96-100%
T1N0M0B0
T1N0M0B1
IB
73-86%
T2N0M0B0
T2N0M0B1
IIA
49-73%
T1N1M0B0
T1N1M0B1
T1N2M0B0
T1N2M0B1
T2N1M0B0
T2N1M0B1
T2N2M0B0
T2N2M0B1
IIB
40-65%
T3N0M0B0
T3N0M0B1
T3N1M0B0
T3N1M0B1
T3N2M0B0
T3N2M0B1
IIIA
50-57%
T4N0M0B0
T4N1M0B0
T4N2M0B0
IIIB
T4N0M0B1
T4N1M0B1
T4N2M0B1
IVA
15-40%
T1N0M0B2
T2N0M0B2
T3N0M0B2
T4N0M0B2
T1N1M0B2
T2N1M0B2
T3N1M0B2
T4N1M0B2
T1N2M0B2
T2N2M0B2
T3N2M0B2
T4N2M0B2
T1N3M0B0
T2N3M0B0
T3N3M0B0
T4N3M0B0
T1N3M0B1
T2N3M0B1
T3N3M0B1
T4N3M0B1
T1N3M0B2
T2N3M0B2
T3N3M0B2
T4N3M0B2
IVB
0-15%
T1N0M1B0
T2N0M1B0
T3N0M1B0
T4N0M1B0
T1N1M1B1
T2N1M1B1
T3N1M1B1
T4N1M1B1
T1N2M1B2
T2N2M1B2
T3N2M1B2
T4N2M1B2
T1N3M1B3
T2N3M1B3
T3N3M1B3
T4N3M1B3
The NCCN recommends that patients be treated at specialized centers with expertise in the management of MF/SS. Unlike other non-Hodgkin lymphoma subtypes, MF/SS criteria have not correlated with prognosis, and treatment decisions are made on a clinical basis. [31]
In 2011, the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the EORTC issued a joint consensus statement proposing new clinical end points and response criteria for use in clinical trials of MF/SS. [26] The NCCN includes the new criteria in its current recommendations. [31]
All three guidelines recommend treatment selection based on clinical stage. [23, 24, 31]
Mycosis fungoides
In general, topical therapies are recommended for localized disease (stages IA, IB and IIA), with systemic or combination systemic and topical therapies beginning with stage IIB. Systemic therapies may also be considered in patients with early-stage disease that does not respond to topical treatments. [23, 24, 31]
Localized therapies endorsed by the guidelines include the following [31, 23, 24] :
Psoralens + ultraviolet A (PUVA)—For thick plaques
Narrow-band ultraviolet B (UVB)—For patch or thin plaques
Topical corticosteroids
Localized radiation therapy (12-36 Gy)
Topical chemotherapy (ie, nitrogen mustard or carmustine)
Topical retinoids (ie, bexarotene)
Because of the high toxicity of total skin electron beam therapy (TSEBT), both NCCN and EOTRTC recommend TSEBT only after other treatments have failed. [23, 31]
Systemic therapies recommended for advanced stages include the following [23, 24, 31] :
Retinoids (ie, bexarotene)
Interferons (IFN-alpha, IFN-gamma)
Histone deacetylase (HDAC)-inhibitors (vorinostat, romidenpsin)—not approved in Europe
Extracorporeal photopheresis (ECP)
Methotrexate (≤100 mg/wk)
All three guidelines recommend IFN-alpha and PUVA or PUVA and retinoids (including bexarotene) as second-line combination therapies for MF stages IA, IB, and IIA. [23, 24, 31]
Other NCCN recommended combination therapies for advanced disease include the following [31] :
PUVA and ECP
TSEBT and ECP
Retinoids and interferons
ECP and retinoids
ECP and interferons
ECP and retinoids and interferons
Sezary syndrome and erythrodermic mycosis fungoides
Participation in a clinical trial as a treatment option for all patients with SS or advanced-stage MF is recommended by both the NCCN and EOTRTC. [23, 31] Treatment for SS or erythrodermic MF (stage IV) is palliative. The preferred modality is ECP, either alone or in combination with other treatments. [23, 24, 31]
In 2011, the the European Organization for Research and Treatment of Cancer (EORTC), the International Society for Cutaneous Lymphoma (ISCL), and the US Cutaneous Lymphoma Consortium (USCLC) published joint consensus recommendations for the management of primary cutaneous CD30+ T-Cell lymphoproliferative disorders (CD30+LPDs). [27]
Under the WHO-EORTC classification system for cutaneous lymphomas, primary CD30+LPDs represent a wide spectrum of disease, with lymphomatoid papulosis (LyP) at the benign end of the spectrum and primary cutaneous anaplastic large cell (PC-ALCL) lymphoma at the malignant end. Borderline lesions lie somewhere in between, with overlapping clinical and histopathologic features. [21]
The National Comprehensive Cancer Network (NCCN) recommendations to establish a diagnosis of CD30+LPDs include the following [31] :
Differentiation of LyP and PC-ALCL from other forms of cutaneous T-cell lymphoma and secondary cutaneous involvement by nodal Hodgkin lymphoma or systemic ALCL requires careful clinicopathologic correlation
Mycosis fungoides can be comorbid
Clinical features include solitary or localized nodules or tumors (often ulcerated); multifocal lesions occur in about 20% of cases; extracutaneous disease occurs in about 10% of cases, usually involving regional lymph nodes
Immunohistochemistry (IHC) panel of skin biopsy specimen: CD3, CD4,CD8, CD20, CD30, CD56, βF1, ALK1
Expanded IHC: CD2, CD5, CD7, CD25,TIA1, granzyme B, perfornin, GM1, EBER-ISH
Histologically characterized by diffuse, cohesive sheets of large CD30-positive (in >75%) cells with anaplastic, pleomorphic, or immunoblastic appearance
Molecular analysis of skin biopsy: TCR gene rearrangements
Excisional or incisional biopsy of suspicious lymph nodes (in absence of definitive skin diagnosis)
Assessment of HTLV-1 serology in at-risk populations to identify CD30+ adult T-cell leukemia/lymphoma (ATLL)
Bone marrow biopsy only in cases of multifocal tumors, unexplained hematologic results, or presence of where extracutaneous disease
EORTC, ISCL, and USCLC guidelines recommend staging according to the 2007 tumor-node-metastasis (TNM) ISCL/EORTC staging of cutaneous lymphomas other than mycosis fungoides/Sezary syndrome. [22, 27]
Both guidelines give similar treatment recommendations for PC-ALCL, as follows [31, 27] :
For solitary or grouped lesions, surgical excision or radiation therapy for first-line treatment
Relapses are equally frequent after both treatments; if confined to the skin, treatment can be repeated
For multifocal lesions, low-dose methotrexate may be used, based on expert consensus; retinoids and interferon alpha are alternative treatments for multifocal disease that is not responsive to other therapies, but data are limited on effectiveness. Newer promising agents include pralatrexate and CD30 antibody-drug conjugate brentuximab vedotin [28, 29]
Multi-agent chemotherapy is not recommended for multifocal or relapsing PC-ALCL limited to the skin; it is recommended only for extracutaneous spread
Overview
What is non-Hodgkin lymphoma (NHL)?
What are the NCCN guidelines non-Hodgkin lymphoma (NHL)?
Which non-Hodgkin lymphoma (NHL) subtypes are covered in the ESMO guidelines?
What are the most commonly used classification schemas for non-Hodgkin lymphoma (NHL)?
Which low-grade non-Hodgkin lymphoma (NHL) subtypes are included in the IWF classification?
Which intermediate-grade non-Hodgkin lymphoma (NHL) subtypes are included in the IWF classification?
How does WHO classify non-Hodgkin lymphoma (NHL)?
What are the WHO classification subtypes for non-Hodgkin lymphoma (NHL)?
What are the NCCN recommendations for the workup of non-Hodgkin lymphoma (NHL)?
What is the Lugano Modification of the Ann Arbor staging system for non-Hodgkin lymphoma (NHL)?
What are the International Prognostic Index (IPI) risk factors in non-Hodgkin lymphoma (NHL)?
How does WHO classify the follicular lymphoma subtypes of non-Hodgkin lymphoma (NHL)?
What are the FLIPI risk factors for the follicular lymphoma type of non-Hodgkin lymphoma (NHL)?
What are the FLIPI risk categories for the follicular lymphoma type of non-Hodgkin lymphoma (NHL)?
What are the FLIPI2 risk for the follicular lymphoma type of non-Hodgkin lymphoma (NHL)?
What are the FLIPI2 categories for the follicular lymphoma type of non-Hodgkin lymphoma (NHL)?
What are the NCCN and ESMO treatment recommendations for non-Hodgkin lymphoma (NHL)?
Which staging systems are used for staging MALT non-Hodgkin lymphoma (NHL)?
What are the Lugano and Paris staging systems for MALT non-Hodgkin lymphoma (NHL) based on?
What are the NCCN and ESMO treatment recommendations for MALT non-Hodgkin lymphoma (NHL)?
What are the IPI risk factors for diffuse large B-cell lymphoma (DLBCL) non-Hodgkin lymphoma (NHL)?
What are the age and race risk factors for the Burkitt lymphoma form of non-Hodgkin lymphoma (NHL)?
How are the risk groups for the Burkitt lymphoma form of non-Hodgkin lymphoma (NHL) categorized?
What are the survival rates for the Burkitt lymphoma form of non-Hodgkin lymphoma (NHL)?
What are the main types of cutaneous B-cell lymphomas (CBCL) of non-Hodgkin lymphoma (NHL)?
How is the range of primary cutaneous CD30+LPDs characterized in non-Hodgkin lymphoma (NHL)?
What are diagnostic recommendations on primary cutaneous CD30+LPDs non-Hodgkin lymphoma (NHL)?
What are the staging guidelines for primary cutaneous CD30+LPDs non-Hodgkin lymphoma (NHL)?
What are treatment recommendations for primary cutaneous CD30+LPDs non-Hodgkin lymphoma (NHL)?
Zorin BO. National Cancer Institute sponsored study of classifications of non-Hodgkin’s lymphomas: summary and description of a working formulation for clinical usage. The Non-Hodgkin’s Lymphoma Pathologic Classification Project. Cancer. 1982 May 15. 49 (10):2112-35. [Medline].
Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood. 1994 Sep 1. 84 (5):1361-92. [Medline]. [Full Text].
Swerdlow SH, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Fourth Edition. Lyon, France: International Agency for Research on Cancer; 2008.
[Guideline] Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014 Sep 20. 32 (27):3059-68. [Medline]. [Full Text].
A predictive model for aggressive non-Hodgkin’s lymphoma. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. N Engl J Med. 1993 Sep 30. 329 (14):987-94. [Medline]. [Full Text].
Federico M, Bellei M, Marcheselli L, Luminari S, Lopez-Guillermo A, Vitolo U, et al. Follicular lymphoma international prognostic index 2: a new prognostic index for follicular lymphoma developed by the international follicular lymphoma prognostic factor project. J Clin Oncol. 2009 Sep 20. 27 (27):4555-62. [Medline]. [Full Text].
Solal-Céligny P, Roy P, Colombat P, White J, Armitage JO, et al. Follicular lymphoma international prognostic index. Blood. 2004 Sep 1. 104 (5):1258-65. [Medline]. [Full Text].
Hoster E, Dreyling M, Klapper W, Gisselbrecht C, van Hoof A, et al. A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. Blood. 2008 Jan 15. 111 (2):558-65. [Medline]. [Full Text].
Jaffe ES. The 2008 WHO classification of lymphomas: implications for clinical practice and translational research. Hematology Am Soc Hematol Educ Program. 2009. 523-31. [Medline]. [Full Text].
[Guideline] Dreyling M, Ghielmini M, Marcus R, Salles G, Vitolo U, Ladetto M, et al. Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014 Sep. 25 Suppl 3:iii76-82. [Medline]. [Full Text].
Brice P, Bastion Y, Lepage E, Brousse N, Haïoun C, Moreau P, et al. Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: a randomized study from the Groupe d’Etude des Lymphomes Folliculaires. Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol. 1997 Mar. 15 (3):1110-7. [Medline].
[Guideline] Zucca E, Copie-Bergman C, Ricardi U, Thieblemont C, Raderer M, Ladetto M, et al. Gastric marginal zone lymphoma of MALT type: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013 Oct. 24 Suppl 6:vi144-8. [Medline]. [Full Text].
Rohatiner A, d’Amore F, Coiffier B, Crowther D, Gospodarowicz M, Isaacson P, et al. Report on a workshop convened to discuss the pathological and staging classifications of gastrointestinal tract lymphoma. Ann Oncol. 1994 May. 5 (5):397-400. [Medline].
Ruskoné-Fourmestraux A, Dragosics B, Morgner A, Wotherspoon A, De Jong D. Paris staging system for primary gastrointestinal lymphomas. Gut. 2003 Jun. 52 (6):912-3. [Medline]. [Full Text].
[Guideline] Dreyling M, Geisler C, Hermine O, Kluin-Nelemans HC, Le Gouill S, Rule S, et al. Newly diagnosed and relapsed mantle cell lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014 Sep. 25 Suppl 3:iii83-92. [Medline]. [Full Text].
Rosenwald A, et al; Lymphoma/Leukemia Molecular Profiling Project. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med. 2002 Jun 20. 346 (25):1937-47. [Medline]. [Full Text].
[Guideline] Tilly H, Gomes da Silva M, Vitolo U, Jack A, Meignan M, Lopez-Guillermo A, et al. Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015 Sep. 26 Suppl 5:v116-25. [Medline]. [Full Text].
Castillo JJ, Winer ES, Olszewski AJ. Population-based prognostic factors for survival in patients with Burkitt lymphoma: an analysis from the Surveillance, Epidemiology, and End Results database. Cancer. 2013 Oct 15. 119 (20):3672-9. [Medline].
[Guideline] Senff NJ, Noordijk EM, Kim YH, Bagot M, Berti E, Cerroni L, et al. European Organization for Research and Treatment of Cancer and International Society for Cutaneous Lymphoma consensus recommendations for the management of cutaneous B-cell lymphomas. Blood. 2008 Sep 1. 112 (5):1600-9. [Medline]. [Full Text].
Willemze R, Jaffe ES, Burg G, Cerroni L, Berti E, et al. WHO-EORTC classification for cutaneous lymphomas. Blood. 2005 May 15. 105 (10):3768-85. [Medline]. [Full Text].
Kim YH, Willemze R, Pimpinelli N, Whittaker S, Olsen EA, Ranki A, et al. TNM classification system for primary cutaneous lymphomas other than mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC). Blood. 2007 Jul 15. 110 (2):479-84. [Medline]. [Full Text].
[Guideline] Trautinger F, Knobler R, Willemze R, Peris K, Stadler R, et al. EORTC consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome. Eur J Cancer. 2006 May. 42 (8):1014-30. [Medline]. [Full Text].
[Guideline] Willemze R, Hodak E, Zinzani PL, Specht L, Ladetto M, ESMO Guidelines Working Group. Primary cutaneous lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013 Oct. 24 Suppl 6:vi149-54. [Medline]. [Full Text].
Olsen E, Vonderheid E, Pimpinelli N, Willemze R, Kim Y, et al. Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood. 2007 Sep 15. 110 (6):1713-22. [Medline]. [Full Text].
[Guideline] Olsen EA, et al; International Society for Cutaneous Lymphomas, United States Cutaneous Lymphoma Consortium, Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer. Clinical end points and response criteria in mycosis fungoides and Sézary syndrome: a consensus statement of the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer. J Clin Oncol. 2011 Jun 20. 29 (18):2598-607. [Medline]. [Full Text].
[Guideline] Kempf W, Pfaltz K, Vermeer MH, Cozzio A, Ortiz-Romero PL, et al. EORTC, ISCL, and USCLC consensus recommendations for the treatment of primary cutaneous CD30-positive lymphoproliferative disorders: lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma. Blood. 2011 Oct 13. 118 (15):4024-35. [Medline]. [Full Text].
Horwitz SM, Kim YH, Foss F, Zain JM, Myskowski PL, et al. Identification of an active, well-tolerated dose of pralatrexate in patients with relapsed or refractory cutaneous T-cell lymphoma. Blood. 2012 May 3. 119 (18):4115-22. [Medline]. [Full Text].
Kim YH, Tavallaee M, Sundram U, Salva KA, Wood GS, Li S, et al. Phase II Investigator-Initiated Study of Brentuximab Vedotin in Mycosis Fungoides and Sézary Syndrome With Variable CD30 Expression Level: A Multi-Institution Collaborative Project. J Clin Oncol. 2015 Jul 20. [Medline].
[Guideline] NCCN Clinical Practice Guidelines in Oncology: B-Cell Lymphomas. National Comprehensive Cancer Network. Available at https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf. Version 3.2018 — April 13, 2018;
[Guideline] NCCN Clinical Practice Guidelines in Oncology: T-Cell Lymphomas. National Comprehensive Cancer Network. Available at https://www.nccn.org/professionals/physician_gls/pdf/t-cell.pdf. Version 3.2018 — February 22, 2018;
Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016 May 19. 127 (20):2375-90. [Medline]. [Full Text].
[Guideline] NCCN Clinical Practice Guidelines in Oncology: Primary Cutaneous B-cell Lymphomas. National Comprehensive Cancer Network. Available at https://www.nccn.org/professionals/physician_gls/pdf/pcbcl.pdf. Version 2.2018 — January 10, 2018;
Stage
Area of Involvement
Extranodal (E) Status
I
Single node or adjacent group of nodes
Single extranodal lesions without nodal involvement
II
Multiple lymph node groups on same side of diaphragm
Stage I or II by nodal extent with limited contiguous extranodal involvement
II bulky*
Multiple lymph node groups on same side of diaphragm with “bulky disease”
N/A
III
Multiple lymph node groups on both sides of diaphragm; nodes above the diaphragm with spleen involvement
N/A
IV
Multiple noncontiguous extranodal sites
N/A
Lugano Staging System
Paris Staging System
Stage
Area of Involvement
TNM
Tumor extension
IE1
Confined to GI tract—mucosa, submucosa
T1m N0 M0
T1sm N0 M0
Mucosa
Submucosa
IE2
Confined to GI tract—muscularis propria, serosa
T2 N0 M0
T3 N0 M0
Muscularis propria
Serosa
IIE1
Extending into abdomen—local nodal involvement
T1-3 N1 M0
Perigastric lymph nodes
IIE2
Extending into abdomen—distant nodal involvement
T1-3 N2 M0
More distant regional nodes
IIE
Penetration of serosa to involve adjacent organs or tissues
T4 N0 M0
Invasion of adjacent structures
IV
T1-4 N3 M0
T1-4 N0-3 M1
Lymph nodes on both sides of the diaphragm/distant metastases (eg, bone marrow or additional extranodal sites)
Disseminated extranodal involvement or concomitant supra-diaphragmatic nodal involvement
Tumor
Involvement
Node
Involvement
Metastatic Spread
Involvement
T1
Solitary skin involvement
T1a: ≤5 cm diameter
T1b: >5 cm diameter
N0
No lymph node involvement
M0
No evidence of extracutaneous non-lymph node disease
T2
Multiple lesions limited to one body region or two contiguous body regions
T2a: all-disease in a < 15-cm diameter
T2b: all-disease in a >15- and < 30-cm diameter
T2c: all-disease in a >30-cm diameter
N1
Involvement of one peripheral lymph node region
M1
Evidence of extracutaneous non-lymph node disease
T3
Generalized skin involvement
T3a: multiple lesions involving two noncontiguous body regions
T3b: multiple lesions involving three body regions
N2
Involvement of two or more peripheral lymph node regions or involvement of any lymph node region that does not drain an area of current or prior skin involvement
N3
Central lymph nodes involvement
Skin
Involvement
Node
Involvement
Viscera
Involvement
T1
Patchy or plaquelike skin disease involving ≤10% of the skin surface area
N0
No abnormal lymph nodes
M0
No visceral organ involvement
T2
Patchy or plaquelike skin disease involving ≥10% of the skin surface area
N1
Histopathology Dutch Gr 1 or NCI LN 0-2
M1
Visceral organ involvement
T3
Tumors are present ≥1 cm in diameter
N2
Histopathology Dutch Gr 2 or NCI LN 3
MX
Abnormal visceral site; no histologic confirmation
T4
Erythroderma ≥80% of body area
N3
Histopathology Dutch Gr 3-4 or NCI LN 4
Blood
Involvement
Nx
Abnormal lymph nodes; no histologic confirmation
B0
≤5% of peripheral blood lymphocytes are Sezary cells
B1
>5% of peripheral blood lymphocytes are Sezary cells but do met B2 criteria
B2
≥1000/mcL Sezary cells or CD4/CD8 ≥10 or ≥40% CD4+/CD7- or ≥30% CD4+/CD26- cells
Clinical Stage
5-Year Survival [23]
TNM (B) Stage
IA
96-100%
T1N0M0B0
T1N0M0B1
IB
73-86%
T2N0M0B0
T2N0M0B1
IIA
49-73%
T1N1M0B0
T1N1M0B1
T1N2M0B0
T1N2M0B1
T2N1M0B0
T2N1M0B1
T2N2M0B0
T2N2M0B1
IIB
40-65%
T3N0M0B0
T3N0M0B1
T3N1M0B0
T3N1M0B1
T3N2M0B0
T3N2M0B1
IIIA
50-57%
T4N0M0B0
T4N1M0B0
T4N2M0B0
IIIB
T4N0M0B1
T4N1M0B1
T4N2M0B1
IVA
15-40%
T1N0M0B2
T2N0M0B2
T3N0M0B2
T4N0M0B2
T1N1M0B2
T2N1M0B2
T3N1M0B2
T4N1M0B2
T1N2M0B2
T2N2M0B2
T3N2M0B2
T4N2M0B2
T1N3M0B0
T2N3M0B0
T3N3M0B0
T4N3M0B0
T1N3M0B1
T2N3M0B1
T3N3M0B1
T4N3M0B1
T1N3M0B2
T2N3M0B2
T3N3M0B2
T4N3M0B2
IVB
0-15%
T1N0M1B0
T2N0M1B0
T3N0M1B0
T4N0M1B0
T1N1M1B1
T2N1M1B1
T3N1M1B1
T4N1M1B1
T1N2M1B2
T2N2M1B2
T3N2M1B2
T4N2M1B2
T1N3M1B3
T2N3M1B3
T3N3M1B3
T4N3M1B3
Priyank P Patel, MD Hematology/Oncology Fellow, Roswell Park Cancer Institute, University
Priyank P Patel, MD is a member of the following medical societies: American Society of Hematology, American Society of Clinical Oncology, European Society for Medical Oncology, American College of Physicians
Disclosure: Nothing to disclose.
Francisco J Hernandez-Ilizaliturri, MD Professor of Medicine, Department of Medical Oncology, Associate Professor of Immunology, Department of Immunology, Chief, Lymphoma and Myeloma Section, Director, The Lymphoma Translational Research Program, Roswell Park Cancer Institute, University of Buffalo State University of New York School of Medicine and Biomedical Sciences
Francisco J Hernandez-Ilizaliturri, MD is a member of the following medical societies: American Association for Cancer Research, American Society of Hematology
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences
Disclosure: Nothing to disclose.
Mariclaire Cloutier Freelance editor, Medscape Drugs & Diseases
Disclosure: Nothing to disclose.
Non-Hodgkin Lymphoma Guidelines
Research & References of Non-Hodgkin Lymphoma Guidelines |A&C Accounting And Tax Services
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