Non-Hodgkin Lymphoma Guidelines 

Updated: Apr 19, 2018
  • Author: Priyank P Patel, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Classification

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

NHL Classification Schemas

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:

  1. Small lymphocytic, consistent with chronic lymphocytic leukemia

  2. Follicular, predominantly small-cleaved cell

  3. 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

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Diagnosis

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:

  • For B-cell lymphoma, an imunohistochemistry (IHC) panel including CD20, CD3, CD5, CD10, BCL2, BCL6, CD21, or CD23, with or without cell surface marker analysis by flow cytometry of kappa/lambda, CD19, CD20, CD5, CD23, CD10 [30]
  • For T-cell lymphoma, the IHC panel may include CD20, CD3, CD10, BCL6, Ki-67, CD5, CD30, CD2, CD4, CD8, CD7, CD56, CD21, CD23, EBER-ISH, TCRbeta, TCRdelta, PD1/CD279, and ALK, with or without cell surface marker analysis by flow cytometry that may include kappa/lambda, CD45, CD3, CD5, CD19, CD10, CD20, CD30, CD4, CD8, CD7, CD2; TCRalpha, TCRbeta, and TCRgam [31]  

 

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Staging

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.

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Risk Stratification

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] :

  • Age ≥ 60 y
  • Elevated lactate dehydrogenase (LDH) level
  • Stage III or IV disease
  • Eastern Cooperative Oncology Group (ECOG) performance status ≥2
  • Two or more extranodal sites

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:

  • 0-1 risk factors - 75%
  • 2-3 risk factors - 50%
  • 4-5 risk factors - 25%
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Follicular Lymphoma

World Health Organization Classification

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.

Diagnosis

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]

Risk Stratification

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.

Treatment

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:

  • Rituximab (preferred) (375 mg/m 2 weekly for 4 doses)
  • Chlorambucil plus rituximab
  • Cyclophosphamide plus rituximab
  • Chlorambucil
  • Cyclophosphamide
  • Ibritumomab tiuxetang (category 2B)
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Marginal Zone Lymphomas of MALT Type

Diagnosis

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]

Staging

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]

Treatment

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]

 

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Mantle Cell Lymphoma

Diagnosis

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

Risk stratification

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]

Treatment

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)

  • For relapsed or refractory disease, recommendations include high-dose therapy with autologous stem cell rescue and second-line agents bendamustine, bortezomib, temsirolimus, ibrutinib or lenalidomide with rituximab; allogeneic stem cell transplantation can be considered in selected patients as part of a second-line consolidation
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Diffuse Large B-Cell Lymphoma

Diagnosis

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]

Risk stratification

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] :

  • Elevated LDH level
  • Stage III or IV disease
  •  ECOG performance status ≥2

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)

Treatment

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.

Follow-up

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]

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Burkitt Lymphoma

Classification

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

Diagnosis

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

Risk stratification

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%

Treatment

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:

  • CODOX-M (original or modified) alternating with IVAC (ifosfamide, cytarabine, etoposide, and intrathecal methotrexate) ± rituximab
  • Dose-adjusted EPOCH + rituximab (for high-risk patients not able to tolerate aggressive treatments); regimen includes intrathecal methotrexate
  • HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with high-dose methotrexate and cytarabine + rituximab (regimen includes intrathecal therapy)

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

Follow-up

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]

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Primary Cutaneous B-Cell Lymphomas

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]

Classification

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.

Diagnosis

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

Staging

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

   

Treatment

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] .

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Cutaneous T-Cell Lymphoma

Classification

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)

Mycosis Fungoides/Sezary syndrome

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]

Diagnosis

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

Staging

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

 

Treatment

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]

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Primary Cutaneous CD30+ T-Cell Lymphoproliferative Disorders

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]

Classification

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]

Diagnosis

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

Staging

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]

Treatment

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

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Questions & Answers

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 WHO classification subtypes of non-Hodgkin lymphoma (NHL) for peripheral B-cell neoplasms?

What are the WHO classification subtypes of non-Hodgkin lymphoma (NHL) for peripheral T-cell and NK-cell neoplasms?

What are the NCCN recommendations for the workup of non-Hodgkin lymphoma (NHL)?

Which immunophenotype studies do the NCCN guidelines consider as essential 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 Lugano Modification of the Ann Arbor staging system recommendations for non-Hodgkin lymphoma (NHL)?

How is the International Prognostic Index (IPI) used to predict outcomes of non-Hodgkin lymphoma (NHL)?

What are the International Prognostic Index (IPI) risk factors in non-Hodgkin lymphoma (NHL)?

How are patients with non-Hodgkin lymphoma (NHL) characterized based on the International Prognostic Index (IPI) score?

What are the 5-year survival rates for non-Hodgkin lymphoma (NHL) based on the International Prognostic Index (IPI) score?

How does WHO classify the follicular lymphoma subtypes of non-Hodgkin lymphoma (NHL)?

What are the NCCN recommendations for diagnostic workup of the follicular lymphoma type of non-Hodgkin lymphoma (NHL)?

What are the GELF criteria for identifying which patients with non-Hodgkin lymphoma (NHL) need immediate therapy?

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 survival rates of the follicular lymphoma type of non-Hodgkin lymphoma (NHL) based on the FLIPI2 score?

What are the NCCN and ESMO treatment recommendations for non-Hodgkin lymphoma (NHL)?

What are the NCCN-recommended chemotherapy regimens for follicular lymphomas (FL) non-Hodgkin lymphoma (NHL)?

What are the NCCN recommendations for the diagnostic workup of gastric mucosa-associated lymphoid tissue (MALT) 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 recommendations for the early staging procedures of MALT non-Hodgkin lymphoma (NHL)?

What are the NCCN and ESMO treatment recommendations for MALT non-Hodgkin lymphoma (NHL)?

What are the NCCN recommendation for the diagnostic workup of the mantle cell lymphoma (MCL) type of non-Hodgkin lymphoma (NHL)?

What are the MIPI risk factors for the mantle cell lymphoma (MCL) type of non-Hodgkin lymphoma (NHL)?

What are the MIPI score risk categories for the mantle cell lymphoma type of non-Hodgkin lymphoma (NHL)?

What are the NCCN and ESMO recommendation for the evaluation of cell proliferation in the mantle cell lymphoma type of non-Hodgkin lymphoma (NHL)?

What are the NCCN and ESMO treatment recommendations for the mantle cell lymphoma (MCL) type of non-Hodgkin lymphoma (NHL)?

Which studies does the NCCN recommend to establish a diagnosis of diffuse large B-cell lymphoma (DLBCL) non-Hodgkin lymphoma (NHL)?

How is an immunohistochemistry (IHC) panel used to diagnose diffuse large B-cell lymphoma (DLBCL) non-Hodgkin lymphoma (NHL)?

Which index do the NCCN and ESMO recommend for the prognosis of diffuse large B-cell lymphoma (DLBCL) non-Hodgkin lymphoma (NHL)?

What are the IPI risk factors for diffuse large B-cell lymphoma (DLBCL) non-Hodgkin lymphoma (NHL)?

What are the IPI score risk categories for diffuse large B-cell lymphoma (DLBCL) non-Hodgkin lymphoma (NHL)?

What are the aa-IPI risk factors for diffuse large B-cell lymphoma (DLBCL) non-Hodgkin lymphoma (NHL)?

What are the aa-IPI score risk categories for diffuse large B-cell lymphoma (DLBCL) non-Hodgkin lymphoma (NHL)?

What are the (NCCN recommendations for the treatment of diffuse large B-cell lymphoma (DLBCL) non-Hodgkin lymphoma (NHL)?

What are the NCCN recommendations for the treatment stage II bulky disease of diffuse large B-cell lymphoma (DLBCL) non-Hodgkin lymphoma (NHL)?

What are the NCCN recommendations for the treatment stage II/III bulky disease of diffuse large B-cell lymphoma (DLBCL) non-Hodgkin lymphoma (NHL)?

What are the second-line regimens for high-dose chemotherapy (HDC) for relapse or refractory disease in diffuse large B-cell lymphoma (DLBCL) non-Hodgkin lymphoma (NHL)?

What are the ESMO treatment guidelines for diffuse large B-cell lymphoma (DLBCL) non-Hodgkin lymphoma (NHL) in older patients?

What are the guidelines for follow-up in patients with complete remission of diffuse large B-cell lymphoma (DLBCL) non-Hodgkin lymphoma (NHL)?

What are the variants of the Burkitt lymphoma (BL) form of non-Hodgkin lymphoma (NHL) identified by the 2008 WHO classification?

What studies are recommended by the NCCN to establish a diagnosis of the Burkitt lymphoma form of 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 NCCN-recommended chemotherapy regimens for the Burkitt lymphoma form of non-Hodgkin lymphoma (NHL)?

What are the NCCN recommendations for follow-up in patients with the Burkitt lymphoma form of non-Hodgkin lymphoma (NHL)?

Which organizations have issued treatment guidelines for primary cutaneous B-cell lymphomas (CBCL) of non-Hodgkin lymphoma (NHL)?

What are the main types of cutaneous B-cell lymphomas (CBCL) of non-Hodgkin lymphoma (NHL)?

What are the NCCN recommendations for the diagnostic workup of cutaneous B-cell lymphomas (CBCL) in non-Hodgkin lymphoma (NHL)?

What is the 2007 TNM classification system of the ISCL/EORTC for cutaneous B-cell lymphomas (CBCL) of non-Hodgkin lymphoma (NHL)?

What are the NCCN and EORTC/ISCL treatment guidelines for cutaneous B-cell lymphomas (CBCL) in non-Hodgkin lymphoma (NHL)?

How does the WHO-EORTC classify indolent cutaneous T-cell lymphomas (CTCLs) in non-Hodgkin lymphoma (NHL)?

How does the WHO-EORTC classify aggressive cutaneous T-cell lymphomas (CTCLs) in non-Hodgkin lymphoma (NHL)?

What are the NCCN recommendations for the diagnostic workup of mycosis fungoides/Sezary syndrome (MF/SS) in cutaneous T-cell lymphoma (CTCL) non-Hodgkin lymphoma (NHL)?

What is the revised TNMB classification for mycosis fungoides/Sezary syndrome (MF/SS) in cutaneous T-cell lymphoma (CTCL) non-Hodgkin lymphoma (NHL)?

What are the treatment recommendations for mycosis fungoides/Sezary syndrome (MF/SS) cutaneous T-cell lymphoma (CTCL) non-Hodgkin lymphoma (NHL)?

What are the considerations for topical therapies to treat mycosis fungoides/Sezary syndrome (MF/SS) in cutaneous T-cell lymphoma (CTCL) non-Hodgkin lymphoma (NHL)?

Which localized therapies are used to treat mycosis fungoides/Sezary syndrome (MF/SS) non-Hodgkin lymphoma (NHL)?

Which systemic therapies are used to treat mycosis fungoides/Sezary syndrome (MF/SS) non-Hodgkin lymphoma (NHL)?

What are the recommended second-line combination therapies for advanced mycosis fungoides/Sezary syndrome (MF/SS) non-Hodgkin lymphoma (NHL)?

What is the role of participation in a clinical trial in the treatment of mycosis fungoides/Sezary syndrome (MF/SS) non-Hodgkin lymphoma (NHL)?

When were recommendations for the management of primary cutaneous CD30+LPDs of non-Hodgkin lymphoma (NHL) issued?

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)?

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