The number of patients with newly diagnosed lymphoma in Japan was reported to be 24,778 in 2011. The prevalence has been increasing over the years, from 5.5 per 100,000 population in 1985 to 8.9 in 1995, 13.3 in 2005, and 19.4 in 2011.

It is more common in men than women (ratio of about 3:2) and incidence peaks in the 70–79 age group [1]. It is broadly classified histologically into Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL), but the vast majority are NHL, and HL only account for approximately 5–10% of all lymphomas in Japan

Essential elements for diagnosis and treatment plan determination

Medical history

The patient’s past medical history, diseases for which they are currently being treated, comorbidities, initial symptoms, timing of symptom onset, general symptoms (e.g., fever, weight loss, and night sweats), and place of birth if necessary should be determined by medical interview and recorded.

Physical findings

The following should be evaluated by physical examination and recorded:

  • Height, weight, body temperature, blood pressure, and pulse.

  • Performance status.

  • Anemia and jaundice, skin rash, auscultation and percussion of chest and abdomen, lymph node enlargement (and sites [region names and laterality], number, size, and properties [e.g., stiffness and mobility] if enlarged lymph nodes are present), palpable hepatomegaly/splenomegaly, edema.

  • Motor nerve paralysis, paresthesia, and meningeal signs.

General tests

The following tests should be performed:

  • Peripheral blood cell count, morphology (white blood cell count, neutrophil count, lymphocyte count, tumor cell count, red blood cell count, hemoglobin level, and platelet count).

  • Blood biochemistry (TP, Alb, ALT, AST, LDH, ALP, γ-GTP, Na, K, Cl, Ca, P, BUN, Cr, FBS, and UA).

  • Serological tests (CRP, IgG, IgA, IgM, protein fractions, soluble IL-2R, and beta-2 microglobulin).

  • Virus tests (HBs antigen, HBs antibody [Ab], HBc Ab, HCV Ab, HIV Ab, and HTLV-1 Ab).

  • Urinalysis (glucose, protein, occult blood, and sediment).

  • Imaging and other tests (chest X-ray, 12-lead electrocardiography, computed tomography [CT] of the neck/chest/abdomen/pelvis, upper and lower gastrointestinal endoscopy [as needed], bone-marrow aspiration or biopsy, echocardiography, and, as needed, positron emission tomography [PET], head CT or magnetic resonance imaging [MRI], cerebrospinal fluid analysis, and arterial blood gas analysis).

Histopathological diagnosis

Histopathological testing by biopsy is essential to the diagnosis of lymphoma and biopsy of the appropriate lesion must be performed before treatment. As the inguinal and axillary lymph nodes can enlarge reactively, biopsy of the cervical lymph nodes is best in patients with generalized lymphadenopathy. Except when open biopsy is not feasible, histopathological testing by needle biopsy alone is often insufficient for diagnosis.

Biopsy specimens should be processed into formalin-fixed paraffin blocks, cut into thin sections, and stained with hematoxylin and eosin. Other immunohistochemical tests such as those listed below, as well as Epstein–Barr encoding region (EBER) in situ hybridization, should also be performed:

  • CD45.

  • Cytoplasmic CD3ε and CD5.

  • CD20, CD79a, CD10, and immunoglobulin (cytoplasmic immunoglobulin).

  • CD56.

  • CD15, CD30, cyclin D1, BCL2, BCL6, MIB1 (Ki-67), IRF4/MUM1, MYC, etc.

Other tests

Cells should be isolated from the specimen as best as possible and the following tests performed:

  • Flow cytometry.

  • Chromosome analysis.

  • Gene analysis.

  • Fluorescence in situ hybridization (e.g., BCL2, BCL6, MYC, CCND1, and MALT1).

Classification of disease type

The 2017 WHO classification is widely used as a classification of lymphoma. Lymphoid neoplasms, which include lymphoma, are classified as follows: [2]:

  • Mature B-cell neoplasms

    • Chronic lymphocytic leukemia/small lymphocytic lymphoma

    • Monoclonal B-cell lymphocytosis

    • B-cell prolymphocytic leukemia

    • Splenic marginal zone lymphoma

    • Hairy cell leukemia

    • Splenic B-cell lymphoma/leukemia, unclassifiable

    • Splenic diffuse red pulp small B-cell lymphoma

    • Hairly cell leukemia variant

    • Lymphoplasmacytic lymphoma

    • Monoclonal gammopathy of undetermined significance, IgM

    • Mu heavy chain disease

    • Lambda heavy chain disease

    • Alpha heavy chain disease

    • Plasma cell myeloma

    • Solitary plasmacytoma of bone

    • Extraosseous plasmacytoma

    • Monoclonal immunoglobulin deposition disease

    • Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)

    • Nodal marginal zone lymphoma

    • Follicular lymphoma

    • Pediatric-type follicular lymphoma

    • Large B-cell lymphoma with IRF4 rearrangement

    • Primary cutaneous follicle center lymphoma

    • Mantle cell lymphoma

    • Diffuse large B-cell lymphoma, not otherwise specified

    • T-cell/histiocyte-rich large B-cell lymphoma

    • Primary DLBCL of the central nervous system

    • Primary cutaneous DLBCL, leg type

    • EBV-positive DLBCL, not otherwise specified

    • EBV-positive mucocutaneous ulcer

    • DLBCL associated with chronic inflammation

    • Lymphomatoid granulomatosis

    • Primary mediastinal (thymic) large B-cell lymphoma

    • Intravascular large B-cell lymphoma

    • ALK-positive large B-cell lymphoma

    • Plasmablastic lymphoma

    • Primary effusion lymphoma

    • HHV8-positive DLBCL, not otherwise specified

    • Burkitt lymphoma

    • Burkitt-like lymphoma with 11q aberration

    • High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangement

    • High-grade B-cell lymphoma, not otherwise specified

    • B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma

  • Mature T-cell and NK-cell neoplasms

    • T-cell prolymphocytic leukemia

    • T-cell large granular lymphocytic leukemia

    • Chronic lymphoproliferative disorder of NK cells

    • Aggressive NK-cell leukemia

    • Systemic EBV-positive T-cell lymphoma of childhood

    • Hydroa vacciniforme-like lymphoproliferative disorder

    • Adult T-cell leukemia/lymphoma

    • Extranodal NK/T-cell lymphoma, nasal type

    • Enteropathy-associated T-cell lymphoma

    • Monomorphic epitheliotropic intestinal T-cell lymphoma

    • Indolent T-cell lymphoproliferative disorder of the gastrointestinal tract

    • Hepatosplenic T-cell lymphoma

    • Subcutaneous panniculitis-like T-cell lymphoma

    • Mycosis fungoides

    • Sézary syndrome

    • Primary cutaneous CD30-positive T-cell lymphoproliferative disorders

    • Lymphomatoid papulosis

    • Primary cutaneous anaplastic large cell lymphoma

    • Primary cutaneous gamma–delta T-cell lymphoma

    • Primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma

    • Primary cutaneous acral CD8-positive T-cell lymphoma

    • Primary cutaneous CD4-positive small/medium T-cell lymphoproliferative disorder

    • Peripheral T-cell lymphoma, not otherwise specified

    • Angioimmunoblastic T-cell lymphoma

    • Follicular T-cell lymphoma

    • Nodal peripheral T-cell lymphoma with T-follicular helper phenotype

    • Anaplastic large cell lymphoma, ALK positive

    • Anaplastic large cell lymphoma, ALK negative

    • Breast implant-associated anaplastic large cell lymphoma

  • Hodgkin lymphoma

    • Nodular lymphocyte-predominant Hodgkin lymphoma

    • Classic Hodgkin lymphoma

      • Nodular sclerosis classic Hodgkin lymphoma

      • Mixed cellularity classic Hodgkin lymphoma

      • Lymphocyte-rich classic Hodgkin lymphoma

      • Lymphocyte depleted classic Hodgkin lymphoma

Clinical classification

The working formulation proposed in 1982 not only classifies NHL into disease entities, but also classifies NHL by grade based on its natural history. If left untreated, low-grade NHL progresses over a matter of years, intermediate-grade over a matter of months, and high grade over a matter of weeks. In 1989, the United States National Cancer Institute proposed a clinical classification in which low-grade lymphomas are classified as indolent, intermediate grade as aggressive, and high grade as highly aggressive to expand classification beyond grade to aggressiveness, which reflects characteristics such as malignant nature, activity, and invasiveness. This classification has been widely used in clinical trials. WHO classification entities roughly fall under the following clinical classifications [3]:

  • Indolent lymphomas

    • B cell

      • Chronic lymphocytic leukemia/small lymphocytic lymphoma

      • Lymphoplasmacytic lymphoma

      • Splenic marginal zone lymphoma

      • Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)

      • Nodal marginal zone lymphoma

      • Follicular lymphoma

      • Mantle cell lymphoma

    • T-cell

      • T-cell large granular lymphocytic leukemia

      • Adult T-cell leukemia/lymphoma (smoldering)

      • Mycosis fungoides/Sézary syndrome

      • Primary cutaneous anaplastic large cell lymphoma

  • Aggressive lymphomas

    • B-cell

      • Diffuse large B-cell lymphoma

    • T-cell

      • Peripheral T-cell lymphoma, not otherwise specified

      • Enteropathy-associated T-cell lymphoma

      • Anaplastic large cell lymphoma

      • Hepatosplenic T-cell lymphoma

      • Adult T-cell leukemia/lymphoma

      • Extranodal NK/T-cell lymphoma, nasal type

      • Angioimmunoblastic T-cell lymphoma

  • Highly aggressive lymphomas

    • B-cell

      • Burkitt lymphoma/leukemia

    • T-cell

      • Aggressive NK-cell leukemia

Staging systems

The extent of lymphoma greatly affects treatment selection and prognosis, which makes accurate staging critical. General staging of lymphoma is determined by medical history, physical findings, complete blood count and morphology, blood biochemistry, chest X-ray, CT of the neck/chest/abdomen/pelvis, and, as necessary, upper and lower gastrointestinal endoscopy and bone-marrow aspiration or biopsy.

Gallium scans were previously performed for staging of lymphoma, but recently have been substituted with PET-CT due to its superior sensitivity and specificity. As FDG avidity differs between histologic types of lymphoma, FDG-PET should also be used for pre-treatment staging to ensure more accurate assessments when using FDG-PET for response assessment, and ideally, PET-CT should be performed if possible to more accurately assess the significance of lesions.

The Ann Arbor classification, which was developed for staging of HL, has also been used for NHL [4]. However, the 2014 Lugano classification was created at the International Conference on Malignant Lymphoma as a modified version of the Ann Arbor classification that would be universal and unambiguous [5]. In the 2014 Lugano classification, stage is determined by PET-CT before treatment for lymphomas that show high FDG uptake if PET-CT will be used for response assessment. General A and B symptoms do not need to be recorded for NHL, and bone-marrow biopsy is not necessary for HL and diffuse large B-cell lymphoma if PET-CT has been performed.

As the main lesion is extranodal in primary gastrointestinal lymphoma, the Ann Arbor stage is often inconsistent with actual disease progression in such lymphomas. Therefore, the 1994 Lugano staging system for primary gastrointestinal lymphoma created at the International Conference on Malignant Lymphoma is used in addition to the Ann Arbor classification [6].

Ann Arbor classification

Stage I

Involvement of a single lymph node region (I); or localized involvement of a single extralymphatic organ or site in the absence of any lymph node involvement (IE)

Stage II

Involvement of two or more lymph node regions on the same side of the diaphragm (II); or localized involvement of a single extralymphatic organ or site in association with regional lymph node involvement with or without involvement of other lymph node regions on the same side of the diaphragm (IIE)

The number of involved regions may be written in subscript, for example, as II3

Stage III

Involvement of lymph node regions on both sides of the diaphragm (III), which also may be accompanied by extralymphatic extension in association with adjacent lymph node involvement (IIIE) or by involvement of the spleen (IIIS) or both (IIIES)

Stage IV

Diffuse or disseminated involvement of one or more extralymphatic organs, with or without associated lymph node involvement; or isolated extralymphatic organ involvement in the absence of adjacent regional lymph node involvement, but in conjunction with disease in distant site(s)

  1. A and B classification (symptoms)
  2. Each stage is classified as A or B based on general symptoms as defined below:
  3. (1) Fever: unexplained fever > 38 °C
  4. (2) Night sweats: drenching sweat so intense that the bed linens (including all bed coverings besides the mattress [e.g., comforter and sheets] but not sleepwear) must be changed
  5. (3) Weight loss: unexplained loss of > 10% of usual body weight within the 6 months preceding diagnosis

2014 Lugano classification (modified staging system for primary nodal lymphomas)

Stage

Involvement

Extranodal status (E)

Limited

 Stage I

One node or group of adjacent nodes

Single extranodal lesion without nodal involvement

 Stage II

Two or more nodal groups on the same side of the diaphragm

Stage I or II by nodal extent with limited, contiguous extranodal involvement

 Stage II bulkya

Stage II as above with bulky disease

N/A

Advanced

 Stage III

Nodes on both sides of the diaphragm, or nodes above the diaphragm with spleen involvement

N/A

 Stage IV

Non-contiguous extranodal involvement in addition to nodal lesions

N/A

  1. Disease progression is assessed by PET for lymphomas that show uptake and by CT for those that do not show uptake. Tonsils, Waldeyer’s ring, and spleen are considered nodal tissue
  2. The A and B classification (symptoms) of the Ann Arbor classification were removed from the 2014 Lugano classification. They are only added for Hodgkin lymphoma
  3. aWhether stage II bulky disease is treated as limited or advanced disease may be determined by histology and number of prognostic factors. As the definition of bulky disease differs by histology, the longest diameter should be recorded rather than using the “X” notation

Lugano staging system for primary gastrointestinal lymphoma (1994)

Stage I

 Confined to gastrointestinal tract

 Single primary, or multiple non-contiguous lesions

Stage II

 Extending into abdomen from primary gastrointestinal site

 Nodal involvement

 II1: local (perigastric if gastric lymphoma or peri-intestinal if intestinal lymphoma)

 II2: distant (mesenteric if primary intestinal, or paracaval, paraaortic, pelvic, or inguinal if not)

Stage IIE

 Penetration of serosa to involve adjacent organ or tissues. Specify site of involvement, e.g., IIE (pancreas), IIE (large intestine), IIE (retroperitoneum).

If both nodal involvement and involvement of adjacent organs, denote stage using both a subscript (1 or 2) and E, e.g., II1E (pancreas).

Stage IV

 Disseminated extranodal involvement or concomitant supra-diaphragmatic nodal involvement.

Prognostic factors

Lymphoma is broadly classified histologically into two prognostic groups: low-grade and intermediate-to-high-grade. Various other factors besides histology, including molecular category, stage, and individual patient characteristics such as performance status, are known to influence prognosis as well. The International Prognostic Index (IPI) [7] is used as a prognostic model for aggressive lymphoma. Recently, the National Comprehensive Cancer Network IPI (NCCN-IPI) has been proposed as a prognostic index for diffuse large B-cell lymphoma based on outcomes from after the introduction of rituximab [8]. The Follicular Lymphoma International Prognostic Index (FLIPI) [9] is used for follicular lymphoma and the International Prognostic Score (IPS) [10] is used for advanced Hodgkin lymphoma.

Aggressive lymphomas

IPI

Prognostic factors in the IPI

Unfavorable prognostic factors

Age

Serum LDH

Performance status

Stage

Number of involved extranodal sites

> 60 years

> upper limit of normal

2–4

Stage III or IV

≥ 2

Age-adjusted IPI

Prognostic factors in the age-adjusted IPI

Unfavorable prognostic factors

Serum LDH

Performance status

Stage

> upper limit of normal

2–4

Stage III or IV

Patients are classified into the following four risk groups by number of prognostic factors in both the IPI and age-adjusted IPI:

  • IPI

    • 0 or 1 factor: low risk

    • 2 factors: low–intermediate risk

    • 3 factors: high–intermediate risk

    • 4 or 5 factors: high risk

  • Age-adjusted IPI

    • 0 factors: low risk

    • 1 factor: low–intermediate risk

    • 2 factors: high–intermediate risk

    • 3 factors: high risk

*Age-adjusted IPI is used for treatments indicated for younger patients but not older patients (e.g., autologous hematopoietic stem cell transplantation) and for clinical studies on treatments exclusively in elderly patients.

Diffuse large B-cell lymphoma

NCCN-IPI

Unfavorable prognostic factors in the NCCN-IPI

Score

Age

 

 > 40 to 60 years

1

 > 60 to 75 years

2

 > 75 years

3

Serum LDH

 

 Above but within 3 times the upper limit of normal

1

 Over 3 times the upper limit of normal

2

Stage III or IV

1

 Extranodal involvement (bone marrow, central nervous system, liver/gastrointestinal tract, and lungs)

1

 Performance status ≥ 2

1

Patients are classified into the following four risk groups by their score:

  • Score of 0 or 1: low risk

  • Score of 2 or 3: low–intermediate risk

  • Score of 4 or 5: high–intermediate risk

  • Score of 6 or higher: high risk

Follicular lymphoma

FLIPI

Prognostic factors in FLIPI

Unfavorable prognostic factors

Age

Serum LDH

Hemoglobin level

Number of nodal sites involved

Stage

> 60 years

> upper limit of normal

< 12 g/dL

≥ 5 regions

Stage III or IV

Patients are classified into the following three risk groups by number of prognostic factors:

  • 0 or 1 factor: low risk

  • 2 factors: intermediate risk

  • 3 or more factors: high risk

FLIPI is a prognostic model for overall survival that was created using data from retrospective studies conducted before the introduction of rituximab. FLIPI2 was later created as a predictive model of progression-free survival using data from prospective studies conducted after the introduction of rituximab [11].

FLIPI2

Prognostic factors in FLIPI2

Unfavorable prognostic factors

Age

> 60 years

Beta-2 microglobulin level

> upper limit of normal

Hemoglobin level

< 12 g/dL

Longest diameter of largest involved node

> 6 cm

Bone-marrow involvement

Yes

Patients are classified into the following three risk groups by number of prognostic factors:

  • 0 factors: low risk

  • 1 or 2 factors: intermediate risk

  • 3 or more factors: high risk

Advanced Hodgkin lymphoma

IPS

Prognostic factors in IPS

Unfavorable prognostic factors

Serum albumin level

Hemoglobin level

Sex

Age

Stage

White blood cell count

Lymphocytes

< 4 g/dL

< 10.5 g/dL

Male

≥ 45 years

Stage IV

≥ 15,000/mm [3]

< 600/mm [3], or < 8% fraction of white blood cells

The IPS is defined as the number of prognostic factors.

Response criteria

Criteria from the “Report of an International Workshop to standardize response criteria for NHL” published in 1999 are widely used in response assessment for treatments for lymphoma [12]. Although CT is usually used for response assessment, the revised response criteria for malignant lymphoma incorporating FDG-PET for diffuse large B-cell lymphoma and HL were published in 2007 in light of the recent surge in adoption of FDG-PET and research results suggesting its clinical usefulness [13]. These response criteria were created as an effort toward global standardization of clinical trial evaluation, but treatment response assessed by FDG-PET are better correlated with subsequent prognosis than response assessed by CT alone [14], which makes FDG-PET useful for response assessment in routine clinical practice as well. It is recommended to use the five-point scale when assessing treatment response by PET-CT [15].

Revised response criteria for NHL (2007) [CT only without PET]

Overall response

Normalization of target lesions and SPD

Non-target lesions

Enlarged liver, spleen, and kidneys

Tumor-related symptoms and tumor-related laboratory abnormalities

Bone-marrow involvement

New lesion(s)

Nodal

Extranodal

Nodal

Extranodal

CR

Normal

Disappearance

Normal

Disappearance

Disappearance

Normal

Negative

No

CRu

Normal

Disappearance

Normal

Disappearance

Disappearance

Normal

Indeterminate

No

 

≥ 75% decrease

Normal

Disappearance

Disappearance

Normal

Negative or indeterminate

No

PR

≥ 75% decrease

Normal

Disappearance

Disappearance

Normal

Positive

No

 

≥ 50% decrease

Normal or no increase in size

Disappearance or no increase in size

Disappearance or no worsening

Normal

Irrelevant (not required to be evaluated)

No

SD

< 50% decrease and < 50% increase

Normal or no increase in size

Disappearance or no increase in size

Disappearance or no worsening

Normal or no worsening

Irrelevant (not evaluated)

No

PD

≥ 50% increase

≥ 50% increase

Increase in size

Increase in size

Worsening

Worsening

Newly positive after previous negative

Yes

RD

Recurrent growth

Recurrent growth

Recurrence

Recurrence

Recurrence

  1. CT computed tomography, PET positron emission tomography, SPD sum of the products of the greatest diameters, CR complete response, CRu complete response/unconfirmed, PR partial response, SD stable disease, PD progressive disease, RD relapsed disease

[With addition of PET]

Overall response

SPD of target lesions

Non-target lesions

Bone-marrow involvement

PET

New lesion (s)

Nodal

Extranodal

Nodal

Extranodal

CR

Changes in SPD are irrelevant (required to be evaluated)

Negative

Negative

No

PR

Changes in SPD are irrelevant (required to be evaluated)

Positive

Negative

No

≥ 50% decrease

Normal or no increase in size

Disappearance or no increase in size

Irrelevant(not required to be evaluated)

Positive

No

SD

< 50% decrease and< 50% increase

Normal or no increase in size

Disappearance or no increase in size

Irrelevant (not required to be evaluated)

Positive

No

PD

≥ 50% increase

Increase in size

Increase in size

Newly positive

Positive

Yes

RD

Recurrent growth

Recurrence

Recurrent increase in size

Recurrence

  1. CT computed tomography, PET positron emission tomography, SPD sum of the products of the greatest diameters, CR complete response, CRu complete response/unconfirmed, PR partial response, SD stable disease, PD progressive disease, RD relapsed disease

Five-point scale

1

No uptake

2

Uptake below mediastinum

3

Uptake above mediastinum, but below or equal to uptake in the liver

4

Uptake slightly to moderately higher than the liver

5

Markedly higher uptake than liver, and/or appearance of any new lesion

X

New area of uptake not overtly attributable to lymphoma

Post-treatment follow-up

Methods of post-treatment follow-up and evaluation differ by disease type and by setting (i.e., clinical trial versus routine clinical practice). Performing a complete blood count, blood biochemistry, and imaging appropriately, alongside careful history-taking and examinations, is important in making appropriate clinical decisions.

Although there is no evidence to provide clear guidelines regarding the frequency and duration of follow-up, it is recommended to perform follow-up assessments for Hodgkin lymphoma and curable aggressive lymphoma every 2–3 months for the first 2 years after a complete response and at least every 3–6 months for 3 years after that point. It is recommended to perform follow-up assessments for indolent lymphoma that is unlikely to be cured, every 2–3 months for the first year after treatment and then every 3–6 months thereafter.

The previous studies reported that relapse of lymphoma is detected by clinical symptoms in over 80% of cases [16, 17]. Although relapse can sometimes be detected before appearance of clinical symptoms by regular CT scans, it is unclear whether early detection improves prognosis [18]. Therefore, whether to perform regular CT scans for follow-up should be determined by carefully weighing the risks and benefits to the patient, including the cost. Regular follow-up by PET is not recommended due to a lack of evidence of any benefit [19,20,21,22].