Non-hodgkin's%20lymphoma Diagnosis

Diagnosis

Physical Examination

Node-bearing areas
Spleen, liver enlargement especially in follicular lymphoma (FL), hairy cell lymphoma (HCL), Mycosis fungoides (MF)/Sézary syndrome (SS), Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL)
Examination of the testicles suggested in extranodal natural killer/T-cell lymphoma (ENKL)
Skin examination
- Inclusion of Waldeyer’s ring in ENKL
- Identification of type of skin lesion in patients with SS

Laboratory Tests

Complete blood count, with differential and platelet count
- Peripheral monoclonal B lymphocyte count ≥5x10⁹/L - chronic lymphocytic leukemia (CLL)
- B lymphocytes ≤5x10⁹/L with lymphadenopathy and/or splenomegaly may indicate small lymphocytic lymphoma (SLL)

Metabolic panel, including LDH levels and serum beta-2-microglobulin
Serum uric acid levels
Hepatitis B screening is recommended for patients with FL, mucosa-associated lymphatic tissue (MALT), marginal zone lymphoma (MZL), HCL, MCL, DLBCL, BL, AIDS-related B-cell lymphoma (BCL), lymphoblastic lymphoma (LL), post-transplant lymphoproliferative disorders (PTLD)
Testing for hepatitis C is also suggested
Testing for Helicobacter pylori for gastric MALT
Viral etiology of NHL should also be examined (eg human T-cell lymphoma virus [HTCLV], Epstein Barr virus [EBV], HIV)
- ENKL patients with ≥6.1x10⁷ copies/mL may suggest inferior disease-free survival rates
- HIV testing is suggested for patients with DLBCL, AIDS-related BCL and BL

Biopsy

Lymph Node Biopsy

Cornerstone of diagnosis
Indicated for nodes >1.5 cm diameter, firm, irregular, clustered, fixed palpable nodes
Also used for suspected SLL patients with lymphadenopathy and/or splenomegaly, and abnormal peripheral blood count
Excisional biopsies are preferred

Core Needle Biopsy

Suggested when lymph nodes are not accessible
Recommended before initiation of radioimmunotherapy (RIT)

Bone Marrow Biopsy

Bone marrow aspiration and trephine biopsy are recommended
Indicated for specimens >1.6 cm and clinical stage I-II FL, MZL, MCL and BL
Bone marrow aspiration is utilized in cases where lymph nodes are unaccessible for biopsy

Skin Biopsy

Indicated for MF/SS and cutaneous B-cell lymphoma
- Incisional/excisional/punch biopsy preferred over shave biopsy
May also be performed for diagnosis of acute T-cell lymphoma/leukemia

Imaging

Positron Emission Tomography (PET)

Recommended for localized diseases and to identify occult sites of the disease or histologic transformation
Aids in evaluating patient response to treatment
Indicated in FL, DLBCL, nongastric MALT lymphoma, MZL, BL, MCL, AIDS-related BCL, LL, PTLD, adult T-cell lymphoma/leukemia (ATLL), primary cutaneous B-cell lymphoma (PCBCL), ENKL and MF/SS

Computed Tomography (CT)

CT scan of the chest, abdomen and pelvic area are recommended for patients with suspected/diagnosed chronic lymphocytic leukemia (CLL), FL, MALT, MZL, HCL, MF/SS, MCL, BL, cutaneous BCL, AIDS-related BCL, LL, PTLD, peripheral T-cell lymphoma (PTCL), ATLL, PCBCL, ENKL, MF/SS
CT scan of the neck is suggested in FL, primary T-cell lymphoma, DLBCL, MF/SS, MCL BL, AIDS-related BCL and ATLL
Head CT may be performed for patients with possible CNS involvement especially in DLBCL, PTCL, BL and ATLL
Use of contrast medium is recommended for patients with FL, MALT, MZL, HCL, MCL, BL, AIDS-related BCL, LL, PTCL and ENKL
More sensitive and specific when combined with PET

Magnetic Resonance Imaging (MRI)

Indicated for ATLL
MRI of the brain is suggested for nongastric MALT lymphoma, BL, AIDS-related BCL, LL and ATLL
MRI of the nasal cavity, hard palate, anterior fossa and nasopharynx are recommended for ENKL

Endoscopy/Endoscopic Ultrasound (EU)

May be performed as endoscopy alone or via ultrasound-guided endoscopy
Suggested for patients with suspected gastric MALT, nongastric MALT lymphoma, MCL, AIDS-related BCL and ATLL (upper GI endoscopy)

Echocardiogram and/or Multi-Gated Acquisition (MUGA) Scan

Performed when Anthracycline/Anthracenedione treatment is anticipated
Indicated for FL, gastric and nongastric MALT lymphoma, nodal MZL, MCL, DLBCL, PTCL, BL, and ENKL

Molecular and Genetic Analysis

Effectively differentiates NHL subtypes by identifying the specific cell lineage using antibodies
Lymph node and spleen tissue samples are preferred over bone marrow tissue samples for cytogenic analysis
Detects immunoglobulin heavy chain variable (IGHV) mutational status

Flow Cytometry

Fast and reliable method of identifying single cell populations of surface antigens
Uses antibodies/markers to identify the presence and proportion of surface antigens by using antibodies/markers
Used in FL, prolymphocytic T-cell lymphoma, MF/SS (expanded CD4 and cells with increased CD4/CD8 ratio), BL (bcl2 via cerebrospinal fluid analysis), LL, nodal and splenic MZL
Suggested for confirmation of clonality of B cells in CLL/SLL

Fluorescence in situ Hybridization (FISH)

Detects chromosomal abnormalities (11q,13q, 17p deletion, trisomy 12) and highly sensitive for known detectable translocation during initial diagnosis
Used in FL (t[14;18], bcl2 and bcl6 rearrangements), MCL (t[11;14] translocation), chronic lymphocytic leukemia (CLL) (t[11;14] translocation with specific CCND1/IGH probes or CCND1 break-apart probe); DLBCL (MYC gene arrangements)
Recommended for diagnosis of BL (t[8;14])

Immunohistochemistry (IHC) Panel

Aids in identification and characterization of the immunophenotype of most lymphomas
IHC panel used for identification of specific lymphomas:
- FL: CD20, CD3, CD5, CD10, BCL2, BCL6, CD21, CD23
- Gastric mucosa-associated lymphatic tissue (MALT) lymphoma: CD20, CD3, CD5, CD10, BCL2, kappa/lambda, CD21 or CD23, cyclin D1, BCL6
- Nongastric MALT lymphoma, nodal MZL: CD20, CD3, CD5, CD10, BCL2, kappa/lambda, CD21 or CD23, cyclin D1
- Splenic MZL: CD20, CD3, CD5, CD10, BCL2, kappa/lambda, CD21 or CD23, cyclin D1, IgD, CD43, annexin A1
- MCL: CD20, CD3, CD5, cyclin D1, CD10, CD21, CD23, BCL2, BCL6, TP53, Ki-67
- DLBCL: CD20, CD3, CD5, CD10, CD45, BCL2, BCL6, Ki-67, IRF4/MUM1, MYC
- BL: CD45, CD20, CD3, CD10, Ki-67, BCL2, BCL6, TdT
- Peripheral T-cell lymphomas: CD20, CD3, CD10, BCL6, Ki-67, CD5, CD30, CD2, CD4, CD8, CD7, CD56, CD21, CD23, EBER-ISH, TCRβ, TCRδ, PD1/CD279, ALK, TP63

Polymerase Chain Reaction (PCR)

Detects specific abnormal DNA translocations and T cell receptor clonality and B cell clonality that may be the origin of leukemic cells
bcl gene rearrangements: B-cell lymphoma, FL, DLBCL
T-cell receptor gene rearrangements: MF/SS, MCL (CCND2 gene - 55%)
MYC gene rearrangements: DLBCL (2-11%)

Other Procedures

Lumbar Puncture

Used for patients with possible CNS involvement with overt symptoms
Indicated for DLBCL patients with paranasal sinus, testicular, epidural, HIV-associated, bone marrow with large cells, >2 extranodal sites and elevated LDH levels, for LL and ATLL

Assessment

The following provides useful prognostic information that may be used to guide therapeutic decisions

International Prognostic Index (IPI)

Risk factors:
- Age >60 years old
- Elevated serum LDH
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2-4
- Ann Arbor stage III-IV
- >1 nodal sites involved
Risk group (all patients):
- 0-1 risk factor: Low
- 2 risk factors: Low-intermediate
- 3 risk factors: High-intermediate
- 4 or 5 risk factors: High
Risk group for patients ≤60 years old (risk factors: Ann Arbor stage III-IV, elevated serum LDH, ECOG PS 2-4):
- 0 risk factor: Low
- 1 risk factor: Low-intermediate
- 2 risk factors: High-intermediate
- 3 risk factors: High
Risk group for patients with stage I or II DLBCL:
- 0 or 1 risk factor: Low
- 2-4 risk factors: High

National Comprehensive Cancer Network (NCCN) - International Prognostic Index (IPI)

Risk factors:
- 1 point:
  - >40-≤60 years old
  - >1 to ≤3 serum LDH
  - ECOG PS ≥2
  - Ann Arbor stage III-IV
  - Positive for extranodal disease
- 2 points
  - >60-<75 years old
  - >3 serum LDH
- 3 points: ≥75 years old
Risk group
- 0-1 risk factor: Low
- 2-3 risk factors: Low-intermediate
- 4-5 risk factors: High-intermediate
- ≥6 risk factors: High

Groupe d’Etude des Lymphomes Folliculaires (GELF) Criteria

≥3 nodal sites involved, each measuring ≥3 cm in diameter
Any nodal/extranodal tumor mass ≥7 cm
Cytopenias (leukocytes <1.0 x 10⁹/L, platelets <100 x 10⁹/L)
Presence of systemic symptoms
Splenomegaly
Pleural effusion/peritoneal ascites
Leukemia (>5.0 x 10⁹/L malignant cells)

Follicular Lymphoma International Prognostic Index (FLIPI) Criteria

ECOG PS >1
Serum LDH/β2-microglobulin level > upper limit of normal (ULN)
Hemoglobin level <12 g/dL
≥60 years old
Ann Arbor Stage III-IV
≥5 nodal sites involved

Prognostic Group
Indolent

Lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia)
Splenic MZL
Primary cutaneous anaplastic large cell lymphoma
Follicular lymphoma
Hairy cell leukemia
Marginal zone lymphoma
MF/SS

Aggressive

Diffuse large B-cell lymphoma
Follicular large cell lymphoma
Anaplastic large cell lymphoma
Extranodal NK-/T-cell lymphoma
Lymphomatoid granulomatosis
Lymphoblastic lymphoma
Burkitt lymphoma/diffuse small noncleaved-cell lymphoma
Enteropathy-type intestinal T-cell lymphoma
Polymorphic post-transplantation lymphoproliferative disorder
Mediastinal large B-cell lymphoma (primary mediastinal large B-cell lymphoma)
Intravascular large B-cell lymphoma (intravascular lymphomatosis)
Adult T-cell leukemia/lymphoma
Mantle cell lymphoma
True histiocytic lymphoma
Primary effusion lymphoma
Angioimmunoblastic T-cell lymphoma
Peripheral T-cell lymphoma
AIDS-related lymphoma

Classification

Classification According To Staging

Developed by the American Joint Committee on Cancer: Ann Arbor Staging Classification and the Cotswold modifications

Stage	Features
I	Involvement of a single lymph node region or lymphoid structure (eg spleen, thymus, Waldeyer’s ring)
II*	Involvement of ≥2 lymph node regions on the same side of the diaphragm
III	Involvement of lymph regions or structures on both sides of the diaphragm
IV	Involvement of ≥1 extranodal site(s) beyond that designated E
For All Stages
A	No symptoms
B	Fever (>38°C [100.4°F]), drenching sweats, weight loss (10% body weight over 6 months)
For Stages I-II
E	Involvement of a single extranodal site contiguous or proximal to known nodal site
Cotswold Modifications
(i)	Suffix X to designate bulky disease as more than one third widening of the mediastinum or >10-cm maximum dimension of nodal mass
(ii)	The number of anatomic regions involved should be indicated by a subscript (eg 113)
(iii)	Stage III may be subdivided into: III1, with or without splenic, hilar, celiac, or portal nodes; III2, with para-aortic, iliac, mesenteric nodes
(iv)	Staging should be identified as clinical stage or pathological stage
(v)	Staging should be identified as clinical stage or pathological stage A new category of response to therapy, unconfirmed/uncertain complete remission should be introduced because of the persistent radiologic abnormalities of uncertain significance
*Divided into Stage II and Stage II bulky based on the Lugano Modification of Ann Arbor Staging System for primary nodal lymphomas Stage II bulky defined as Stage II with bulky disease

Classification According To Histologic Types

2016 classification based on the World Health Organization (WHO) modification of the Revised European American Lymphoma (REAL) classification
Further subdivided into precursor and mature subtypes

B-cell Lymphomas
Precursor

Acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL)

Mature

Diffuse large B-cell lymphoma (DLBCL): Most common histologic subtype
Follicular lymphoma (FL): The second most frequent NHL subtype
Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL): The most common leukemia among adults
- Please see Chronic Lymphocytic Leukemia disease management chart for further information
B-cell prolymphocytic leukemia (B-PLL)
Lymphoplasmacytic lymphoma/immunocytoma
Mantle cell lymphoma (MCL)
Burkitt lymphoma (BL)
Hairy cell leukemia (HCL)
Plasmacytoma/plasma cell myeloma
AIDS-related B-cell lymphoma
Primary cutaneous B-cell lymphoma (PCBCL)
Marginal zone lymphoma (MZL)
- Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphatic tissue (MALT) type
- Nodal MZL
- Splenic MZL

T-cell/Natural Killer (NK)-cell Lymphomas
Precursor

Acute lymphoblastic leukemia/LBL

Mature

T-cell prolymphocytic leukemia (T-PLL)
T-cell chronic lymphocytic leukemia
T-cell large granular lymphocytic leukemia
Mycosis fungoides (MF)/Sézary syndrome (SS)
Enteropathy-type intestinal T-cell lymphoma
Adult T-cell lymphoma/leukemia (ATLL)
Anaplastic large cell lymphoma (ALCL), primary systemic type
Angioimmunoblastic T-cell lymphoma
ALCL, primary cutaneous type
Aggressive NK-cell leukemia
Peripheral T-cell lymphoma (PTCL)
Hepatosplenic gamma/delta T-cell lymphoma
Subcutaneous panniculitis-like T-cell lymphoma
Extranodal T-/NK-cell lymphoma, nasal type (ENKL)

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