Non-hodgkin's%20lymphoma Diagnosis

• 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

• 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 for staging, especially for those with no access to positron emission tomography (PET)-computed tomography (CT) scans and for non-fluorodeoxyglucose (FDG)-avid non-Hodgkin's lymphoma (NHL)
• 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

• 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

• 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

• 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

• 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)

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

• 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
• Provides prognostic information for most NHL subtypes
  

• 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

• 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])

• 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 (noncutaneous), 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

• Detects specific abnormal DNA translocations and immunoglobulin gene rearrangements 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%)

• 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

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

• 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 

• 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

• Lymphoplasmacytic lymphoma (Waldenström macroglobulinemia)
• Primary cutaneous anaplastic large cell lymphoma
• FL
• HCL
• MZL (extranodal, nodal, splenic)
• MF/SS
• T-LGLL

Aggressive

• DLBCL
• Follicular large cell lymphoma
• ALCL
• ENKL
• Lymphomatoid granulomatosis
• Lymphoblastic lymphoma
• BL/diffuse small noncleaved-cell lymphoma
• EATL
• Polymorphic post-transplantation lymphoproliferative disorder
• Mediastinal large B-cell lymphoma (primary mediastinal large B-cell lymphoma)
• Intravascular large B-cell lymphoma (intravascular lymphomatosis)
• ATLL
• MCL
• True histiocytic lymphoma
• Primary effusion lymphoma
• Angioimmunoblastic T-cell lymphoma
• PTCL
• AIDS-related lymphoma

• 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 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

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

• 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

• Acute lymphoblastic leukemia/LBL

• T-cell prolymphocytic leukemia (T-PLL)
• T-cell chronic lymphocytic leukemia
• T-cell large granular lymphocytic leukemia (T-LGLL)
• Mycosis fungoides (MF)/Sézary syndrome (SS)
• Enteropathy-type intestinal T-cell lymphoma (EATL)
• Adult T-cell lymphoma/leukemia (ATLL)
• Anaplastic large cell lymphoma (ALCL), primary systemic type
• Angioimmunoblastic T-cell lymphoma (AITL)
• ALCL, primary cutaneous type
• Aggressive NK-cell leukemia
• Peripheral T-cell lymphoma (PTCL)
• Hepatosplenic gamma/delta T-cell lymphoma (HTCL)
• Subcutaneous panniculitis-like T-cell lymphoma
• Extranodal T-/NK-cell lymphoma, nasal type (ENKL)
• Nodal peripheral T-cell lymphoma with T-follicular helper (TFH) phenotype (Nodal PTCL, TFH)
• Follicular T-cell lymphoma (FTCL)
• Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL)