Diffuse Large Cell Lymphoma Workup

Updated: Oct 21, 2017
  • Author: Shipra Gandhi, MBBS; Chief Editor: Emmanuel C Besa, MD  more...
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Workup

Approach Considerations

The initial evaluation of diffuse large B-cell lymphoma (DLBCL) patients is aimed at determining the stage of the disease, assessing for end-organ damage by the disease and/or preexisting comorbid conditions, and identifying situations that may affect treatment design. The evaluation of patients with lymphoproliferative disorders should include a detailed history and physical examination.

Complete blood cell (CBC) count with differential

Laboratory testing to assess bone marrow and immunological function includes CBC count with differential and platelet counts, which should be performed in all newly diagnosed patients to evaluate involvement of the bone marrow, which may result in anemia, thrombocytopenia, and/or leukopenia. In addition, perform a peripheral blood examination for circulating tumor cells by flow cytometry.

Comprehensive metabolic panel

A comprehensive chemistry panel should be performed to help evaluate serum electrolytes, lactic dehydrogenase (LDH), renal function, and hepatic function. In addition, perform serum β2 microglobulin (B-cell lymphoma) testing.

Electrolyte abnormalities may occur from renal involvement with lymphoma. Abnormal renal function may require a chemotherapy dose adjustment.

Elevated levels of lactate dehydrogenase (LDH) and uric acid correspond with the tumor burden. The LDH value is a factor in the International Prognostic Index (IPI) and is a useful indicator of the extent of disease and of the response to treatment. It can be used as an early, nonspecific indicator of disease relapse. [25] An elevated uric acid level also signifies an increased likelihood of tumor lysis syndrome with chemotherapy

Computed tomography (CT) scanning

Routine CT scanning of the neck, chest, abdomen, and pelvis is the standard imaging study for patients with lymphoma.

Functional imaging

Functional imaging with positron emission tomography (PET) has become an important diagnostic and prognostic tool in the management of patients with various subtypes of lymphoma, such as DLBCL, Hodgkin lymphoma (HL), and mantle cell lymphoma (MCL). Most academic institutions recommend routine PET scanning to complement staging and posttreatment evaluation of all patients with aggressive lymphoma. Retrospective studies have demonstrated that midtreatment and/or end-of-treatment PET scanning provides strong prognostic information in terms of progression-free survival (PFS) and overall survival (OS). The adequate timing for PET scanning for response assessment is a subject of controversy and recommendations vary among academic institutions. [26]

Bone marrow sampling

Bone marrow biopsy and aspiration should be performed in all newly diagnosed lymphoma patients. Routine pathological, flow cytometry, and cytogenetic studies should also be performed.

CNS imaging and lumbar puncture

CNS imaging and cerebrospinal (CSF) analysis should be considered in clinically symptomatic patients or in those patients at high risk for occult CNS disease (eg, high-grade lymphoma, HIV-associated lymphoma, select patients with aggressive lymphoma).

Gastrointestinal imaging

While gastrointestinal evaluation (ie, upper and/or lower endoscopy) is recommended in patients with MCL, it is not routinely required in the staging of DLBCL.

Cardiac evaluation

Cardiac studies evaluating ejection fraction are required in patients expected to receive anthracycline-based chemotherapy.

Serological evaluation for pathogens

This includes evaluations for hepatitis B virus (HBV), and hepatitis C virus (HCV), and HIV.

Serological evaluation for HBV and HCV is mandatory for those patients expected to receive monoclonal antibody–based therapy (ie, rituximab). As rituximab use has become an integral part of the management of DLBCL, rare but serious adverse events have been associated with hepatitis B and C reactivation. Fatal cases of fulminate hepatic failure due to active hepatitis B or C have been reported in DLBCL patients undergoing chemoimmunotherapy. Therefore, routine HBV and HCV serology is recommended.

In addition, serologic testing for HIV infection should be considered in patients with coexistent HIV risk factors, aggressive histologies (DLBCL, Burkitt or T-cell lymphoma), or unusual clinical presentations.

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Flow Cytometry and Genetic Studies

Flow cytometry to identify the expression of different immunophenotypes helps in determining a clonal cell population and in differentiating between B- and T-cell origins.

Cytogenetic or fluorescent in situ hybridization (FISH) studies may reveal common chromosomal translocations, such as the following:

  • t(3q27) (bcl-6) - Occurs in 35% of patients with diffuse large B-cell lymphoma
  • t(14;18)(q32;q21) (bcl-2) - Occurs in 15-20% of patients with diffuse large B-cell lymphoma
  • t(8;14)(q24;q32) - Occurs in less than 5% of patients with diffuse large B-cell lymphoma

Gene expression profiling may be able to distinguish 2 separate subtypes of diffuse large B-cell lymphomas (normal germinal center B-cell pattern vs activated B-cell–like), each of which has a different prognosis. In addition, results from gene rearrangement studies can be used to establish clonality. [27, 28]

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Imaging Studies

CT scanning

CT scans of the neck, chest, abdomen, and pelvis are used to help identify the degree of lymphadenopathy, the presence or absence of extranodal disease, and/or the presence of visceral involvement. CT scans are also part of the complete staging workup for diffuse large cell lymphoma.

In addition, baseline CT-scan findings aid in disease follow-up care after chemotherapy to assess the degree of response to therapy; they also aid in planning consolidating radiation therapy, if used. (See the images below.)

Computed tomography (CT) scan of the abdomen showi Computed tomography (CT) scan of the abdomen showing mesenteric and retroperitoneal adenopathy in a patient with diffuse large cell lymphoma.
Patient with diffuse large B-cell lymphoma with ex Patient with diffuse large B-cell lymphoma with extranodal involvement. This computed tomography (CT) scan shows an enlarged spleen and liver as a result of lymphomatous involvement.
Patient with diffuse large B-cell lymphoma with ex Patient with diffuse large B-cell lymphoma with extranodal involvement (same patient as in the previous image). This patient has an enlarged spleen and liver as a result of lymphomatous involvement. Extensive retroperitoneal lymphadenopathy is also present.
Diffuse large B-cell lymphoma. Hematoxylin and eos Diffuse large B-cell lymphoma. Hematoxylin and eosin stain of a lymph node biopsy sample showing a mixture of large and small cells. The architecture of the node is lost, with a diffuse pattern of involvement.

Bone imaging

Patients with unexplained bone pain or elevated alkaline phosphatase levels should be evaluated with a bone scan. Obtain plain radiographs of any abnormal area on the bone scan to check for lymphomatous involvement of the skeleton.

Gallium-67 scanning

Gallium-67 (67 Ga) scans are valuable in the staging of diffuse large cell lymphomas (DLCLs). Gallium uptake correlates with disease activity and is useful as an indicator of response and prognosis. Uptake of67 Ga occurs in approximately 50% of indolent lymphomas and in most aggressive and highly aggressive types.67 Ga scans are also sometimes used as a means of assessing sites of relapse. (See the image below.)

This image depicts gallium scans performed as part This image depicts gallium scans performed as part of a staging workup for a patient with diffuse large B-cell lymphoma. The scans show extensive hepatosplenic and multiple sites of nodal involvement with a gallium-avid tumor.

MUGA scanning

Multigated acquisition (MUGA) scans are used to evaluate the patient's ejection fraction before chemotherapy, because anthracyclines used in the treatment of diffuse large cell lymphomas have a potential cardiotoxic effect.

PET scanning

Positron emission tomography (PET) scans are increasingly being used to stage disease through the use of fluorodeoxyglucose (FDG), since findings for glucose uptake can indicate areas of increased metabolic activity. [29] PET-scan data can also be useful in helping to determine whether residual masses represent scars or persistent lymphoma.

PET scan findings are being investigated for use as prognostic indicators during treatment (after 2-4 cycles), but the clinical utility of this is still unclear.

PET scanning may be more sensitive than gallium scans for more indolent lymphoproliferative diseases, but definitive data comparing gallium to PET scanning of lymphomas are not available.

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Biopsy and Lumbar Puncture

Bone marrow aspiration and biopsy is performed as part of the staging process to help rule out involvement with lymphoma. Bilateral iliac crest bone marrow biopsies should also be performed as part of the staging.

Lymph node biopsy is required to establish a definitive diagnosis of non-Hodgkin lymphoma (NHL); this should be an excisional biopsy rather than a needle biopsy, because nodal architecture is often difficult to assess when small amounts of tissue are used.

Because bone marrow involvement increases the likelihood of lymphomatous involvement of the meninges, in patients with advanced-stage disease, a lumbar puncture for cytologic and chemical analysis of the cerebrospinal fluid may be necessary.

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Histologic Findings

The diagnosis of diffuse large cell lymphoma is usually confirmed after positive findings are obtained from a lymph node biopsy specimen. Pathology findings should be reviewed by an expert hematopathologist, because lymphomas can be difficult to classify.

Diffuse large B-cell lymphomas are more or less composed of equal numbers of small and large cells. The small cells are usually slightly larger than normal lymphocytes, and they have a cleaved or indented nucleus and coarse chromatin.

The large cells can be cleaved or noncleaved. The cytoplasm of these cells is pale, and the cells have an irregular, central, indented nucleus with inconspicuous nucleoli. A subset of the large cells has rounded nuclei with 1 or more nucleoli; these are the noncleaved large cells and are somewhat larger than the cleaved cells. (See the images below.)

Biopsy of a cervical lymph node showing infiltrati Biopsy of a cervical lymph node showing infiltration with a population of large cells (B cells) consistent with diffuse large cell lymphoma.
Diffuse large B-cell lymphoma. Hematoxylin and eos Diffuse large B-cell lymphoma. Hematoxylin and eosin stain of a lymph node biopsy sample showing a mixture of large and small cells. The architecture of the node is lost, with a diffuse pattern of involvement.
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Pathology of DLBCL

Pathological evaluation is extremely important in the diagnosis of diffuse large B-cell lymphoma (DLBCL). Sufficient biopsy material and formal consultation by an experienced hematopathologist is mandatory. The preferred diagnostic procedure is an excisional biopsy, unless contraindicated because of significant comorbid conditions, the clinical scenario (eg, rapidly growing nodal masses requiring urgent treatment), or the location of nodal/extranodal-involved sites. In cases in which excisional biopsy cannot be performed, multiple core biopsies are acceptable. Fine-needle aspiration (FNA) has a high yield of false-negative results and is not recommended in the workup and diagnosis of patients with a suspected diagnosis of DLBCL or any other forms of lymphoma.

Pathological classification of lymphomas

The classification of lymphomas has undergone significant modifications over the last 3 decades. Currently, 2 classification systems are widely used: the World Health Organization (WHO) and revised European-American (REAL) classification of lymphoid malignancies. [30, 4] The nomenclature of DLBCL has undergone several changes as a result of revisions in the pathological classification of lymphomas over the last decades. It had been previously named a diffuse histiocytic lymphoma (Rappaport’s classification), centroblastic lymphoma (Kiel’s classification), and a large cleaved follicular center cell or large cell immunoblastic lymphoma (working formulation). [30, 4, 3]

Pathological characteristics of DLBCL

Morphologically, DLBCL is composed of large B cells with a high proliferation index resembling germinal centroblasts. DLBCL usually develops de novo but can also emerge as a clonal transformation in patients with low-grade lymphomas or chronic lymphocytic leukemia (CLL). De novo DLBCL tends to have a better response rate to standard therapy and better prognosis than transformed DLBCL. Several morphologic variants of DLBCL have been described, such as centroblastic, immunoblastic, plasmablastic, T-cell/histiocyte-rich, and anaplastic B-cell lymphoma (usually anaplastic lymphoma kinase [ALK]) positive). [31, 32] While each of these variants can be determined by pathological evaluation, the clinical prognostic significance remains controversial.

Immunophenotype studies demonstrate that DLBCL co-expresses pan B-cell markers, including CD19, CD20, CD79a, CD45RA, and the nuclear transcription factor PAX5. The expression of additional markers may have prognostic implications. The proliferation factor Ki67 is usually high, at 65% mean percentage. High Ki67 levels (>80%) have been associated with a shorter survival. [33] Germinal center–associated markers CD10 and Bcl-6 are expressed in approximately 30-40% and 60%, respectively. Bcl-6 expression has been associated with a prolonged progression-free survival (PFS) and overall survival (OS) following rituximab chemotherapy in retrospective studies. [34, 35] On the other hand, CD5 is expressed only in 10% of DLBCL cases, and its expression should raise the suspicion of transformation from a more indolent form of NHL such as small lymphocytic lymphoma (SLL) or CLL, and it has been associated with a shorter survival. [36]

Subclassification of DLBCL

Under the WHO and/or REAL classification of lymphoid malignancies, the following histological variants are considered clinical and/or pathological distinct subtypes of DLBCL:

  • DLBCL, not otherwise specified
  • T-cell/histiocyte-rich large B-cell lymphoma
  • DLBCL associated with chronic inflammation
  • Epstein-Barr virus (EBV)–positive DLBCL of the elderly
  • Primary mediastinal (thymic) large B-cell lymphoma
  • Intravascular large B-cell lymphoma
  • Primary cutaneous DLBCL, leg type
  • ALK-positive large B-cell lymphoma
  • Plasmablastic lymphoma
  • Primary effusion lymphoma
  • Large B-cell lymphoma arising in human herpes virus type 8–associated multicentric Castleman disease
  • B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma

Gene expression profiling (GEP) studies provide significant insightful information in the understanding of the DLBCL biology. GEP studies have identified and validated 3 different subtypes of DLBCL, (1) germinal center B-cell (GCB) lymphoma, (1) activated B-cell (ABC) lymphoma, and (3) primary mediastinal lymphoma (PML), each with significant differences in terms of prognosis, PFS, and OS following systemic chemotherapy or, more recently, chemoimmunotherapy. [37, 38, 39]

GCB-DLBCL appears to be derived at the postgerminal state, primarily driven by deregulation of apoptosis by Bcl-6, and has an excellent response to rituximab-based chemoimmunotherapy regimens. ABC-DLBCL is driven by high levels of nuclear factor Kappa-B (NFkB) activity and is associated with a poor outcome, despite chemoimmunotherapy. PML shares GEP signatures similar to those of classic Hodgkin lymphomas (HLs), and, although it has a good prognosis when compared with other DLBCL subtypes, treatment-related toxicities (ie, involved-field radiation) continue to be a significant problem being addressed in clinical trials.

Although GEP studies are the best way to differentiate different subtypes of DLBCL that might be clinically relevant, the use of the GEP studies has not been validated prospectively and widespread use as a routine diagnostic tool is still not practical. Hence, GEP studies are not recommended outside from a clinical trial. Recently, GEP results have been translated into a clinically applicable approaches using immunohistochemistry (IHC). [40, 41, 42]

IHC appears to be an easy and practical method for differentiating DLBCL subgroups. Several attempts to subtype DLBCL cases into GCB and non-GCB have been made, with algorithms using several markers (eg, CD10, Bcl-6, IRF4/MUM1), such as the Hans algorithm and the algorithm proposed by Muris et al. [40, 41, 43] The Hans algorithm reproduces the gene expression-based classification of DLBCL and has a misclassification rate of 20%. [40] Both algorithms have been evaluated as predictors of clinical outcomes in DLBCL patients undergoing front-line therapy with standard chemotherapy or chemoimmunotherapy. [42, 43] On the other hand, the differences in the clinical behavior and therapeutic response of patients with relapsed/refractory GBC and non-GBC DLBCL have been defined in recently completed or ongoing clinical studies. [44, 45, 46]

Genetic abnormalities in DLBCL

Information obtained from genetic studies performed in DLBCL tumor specimens stresses the complexity in the biology of this disease. DLBCLs express clonally rearranged immunoglobulin H (IgH) genes with somatic mutations in the variable region. For this reason is thought that DLBCL cells are derived from antigen-exposed B-cells. No gene abnormality is pathognomonic for DLBCL. Recurrent translocations involving the BCL6, BCL2, and MYC genes have been described in approximately 50% of cases. Chromosomal translocation leading to up-regulation of BCL2 [t(14;18)] is present in 20-30% of DLBCL cases and is especially observed GCB variants. Gene abnormalities in ABC-DLBCL are more complex and include trisomies, deletions, and chromosomal inactivation. [47, 48]

The clinical value of testing for genetic aberrations in DLBCL continues to grow in recognition. Recently, a subset of DLBCL patients carrying both c-Myc and Bcl-2 translocations as detected by fluorescence in situ hybridization (FISH) were identified. Those patients are known as having “double-hit DLBCL” which represents approximately 8% of newly diagnosed DLBCL patients. It exhibits a poor response to standard doses of rituximab chemotherapy regimens and has a poor OS. [49, 50, 51, 52] Moreover, IHC studies have demonstrated that concurrent over-expression of c-Myc and Bcl-2 is associated with a poor clinical outcome. [53, 54] Currently, c-Myc and Bcl-2 cytogenetic studies (ie, FISH) and IHC analysis for Bcl2 and c-Myc over-expression should be performed in DLBCL patients exhibiting a high proliferation index (ie, Ki67 ≥90%).

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Molecular Biology of DLBCL

Numerous genetic and molecular changes accumulate through a multistep process leading to the selective growth advantage of a malignant clone. B-cell lymphomas arise at various stages of B-cell development. Under normal circumstances, a pro-B cell undergoes various stages of maturation that include (1) the recombination of the V, D, and J gene segments necessary for assembling of the immunoglobulins’ heavy and light chains; (2) somatic hypermutation; and (3) immunoglobulin-class switching. During the process of V(D)J recombination (regulated by the recombination activating genes 1 [RAG1] and 2 [RAG2] enzymes) and somatic hypermutation/immunoglobulin-class switching (regulated by the activation-induced cytidine deaminase [AID] enzyme) phases, multiple DNA alterations occur and normal B cells are susceptible to the development of undesirable chromosomal translocations or gene mutations, leading to the development of B-cell lymphoma. [55]

Abnormalities in the process of B-cell maturation lead to the development of lymphoid malignancies. The type of mutation(s) and the stage of lymphoid maturation at the time of genetic aberration(s) play a role in the type of lymphoma that may develop in a given patient. [56] Subtypes of diffuse large B-cell lymphoma (DLBCL) arise from genetic alterations occurring during the process of B-cell differentiation/maturation and, in general, are characterized by a blockage of the programmed cell death process (ie, up-regulation of Bcl-2, loss of Bcl-6 function, p53 deletion/mutation), an increase in cell proliferation (eg. increase in nuclear factor kappa B [NFkB], up-regulation of c-Myc), or impaired terminal differentiation (ie, defective Blimp-1 function). Specific genetic alteration(s) or protein expression/function deregulation varies depending on the subtype of DLBCL.

Several oncogenic pathways have been identified in DLBCL (B-cell receptor [BCR] signaling pathway, constitutive activation of NFkB activity pathways, and deregulation of the Bcl-6/apoptosis pathway); however, only one pathway appears to play a pivotal role in the biology of distinct types of DLBCL (ie, germinal center B-cell [GCB] vs activated B-cell [ABC] DLBCL). [55]

Constitutive NF kappa-B signaling

Lymphoid malignancies usually avoid cell death by constitutive activation of the NFkB pathway. It is a transcription factor regulating the expression of the immunoglobulin kappa light chain. [57] In B cells, NFkB activation occurs transiently downstream of numerous receptors, including the BCR, CD40, the B-cell–activating factor (BAFF) receptor, and various Toll-like receptors (TLRs). [58] Alternatively, activation of NFkB results from the proteasome degradation of its inhibitor (inhibitor of kappa B [IkB]).

The hallmark of ABC-DLBCL is the activation of NFkB through the classic pathway. Many of the NFkB target genes are expressed in ABC-DLBCL compared with GCB-DLBCL, and this explains how genetic inhibition of this pathway is lethal to ABC- but not GCB-DLBCL lines. [59] Clinically, it has been observed that ABC-DLBCL patients are more refractory to standard immunochemotherapy than other DLBCL subtypes. This could be explained by the ability of NFkB to antagonize the antitumor activity of chemotherapy agents. [60] Moreover, pharmacological inhibitors of NFkB activity (ie, lenalidomide or bortezomib) appear to have selective activity in non–GCB-DLBCL. [45, 46]

Recently, additional mechanisms leading to an increase in NFkB activity have been described in ABC-DLBCL, particularly caspase recruitment domain 11 (CARD11) mutations. The survival of most ABC-DLBCL cell lines depends on the CBM complex (a signaling hub consisting of CARD11, BCL-10, and MALT1). [61] The CBM complex is required for activation of the classic NFkB pathway downstream of the antigen receptors in B and T cells. [62] CARD11 is a multidomain signaling adapter that contains (1) an amino-terminal CARD and coiled-coil domains, (2) an intervening linker domain, and (3) a C-terminal membrane-associated guanylate kinase (MAGUK) domain.

In normal resting conditions, CARD11 is located in the cytosol, where it is presumably kept in an inactive conformation through an intramolecular interaction between its coiled-coil and linker domains. Following signaling via the BCR, protein kinase C (PKC) beta–dependent serine phosphorylation within the CARD11 linker domain occurs and activates CRD11. [63] CARD11 is then able to translocate into the plasma membrane, where it binds to BCL10 and MALT1, forming the CBM complex. Subsequently, the CBM complex plays a pivotal role in the phosphorylation and proteasome degradation of IkB. CARD11 mutations resulting in constitutive engagement of the CBM complex have been described in 10% of ABC-DLBCL patients. [64]

NF kappa-B activation via tonic BCR signaling

Activation of NFkB has also been described in ABC-DLBCL with wild-type CARD11. In this subtype of DLBCL, BCR signaling appears to play a key regulatory role. BCRs present in the surface of B cells are responsible for downstream proliferation and survival signals. [65] The BCR affects B-cell development, antigen-driven clonal selection, and humoral immunity. Structurally, the BCR consists of antigen-binding IgH and immunoglobulin L (IgL) chains noncovalently coupled to CD79A and CD79B subunits. [66] Upon antigen stimulation, clustering of the BCRs occurs, leading to signal transduction via the CD79A and B subunits. [67] CD79A or B mutations have been described in 20% of patients with ABC-DLBCL and lead to the over-expression of CD79 and over-amplification of BCR signaling. [68]

Genetic aberrations in DLBCL group patients

Distinct cytogenetic abnormalities have been described in DLBCL patients. It is unclear to what degree such abnormalities contribute to the development or disease biology. Cytogenetic abnormalities vary between different DLBCL subtypes.

GCB-DLBCL

The most common translocation is t(14,18), with rearrangements of the BCL2 and IGH chain genes. [58] Because of the increased expression of BCL2, the cells are immortalized. Increased BCL2 expression is associated with a poor prognosis and shorter survival. The second most frequent cytogenetic aberration in the GCB subgroup is translocation leading to rearrangement of the MYC gene. A recurrent change noted in few patients is deletion of the tumour suppressor gene PTEN.

ABC-DLBCL

The most common aberration in ABC-DLBCL is translocation involving the BCL6 gene. [59] Another frequent aberration in the ABC group is trisomy 3. [60] Approximately 18 % of the patients diagnosed with ABC-DLBCL are diagnosed to have a deletion of the tumor suppressor gene P53. Inactivation of P53 results in uncontrolled cell proliferation and subsequent tumor genome instability. Mutations or deletions of P53 decrease the overall survival of all DLBCL patients.

Primary mediastinal lymphoma (PML)

Gain of the long arm of chromosome 9 is reported. [61] Duplication or multiplication of this locus is associated with up-regulation of the Janus kinase 2 (JAK2) gene. A gain of this gene is observed in 50% of the patients with PML. [62]

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Staging

Clinical staging of patients with diffuse large B-cell lymphoma (DLBCL) is fundamental in order to (1) define the treatment plan (ie, combined-modality vs systemic therapy plus/minus CNS prophylaxis), (2) determine risk stratification according to the International Prognostic Index (IPI) score system, and (3) predict the likelihood of survival following frontline therapy.

The staging of lymphoma patients provides information necessary for treatment planning and has prognostic significance, especially in Hodgkin lymphoma (HL). Currently the Ann Arbor staging system is the preferred staging system for DLBCL (see below).

After histologic and immunologic findings confirm the diagnosis of diffuse large cell lymphoma, a pretreatment staging evaluation should be performed. At minimum, patients should have routine blood counts and blood chemistries, particularly a lactate dehydrogenase (LDH) level, which is a prognostic parameter. Carefully examine the peripheral blood smear for any abnormal lymphoid cells.

Note that tumor lysis syndrome manifests as a rapid rise in potassium, phosphorus, and uric acid and a drop in calcium; this can lead to a sudden death from electrolyte abnormalities.

Radiologic staging studies include chest radiography and computed tomography (CT) scanning of the chest, abdomen, and pelvis. Bone, gallium, and PET scans, as well as plain films, may be helpful in selected patients.

Ann Arbor staging system

The Ann Arbor staging system, originally designed for Hodgkin disease, is traditionally used to assess the extent of disease involvement in patients with non-Hodgkin lymphoma (NHL). The stages are characterized as follows:

  • Stage I - Involvement of a single lymph node region (I) or localized involvement of a single extralymphatic organ or site (I E)
  • Stage II - Involvement of 2 or more lymph node regions on the same side of the diaphragm (II) or localized involvement of a single associated extralymphatic organ or site and its regional lymph nodes, with or without involvement of other lymph node regions on the same side of the diaphragm (II E)
  • Stage III - Involvement of lymph node regions on both sides of the diaphragm (III), which may also be accompanied by localized involvement of an associated extralymphatic organ or site (III E ), by involvement of the spleen (III s), or by both (III E+S)
  • Stage IV - Disseminated (multifocal) involvement of one or more extra lymphatic organs, with or without associated lymph node involvement, or isolated extralymphatic organ involvement with distant (nonregional) nodal involvement
  • A - No systemic symptoms present
  • B - Unexplained fever ≥ 38 o C; drenching night sweats; weight loss ≥ 10% body weight

Cotswold’s modifications are as follows:

  • X = bulky disease - Bulky disease is defined as a mass of nodes with one diameter of >10 cm or a mediastinal mass larger than one third of the transthoracic (mediastinal) width
  • Number or anatomic regions involved - The number of anatomic regions involved should be indicated by a subscript (eg, II 3)
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