Mantle Cell Lymphoma

Mantle cell lymphoma occurs in older adults and commonly presents as generalized disease with spleen, bone marrow, and gastrointestinal tract involvement. Circulating lymphoma cells are frequently found in the blood. This type of lymphoma is associated with a characteristic immunophenotype (CD5+, CD10±, and CD23−) and genotype with t(11;14) translocation and BCL1 (CCND1/PRAD1) gene overexpression.²⁸ Currently, advanced disease is not curable with chemotherapy. The median survival for patients with generalized disease is 4 to 6 years, and early use of high-dose therapy is promising.^30,32,33 Expression of a microarray gene profile characterized by high proliferation,³⁴ or a high Ki-67 growth fraction,³⁵ confers a worse prognosis. Localized stage I and II mantle cell lymphoma is uncommon, and there are little data on curability. Existing datasets suggest that the survival of patients with localized mantle cell lymphoma is better than those with advanced disease and that RT has an important role in localized disease.^36,37 Stage I and II mantle cell lymphomas may be curable.

T-Cell Lymphoma

Peripheral T-cell lymphomas are a heterogeneous group of T-cell neoplasms that are more common in Asia^38,39 and usually affect adults and are commonly generalized at presentation. An aggressive clinical course is typical; and although potentially curable, many T-cell lymphomas are resistant to current chemotherapy regimens. TCR gene rearrangements may be identified but this is not mandatory for diagnosis. Specific subtypes of T-cell lymphoma to consider include extranodal natural killer (NK)-cell/T-cell lymphoma of nasal type and enteropathy-associated T-cell lymphoma (EATL), previously called malignant histiocytosis of the intestine. This latter disease (EATL) usually involves the jejunum and in approximately 50% of cases is associated with a history of celiac disease.⁴⁰ Most EATLs express the human mucosal lymphocyte-1 (HML-1) antigen, supporting an origin from the intraepithelial T cells of MALT. EATLs are high-grade pleomorphic large cell lymphomas associated with a very poor prognosis. The entity of NK-cell/T-cell lymphoma of nasal type includes disorders previously known as lethal midline granuloma and nasal T-cell lymphoma. It is characterized by an angiocentric and angioinvasive infiltrate^28,41 (Fig. 75-2), with CD56-positive (T-cell/NK-cell) immunophenotype and is characteristically EBV positive. This disease responds poorly to chemotherapy and usually follows an aggressive course.^42,43,44 Other rare presenting sites may include skin, lung, testis, and central nervous system (CNS).

Figure 75-2 A, Photomicrograph of an extranodal natural killer (NK)/T-cell lymphoma, nasal type (H&E). There is abundant necrosis, and the lymphoma cells have an angiocentric and angioinvasive growth pattern (inset right lower corner). The lymphoma cells are immunoreactive for Epstein-Barr virus latent membrane protein (inset left lower corner). B, Extranodal NK-cell/T-cell lymphoma, nasal type. Axial CT scan showing involvement of the left nasal cavity.

A, Courtesy Dr. Bruce Patterson, Princess Margaret Hospital, Toronto.

The WHO classification, although aimed to classify distinct disease entities and acknowledging the uniqueness of certain presentations (e.g., the T cell lymphomas just cited), does not always consider the presenting site of the lymphoma. Recent evidence strongly suggests that the presenting site is an important factor for primary extranodal lymphomas. Examples include different causes for MALT lymphoma arising in different sites that are associated with differences in relapse rate.⁴⁵ Similar histology lymphomas may have distinct outcomes (e.g., diffuse large B-cell lymphoma involving the brain and thus with a poor prognosis) that are now clearly identified in the fourth edition of the WHO classification versus stomach or Waldeyer’s ring structures, which have a good prognosis.⁴⁶ With further understanding of etiology and pathogenesis of lymphomas, future modifications to classification of these diseases are expected.

BCL2

The t(14;18)(q32;q21) translocation involving BCL2 is the most common chromosome translocation in NHL. BCL2 encodes a 26-kd membrane protein that controls and prevents cellular apoptosis. The gene is translocated to a J segment of the IGH gene on chromosome 14, giving rise to deregulation of BCL2, with the result being the inhibition of apoptosis of B cells. This lesion is present in more than 90% of follicular lymphomas and in transformed follicular lymphomas.⁴⁷ In the latter situation, additional genetic lesions are acquired (TP53 mutation, deletion of chromosome 6q27, MYC) in parallel with more rapid growth and an aggressive clinical course. The TP53 mutation is associated with a poor survival rate in aggressive B-cell lymphomas, independent of the predictive effects of the International Prognostic Index (IPI).⁴⁸ The t(14;18) translocation is also found in 20% of de novo DLBCL and appears to be an unfavorable prognostic factor.

BCL1

The t(11;14)(q13;q32) translocation is found in the majority of mantle cell lymphomas. BCL1, now known as CCND1, encodes for cyclin D1 that regulates cell cycle progression. This lesion appears to be highly specific for mantle cell lymphoma, with the translocation of BCL1 on chromosome 11 to the IGH gene on chromosome 14, making it an extremely useful adjunct to immunophenotyping in distinguishing mantle cell lymphoma from other types of lymphomas.

BCL6

The BCL6 gene located on 3q27 is translocated in 40% of diffuse large B-cell lymphomas.^49,50 Reciprocal translocations can involve a number of other chromosomal locations, including 14q32 (IGH), 2p11 (IGK), and so on, all juxtaposing to 3q27.⁵¹ BCL6 is thought to mediate the DNA-binding activity of a number of zinc-finger transcription factors and characterizes the germinal center B-cell gene signature in microarray studies.⁵² The presence of the BCL6 translocation in DLBCL carries a favorable prognosis, in comparison with those carrying BCL2 who have a worse outcome and those with neither translocation who have an intermediate prognosis.^49,53

MYC

The MYC oncogene, located on chromosome 8q24, regulates cellular proliferation and differentiation. Its translocation is seen in 100% of Burkitt’s lymphomas typically to chromosome 14q32 (IGH), less commonly to 2p11 (IGK) and 22q11 (IGG). EBV infection is responsible for and can be documented in almost all cases of endemic Burkitt’s lymphoma and about 30% of the sporadic cases.^51,54 Aberrations of 8q24 can also be seen in follicular lymphoma, DLBCL, and mantle cell lymphoma and is characterized by transformation or progression of the disease, generally denoting a poor prognosis.^55,56

Other Chromosome Translocations

The t(2;5)(p23;q35) translocation characterizes anaplastic large cell lymphomas of T-cell origin. This translocation involves the fusion of the NPM1 (nucleophosmin) gene on 5q35 and the ALK (anaplastic lymphoma kinase) gene on 2p23.²⁸ Others involving ALK-2p23 include t(1;2)(q25;p23), Inv² (p23q35), and many others.²⁸ T-cell lymphomas may have 14q11 abnormalities involving the T-cell receptor-alpha gene. In MALT lymphomas, characteristic genetic abnormalities can include trisomy 3⁵⁷ and chromosomal translocations t(11;18)(q21;q21),⁵⁸ t(1;14)(p22; q32),⁵⁹ and t(14;18)(q32;q21)⁶⁰ (see Table 75-5).

Microarray Gene Profiling Studies

Gene-expression studies have been increasingly utilized to characterize various lymphomas. Microarray analysis of cDNA (the “lymphochip”) using hierarchical clustering techniques initially classified DLBCL into two groups.⁶¹ One expressed “germinal center B-cell–like” genes (GCB signature), such as MYBL1, LMO2, JNK3, CD10, BCL6, CREL, and BCL2, whereas the other expressed “activated B-cell–like” genes (ABC signature), such as CCND2, IRF4, FLIP, NF-κB, and CD44. For patients treated with anthracycline-based chemotherapy in the pre-rituximab era, the 5-year survival for the GCB group was 60%, compared with the ABC group of 35%, whereas that for a type 3 group was 39%.⁵² Based on a selection of the most prognostic genes, either a larger series of 17 genes⁵² or condensing further to three immunostains for CD10, BCL6, and MUM1,⁶² studies have shown that gene expression profiling provides additional prognostic information in addition to the clinical IPI scores.^52,62 Additional studies using oligonucleotide microarrays and a different analysis technique have also successfully identified two categories of patients with very different survival rates (70% vs. 12%) in DLBCL.⁶³ Gene profiling of the nonmalignant infiltrating cells in the tumor has also been found to be prognostic in DLBCL, whether treatment included rituximab or not.⁶⁴ The “stromal-1” group reflected extracellular matrix deposition, and histiocytic infiltration had a better prognosis than the “stromal-2” group, which reflected tumor angiogenesis activity.⁶⁴ Presently, the microarray assays are still not widely available. Other examples of microarray studies discovering significant findings correlating with clinical outcome include primary mediastinal B-cell lymphomas,⁶⁵ Burkitt’s lymphoma,^66,67 mantle cell lymphoma,^34,68 and follicular lymphoma.⁶⁹ In the case of follicular lymphoma it is of interest that it was the gene signature of the nonmalignant infiltrating immune cells, rather than the malignant cells, that had the prognostic effect.⁶⁹ It is likely that within the next decade most lymphomas will have their distinct genetic signatures identified. In addition to its usefulness in obtaining an accurate diagnosis (e.g., between DLBCL and Burkitt’s lymphoma),⁶⁶ and enhancing prognostication, these techniques could also be helpful in the study of minimal residual disease, that is, the detection of a small number of morphologically normal but genetically monoclonal population of malignant cells. The most important aspect of this evolving field is the insight provided into the molecular events underlying malignant transformation, cell cycle regulation, signal transduction, and cell death. Characterization of these mechanisms opens up the potential for novel therapeutic strategies, for example, targeting small molecules such as NF-κB.⁷⁰

Clinical Manifestations

NHL may present in any part of the body. Therefore, the presenting signs and symptoms of NHL are highly variable. The most common presentation is with an asymptomatic lymph node enlargement. Peripheral lymph node involvement (e.g., cervical, inguinal) is most common in indolent lymphomas and in generalized presentations. Lack of progressive enlargement of lymph nodes may lead to a delay in diagnosis. The most common presenting sites of nodal lymphomas are cervical, inguinal, and retroperitoneal lymph nodes. Mediastinal lymph node involvement is much less common than in Hodgkin’s lymphoma, except for the primary mediastinal large B-cell lymphoma. Patients may present with systemic symptoms of fever, weight loss, and night sweats, usually heralding the presence of more advanced disease.

As in nodal NHL, the presenting symptoms in primary extranodal lymphomas depend on the site of origin and do not differ significantly from symptoms of other malignancies affecting a specific organ. Occasionally, the clinical appearance of a lymphomatous lesion may not be characteristic of a malignancy and may mimic benign inflammatory lesions. Careful histopathologic examination, therefore, is extremely important in arriving at an early diagnosis. Characteristically, gastric lymphomas present as symptoms of peptic ulcer, bowel lymphomas present as intestinal obstruction or diarrhea, and primary bone lymphoma presents as pain. Primary lymphomas with diffuse involvement of an organ (e.g., liver, spleen, bone marrow) rather than a distinct tumor are particularly difficult to diagnose and are often a component of advanced disease. Tumor bulk at presentation is also related to primary site. Usually, primary lymphomas of skin or orbital structures are visible and therefore diagnosed early; extradural lymphomas develop symptoms early and present as small bulk disease. In contrast, intestinal lymphomas present as nonspecific symptoms and thyroid lymphomas (especially if associated with preexisting goiter) often present as bulky disease. In the absence of nodal involvement, lymphoma is often not suspected or distinguished clinically from carcinoma; therefore, immunophenotypic and histochemical analysis is particularly important.

Patient Evaluation

The goal of evaluation is to determine disease extent and bulk and its anatomic distribution and to ascertain normal organ and immune function relevant to the choice of therapy. With the diverse presentation of lymphomas, the recommended investigations may vary,⁷¹ but the following procedures serve as minimum recommended investigations (Table 75-5). Additional tests may be necessary based on such factors as the presenting complaint, the subtype of lymphoma, and predilection of organ involvement (e.g., brain and cerebrospinal fluid).

Staging Classification

The American Joint Committee on Cancer (AJCC) and Union Internationale Contre le Cancer (UICC) have endorsed the use of the Ann Arbor classification for staging of NHL. The Ann Arbor staging classification has been used for more than 40 years.^80,81 In the Ann Arbor system, Waldeyer’s ring, thymus, spleen, appendix, and Peyer’s patches of the small intestine are considered as lymphatic tissues and involvement of these areas does not constitute an “E” lesion, originally defined as extralymphatic involvement. However, because of the unique pathologic and clinical characteristics of primary lymphoma affecting these organs, most clinicians consider them as separate clinical entities and report their involvement as extranodal presentation. The Ann Arbor classification differentiates locoregional from widespread lymphoma and documents anatomic extent of disease and B symptoms, but it is not optimal for describing the extent of local disease, invasion of adjacent organs, tumor bulk, or multiple sites of involvement within one organ (e.g., skin, gastrointestinal tract). Several modifications to the Ann Arbor classification have been proposed in the past. In gastric lymphoma, substaging of stage I to reflect the depth of the stomach wall penetration has been suggested. In stage II disease, distinction of involvement of the immediate nodal region (II₁) versus more extensive regional lymph node involvement (II₂) has been found to be of prognostic significance in primary gastrointestinal lymphomas.^82,83 Currently, the Ann Arbor staging classification supplemented by description of prognostic factors, including tumor bulk, hematologic and biochemical parameters, sites of involvement, and pathology, remains the basis for patient assessment.

TABLE 75-6 Diagnostic Workup for Non-Hodgkin’s Lymphoma