Indolent Mantle-Cell Lymphoma: Immunoglobulin Variable Region Heavy Chain Sequence Analysis Reveals Evidence of Disease 10 Years Prior to Symptomatic Clinical Presentation

Abstract

We report on a 60-year-old man who presented as an emergency with an acute abdomen in 2003. He had been completely well until shortly before this presentation with no symptoms of note; specifically, he described no weight loss, no night sweats, no fevers, and no change in bowel habit. Apart from the obvious acute abdomen, clinical examination was unremarkable. There was no peripheral lymphadenopathy and no hepatomegaly, and it was noted that the man had previously had a splenectomy. At presentation, routine blood analysis was normal apart from a lymphocytosis of 19.8 ϫ 10 9 /L. The patient underwent an emergency laparotomy. During the operation, he was found to have a perforated duodenum and several large periduodenal lymph nodes. These were biopsied, and he underwent a gastrojejunostomy. The duodenum had perforated through a macroscopic tumor.The resected duodenum and lymph node biopsy obtained during the operation showed a nodular infiltrate of small lymphoid cells with irregular nuclei and inconspicuous cytoplasm, interspersed with histiocytes with copious cytoplasm. The cells were strongly CD20 ϩ , CD3 Ϫ , and CD5 ϩ and demonstrated nuclear expression of Cyclin D1 protein. Flow cytometric analysis of the circulating lymphocytes revealed a clonal population of B cells that were positive for CD19, CD5, CD23, CD79b, and FMC7 and were strongly positive for Lambda surface immunoglobulin. This was all consistent with a diagnosis of mantle-cell lymphoma (MCL). Fluorescent in situ hybridization (FISH) analysis using an IGH/CCND1 dual-color fusion probe set from Abbott Laboratories (Abbott Park, IL) demonstrated a t(11; 14)(q13:q32) translocation. Staging computed tomography revealed widespread lymphadenopathy, including in the mediastinal, retrocrural, and para-aortic regions, with subhepatic soft tissue masses of up to 3.5 cm. His bone marrow was heavily infiltrated with disease.After recovery from the operation, the patient was treated within a United Kingdom national MCL trial and entered complete remission. Treatment was with oral fludarabine and cyclophosphamide. Four years later, he developed acute myeloid leukemia while still in complete remission of lymphoma and unfortunately died as a result.Review of his notes shows that, in 1993, 10 years before diagnosis, the patient had been admitted to the hospital with an episode of severe abdominal pain. In addition, he had recently lost weight but had no other symptoms. His full blood count revealed a mild thrombocytopenia (78 ϫ 10 9 /L) with normal hemoglobin (15.9 g/dL) and lymphocyte counts (1.32 ϫ

Molecular pathogenesis of mantle cell lymphoma

“…The detection of SOX11 by immunohistochemistry or quantitative PCR in larger series of patients has confirmed the relationships among its lack of expression, hypermutated IGHV, low karyotype complexity, nonnodal leukemic disease, and longer survival with stable disease in independent cohorts of patients, suggesting that these biological and clinical features may identify a different subtype of MCL (63)(64)(65)(66)(67). Some patients with nonnodal disease may progress to an aggressive form of MCL after several years of a stable clinical course.…”

Prognostic role of SOX11 in a population-based cohort of mantle cell lymphoma

“…1,6,9,[26][27][28][29] The choice to treat or not to treat a patient with MCL may therefore have changed over time because of the increased awareness that not all MCLs are aggressive. 29 In our population-based cohort the SOX11 Ϫ cases and cases with an indolent clinical disease course were, however, not enriched in the later years of the study but were rather present at similar frequencies in the early and late years of the study.…”

“…1 A subgroup of MCL cases, ϳ 10%-15% of cases, has an indolent clinical course and may not need therapy for several years. [1][2][3][4][5][6][7][8][9] The initial event in MCL biology is the translocation of the cyclin D1 gene (CCND1) to the immunoglobulin heavy chain locus, t(11;14)(q13;q32), 10 resulting in aberrant expression of cyclin D1. A small number of cases have CCND1 translocation to the light chain loci 11,12 or lack CCND1 translocation.…”

Risk factors for etiology and prognosis of mantle cell lymphoma

“…For example, in an U.S. study, infection with strains of B. burgdorferi was not associated with an increased risk of MCL [23]. Frequent involvement of the gastrointestinal tract has been observed in MCL patients, leading to speculation that the risk of MCL development is associated with infectious agents that affect the gastrointestinal tract or cause a variation in microbial gut flora [24,25]. …”