Evidence of Long Latency Periods Prior to Development of Mantle Cell Lymphoma
Authors: Racke Frederick , Simpson Sabrina , Christian Beth , Blum Kristie A. , Hasserjian Robert , Zhao Weiqiang 
Published: October 2019

Abstract
Abstract 323
Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma characterized by treatment failures and short survival. At presentation, MCL is often widely disseminated. Occasionally, early lymphoma can be seen as in situ lesions involving the mantle zones of secondary follicles. The primary genetic lesion involved in the pathogenesis of the disease is the t(11;14)(q13;q32)/(IGH/CCND1) which leads to the overexpression of cyclin D1, a cell cycle regulatory protein that is not normally expressed in B-cells. However, MCL frequently has numerous additional chromosomal alterations making it one of the most genetically unstable lymphomas. Thus, while the IGH/CCND1 rearrangement is the critical initiating event, it appears that additional alterations are necessary to develop MCL. However, little is known about the latency period required to accumulate sufficient lesions to develop MCL. Recently, it has been appreciated that the initiating chromosomal events in other B-cell malignancies may precede the development of overt disease by many years. In particular, the defining chromosomal events in childhood ALL may be found in the heel sticks of children at birth, even if leukemia does not develop until a number of years later. We recently reported a unique case of mantle cell lymphoma arising simultaneously in the donor and recipient 12 years following allogeneic bone marrow transplantation for chronic myelogenous leukemia(J. Clin. Oncol., in press). This suggested that MCL may exhibit long latency periods prior to the development of frank lymphoma. In order to determine whether in situ MCL may be identified in patients with MCL, we identified 7 patients who were diagnosed with mantle cell lymphoma and who had previous pathological material available that contained lymphoid tissue and that was unrelated to the subsequent MCL. Remarkably, all 7 specimens showed evidence of in situ mantle cell lymphoma, as judged by cyclin D1 over-expression localized to lymphoid cells. Pathological specimens ranged from 2.1–15.5 years prior to the diagnosis of MCL. In all 7 specimens, cyclin D1 positive collections of lymphocytes were identified, 5 with distinct homing to mantle zones, one with follicular colonization and mantle homing, and 1 with a diffuse distribution. FISH studies were undertaken to identify cyclin D1 chromosomal translocations, and evidence of chromosomal translocations could be identified in 2/3 cases evaluated whereas no signals were seen in adjacent uninvolved lymphoid tissue. Taken together, the data presented strongly suggest that a long latency period following the initiating IGH/CCND1 translocation may occur in MCL with patients harboring in situ lesions for years prior to the development of clinical disease. These findings shed interesting new light on the natural history of MCL.
Pre-lymphoma location Pattern of in situ MCL Latency (yrs) Lymphoma location CCND1 FISH in pre-lymphoma specimen Obturator node from radical prostatectomy CyclinD1+ focal colonized follicles, scattered cells in mantles 7.4 Sigmoid colon biopsy ND Duodenal serosal lymph node (perforated benign gastric ulcer) Diffuse scattered CyclinD1+ cells 2.1 Sigmoid colon biopsy ND Right neck subcutaneous lymph node (neurofibroma excision) CyclinD1+ cells in follicular mantles 3.2 Bone marrow biopsy ND Periesophageal lymph nodes from esophagectomy Several CyclinD1+ colonized primary follicles 8.0 Right cervical lymph node ND Axillary lymph node from mastectomy CyclinD1+ cells in follicular mantles 15.5 Mesenteric lymph node <5% positive signals Mesenteric lymph node dissection for colon cancer CyclinD1+ cells in follicular mantles 10.6 Base of tongue lesion Positive Cervical lymph node involved with T cell lymphoma CyclinD1+ cells in follicular mantles 3.1 Right axillary lymph node Positive

Disclosures:
No relevant conflicts of interest to declare.