Lymphoma occurring during pregnancy: antenatal therapy, complications, and maternal survival in a multicenter analysis.

PURPOSE: Lymphoma is the fourth most frequent cancer in pregnancy; however, current clinical practice is based largely on small series and case reports. PATIENTS AND METHODS: In a multicenter retrospective analysis, we examined treatment, complications, and outcomes for Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) occurring during pregnancy. RESULTS: Among 90 patients (NHL, n = 50; HL, n = 40), median age was 30 years (range, 18 to 44 years) and median diagnosis occurred at 24 weeks gestation. Of patients with NHL, 52% had advanced-stage versus 25% of patients with HL (P = .01). Pregnancy was terminated in six patients. Among the other 84 patients, 28 (33%) had therapy deferred to postpartum; these patients were diagnosed at a median 30 weeks gestation. This compared with 56 patients (67%) who received antenatal therapy with median lymphoma diagnosis at 21 weeks (P < .001); 89% of these patients received combination chemotherapy. The most common preterm complication was induction of labor (33%). Gestation went to full term in 56% of patients with delivery occurring at a median of 37 weeks. There were no differences in maternal complications, perinatal events, or median infant birth weight based on deferred versus antenatal therapy. At 41 months, 3-year progression-free survival (PFS) and overall survival (OS) for NHL were 53% and 82%, respectively, and 85% and 97%, respectively, for HL. On univariate analysis for NHL, radiotherapy predicted inferior PFS, and increased lactate dehydrogenase and poor Eastern Cooperative Oncology Group performance status (ECOG PS) portended worse OS. For HL patients, nulliparous status and "B" symptoms predicted inferior PFS. CONCLUSION: Standard (non-antimetabolite) combination chemotherapy administered past the first trimester, as early as 13 weeks gestation, was associated with few complications and expected maternal survival with lymphoma occurring during pregnancy.

Malignant B-cell intra-clonal diversification: following the yarn in the labyrinth.

The generation of cellular diversity is considered a key factor in the development of cancer. The research of B-cell malignancies provides a unique opportunity to study the origin, regulation, and physiological significance of diversification mechanisms, due to active alterations of the immunoglobulin genes in these cells. These genes provide a distinctive marker common to all of the malignant cells in a single patient, and, in addition, serve as 'molecular clocks' that are associated with specific developmental stages of the B-cell lineage. Moreover, the mechanisms underlining the normal molecular alterations of the immunoglobulin genes may also generate genetic lesions associated with the progression of B-cell malignancies. Analyses of cellular populations of several types of B-cell malignancies revealed remarkable diversity with respect to different properties of the cells, including stages of differentiation, accumulation of mutations, gene expression, and drug resistance. These studies indicate that the diversity of malignant B-cells is generated along two major dimensions. One is aligned with the developmental program of B-cells, where malignant cells of a single clone, but at several distinct differentiation stages, can be found in a single patient. The second dimension of diversity is established by the location of the malignant cells in a specific tissue, or in specialized microenvironmental niches within the tissue. Elements composing the microenvironment, including stromal cells, the extracellular matrix, and soluble factors, regulate the gene expression profile in the malignant cells, and hence affect also their physiology. The involvement of microenvironmental factors in the development of B-cell malignancies may provide novel targeting opportunities for therapy.

Adhesive interactions regulate transcriptional diversity in malignant B cells.

The genetic profiling of B-cell malignancies is rapidly expanding, providing important information on the tumorigenic potential, response to treatment, and clinical outcome of these diseases. However, the relative contributions of inherent gene expression versus microenvironmental effects are poorly understood. The regulation of gene expression programs by means of adhesive interactions was studied here in ARH-77 human malignant B-cell variants, derived from the same cell line by selective adhesion to a fibronectin matrix. The populations included cells that adhere to fibronectin and are highly tumorigenic (designated "type A" cells) and cells that fail to adhere to fibronectin and fail to develop tumors in vivo ("type F" cells). To identify genes directly affected by cell adhesion to fibronectin, type A cells deprived of an adhesive substrate (designated "AF cells") were also examined. Bioinformatic analyses revealed a remarkable correlation between cell adhesion and both B-cell differentiation state and the expression of multiple myeloma (MM)-associated genes. The highly adherent type A cells expressed higher levels of NFkappaB-regulated genes, many of them associated with MM. Moreover, we found that the transcription of several MM-related proto-oncogenes is stimulated by adhesion to fibronectin. In contrast, type F cells, which display poor adhesive and tumorigenic properties, expressed genes associated with higher levels of B-cell differentiation. Our findings indicate that B-cell differentiation, as manifested by gene expression profiles, is attenuated by cell adhesion to fibronectin, leading to upregulation of specific genes known to be associated with the pathogenesis of MM.