Bowzyk Al-Naeeb, A., Ajithkumar, T., Behan, S., & Hodson, D. J. (2018). Non-Hodgkin lymphoma. BMJ, 362, k3204. https://doi.org/10.1136/bmj.k3204
Pathophysiology
Genetic hallmark: t(11:14) translocation
t(11:14) translocation involving IGH & BCL1 gene
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Overexpression of BCL-1 protein “Cyclin D1”
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Cancer
Origin of mature B cell lymphomas:
B cell lymphomas are cancers that develop from the malignant transformation of B lymphocytes at various stages of ontogeny. Most are of mature B cell origin, and revolve around the germinal centre (GC) reaction, a critical step in which B cells are subject to intense proliferation and genomic remodelling processes — namely, somatic hypermutation and class-switch recombination — to generate memory B cells and plasma B cells that produce high-affinity antibodies. From naive B cells to memory B cells, most differentiation steps are associated with a malignant B cell subtype (defined as the cell of origin (COO)) on the basis of classic histological definitions and gene expression profiling. The COO assumes that B cell malignancies are ‘frozen’ at a given B cell differentiation stage arising in a particular location of the B cell follicle. For example, follicular lymphoma (FL) is a follicle-related B cell lymphoma that is considered the malignant counterpart of normal ‘frozen’ GC B cells. Unmutated mantle cell lymphoma (UM-MCL) originates from mantle zone B cells, marginal zone lymphoma (MZL) resembles marginal zone B cells whereas Burkitt lymphoma (BL) resembles dark zone B cells. Based on the COO, distinct diffuse large B cell lymphoma (DLBCL) molecular subtypes are defined as not otherwise specified DLBCL (DLBCL NOS), whereas, the GC B cell-like DLBCL corresponds to B cells that are arrested at various stages of the GC transit (from dark zone to light zone B cells) and the activated B cell-like DLBCL seems to derive from GC B cells en route to plasma cell differentiation, resembling plasmablasts. BCR, B cell receptor; FDC, follicular dendritic cell; M-MCL, mutated mantle cell lymphoma; MHC, major histocompatibility complex; TCR, T cell receptor; TFH, follicular T helper. | Basso, K. & Dalla-Favera, R. Germinal centres and B cell lymphomagenesis. Nat. Rev. Immunol. 15, 172–184 (2015). Return to ref 44 in article
Clinical features
Typically disseminated at presentation, with a leukemic component in 20%-30% of patients.
Bulky disease: Transverse diameter of tumour mass > 10 cm and confers a poorer prognosis in early-stage patients.
B symptoms:
Fevers, chills, night sweats or unexplained weight loss >10% of body weight
Frequent in patients with advanced-stage or bulky disease
The Calgary Guide | http://calgaryguide.ucalgary.ca/
Extranodal involvement:
Leukemic phase (20%-30% cases): Bone marrow & peripheral blood involvement
Lymphomatous polyposis (LP): Mantle cell lymphoma (MCL) of the gastrointestinal (GI) tract (Waldeyer’s ring involvement)
Staging colonoscopy findings. a Colonoscopy with multiple colonic polyps. b Dense lymphocytic infiltrate on hematoxylin and eosin staining (scale bar: 300 μm). c CD5 positivity (scale bar: 90 μm). d CD20 positivity (scale bar: 200 μm). e Cyclin D1 positivity (scale bar: 200 μm). This staining pattern along with CD23 negativity and the classic MCL genetic abnormality of t(11; 14)(q13;q32) are consistent with MCL. | Dawsey, S. P., Gregory, J. A., Brown, A. W., & Jones, F. J. (2016). Asymptomatic Multiple Lymphomatous Polyposis Identified during Staging Bidirectional Endoscopy of Mantle Cell Lymphoma. Case reports in oncology, 9(3), 661–665. doi:10.1159/000450596
Complications
Transformation to diffuse large B-cell lymphoma (DLBCL)
Tumour lysis syndrome (TLS):
Potential complication of therapy due to rapid growth rates of tumor cells caused by release of cellular products overwhelming the kidneys’ excretory capacity.
Clinical and biologic characteristics of MCL: (A) MCL diagnosis is based on morphology and immunophenotyping (CD20+, CD5+, CD23−, FMC7+). Pathologic subclassification recognizes 2 main subsets: classic and blastoid. (B) Fluorescence in situ hybridization (FISH) cytogenetics showing translocation t(11;14)(q13;q32) and immunohistochemistry for detection of cyclin D1 overexpression are helpful adjuncts in the diagnosis of MCL. (C) Tumor proliferation determines outcome. The expression levels of 20 genes related to cell proliferation were summarized in the proliferating signature average. Lowest (green) to highest (red) expression of the proliferation signature average in lymph node biopsies from 92 patients with MCL is shown with across a 16-fold range. Kaplan-Meier analysis for patients grouped into 4 quartiles on the basis of this score is shown. (D) CCND1 locus at 11q13 and cyclin D1 mRNA isoforms. Shaded boxes represent coding sequences, open boxes represent noncoding exon sequences. The 3′UTR of full-length 4.5-kb cyclin D1a contains binding sites for miRs (blue boxes) and AU-rich elements (red triangles); cyclin D1a isoforms with a truncated 3′UTR lack these elements. The alternatively spliced 1.7-kb cyclin D1b mRNA lacks exon 5 and retains part of intron 4. | Pérez-Galán, P., Dreyling, M., & Wiestner, A. (2011). Mantle cell lymphoma: biology, pathogenesis, and the molecular basis of treatment in the genomic era. Blood, 117(1), 26–38. doi:10.1182/blood-2010-04-189977
Core-needle/excisional biopsy (no FNAC):
Immunophenotype: B-cell antigens (CD19+, CD20+, CD21+, Cd22+), CD23(-), CD 5+
High power H&E of mantle cell lymphoma showing monotonous mature lymphocytes with mildly irregular nuclei. A pink histocyte is highlighted by the black arrow. | David Lynch, MD
Staging
Ann Arbor staging system with Cotswolds modification:
Staging system for lymphomas, both in Hodgkin’s lymphoma (formerly designated Hodgkin’s disease) and non-Hodgkin lymphoma (abbreviated NHL)
Principal stages (determined by location):
Stage I: Single site (nodal/extranodal)
Stage II: ≥ 2 LN on same side of diaphragm (number of anatomic sites should be indicated in a suffix: e.g. II2)
Stage III: LN/structures on both sides of diaphragm:
III1: With/without splenic, hilar, celiac or portal nodes
III2: With paraaortic, iliac or mesenteric nodes
Stage IV: Diffuse, disseminated, several extranodal ± nodal involvement
Modifiers (can be appended to some stages):
A: No B symptoms
B: B symptoms present
S (spleen)
E “extranodal”
X (largest deposit is >10 cm large (“bulky disease”), or whether the mediastinum is wider than ⅓ of the chest on a chest X-ray)
Stage I is involvement of a single lymph node region (I) (mostly the cervical region) or single extralymphatic site (Ie) | By Cancer Research UK – Original email from CRUK, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=34333633
Stage I is involvement of a single lymph node region (I) (mostly the cervical region) or single extralymphatic site (Ie) | By Cancer Research UK – Original email from CRUK, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=34333665
Stage III is involvement of lymph node regions on both sides of the diaphragm, which may include the spleen (IIIs) or limited contiguous extralymphatic organ or site (IIIe, IIIes) | By Cancer Research UK – Original email from CRUK, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=34333711
Stage IV is disseminated involvement of one or more extralymphatic organs. | By Cancer Research UK – Original email from CRUK, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=34333755
