Atypical Lymphoid Proliferations

The Pathologist's Viewpoint

Mahmoud Rezk Abdelwahed Hussein

Expert Rev Hematol. 2013;6(2):139-153.

Five-year View

In 5 years' time, this author would expect further studies directed at unrevealing the molecular basis of reactive hyperplasia, atypical lymphoid proliferations and lymphomas. There will be more reliable criteria to define benign, atypical (premalignant, borderline, precursor) and malignant lymphoproliferative disorders. These future criteria will help identify patients with atypical lymphoid proliferations at risk of developing lymphomas.

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Table 1. Lymphoid markers.
Aspects	Markers
Markers of B lymphocytes	CD20 and CD79a
Markers of T lymphocytes	CD45RO, MT1, CD3, OPD4, βF1, CD4, CD8 and CD5
Markers of Reed–Sternberg cells	CD15, CD30, peanut agglutinin, fascin and LMP1
Markers of immature lymphocytes	TdT, CD79a, CD43, CD10, CD3 and CD34
Immunoglobulin restriction	κ and λ light chains
Follicular lymphoma versus follicular hyperplasia	BCL-2, CD45RA (MT2), immunoglobulin light chain restriction, CD21 and CD35
Small-cell lymphoma	CD3, CD5, CD10, CD43, CD23, BCL-2, Cyclin D1, CD10, CD21 and CD35
Blastic lymphomas	TdT, CD1, CD3, CD4/CD8, CD5, CD10, CD20, CD34, CD43, CD79a, cyclin D1 and MIB1
Large-cell lymphoma	CD45, CD20, CD3, CD43, MIB1, BCL-2, MUM1, CD10 and BCL-6
Classic and lymphocyte predominant Hodgkin lymphoma	CD15, CD20, CD30, CD43, CD45, ALK, CD57 and EMA
Anaplastic large-cell lymphoma	CD45, EMA, ALK1, CD3, CD45RO, CD4, CD8, CD20, CD30, CD15 and cytotoxic antigens (TIA1, perforin)

Table 2. Distinction between atypical lymphoid proliferations rich in Reed–Sternberg-like cells (reactive immunoblasts) and classic Hodgkin lymphomas.
Aspects	Atypical lymphoid proliferations rich in Reed–Sternberg-like cells (reactive immunoblasts)	Classic Hodgkin lymphomas
Histological features	Paracortical expansion, with several reactive immunoblasts (Reed–Sternberg-like cells)	Effacement of the nodal architecture with Reed–Sternberg cells in a cellular milieu appropriate for one of the specific subtypes of Hodgkin lymphoma
Cytologic features of Reed–Sternberg cells	Binucleate or multilobated cells with abundant cytoplasm, large eosinophilic nucleoli, which can be round or linear, surrounded by a clear halo. The cells have tendency for clustering rather than even distribution	Large mononuclear cells, their nucleoli tend to be basophilic rather than eosinophilic and their cytoplasm is basophilic/amphophilic rather than eosinophilic. The cells have tendency for even distribution
Characteristic immunophenotype	CD15⁺, CD30⁺ and CD45/45RB^–	CD15^–, CD30^± and CD45/45RB⁺

Table 3. Distinction between atypical lymphoid proliferations with follicular pattern and follicular lymphoma.
Atypical lymphoid proliferations with follicular pattern	Follicular lymphoma
Histology
Widely spaced follicles separated by intervening interfollicular lymphoid tissue	Back-to-back follicles without or with little intervening interfollicular lymphoid tissue
Follicles are variable in size and shape, sharply demarcated by mantles	Follicles are variable in size, poorly demarcated by mantels
Polarity is present (Ki-67 stain)	Polarity is lost (Ki-67 stain)
Mottled germinal centers (tingible body macrophages)	Homogeneous-appearing germinal centers (absent tingible body macrophages)
No predominance of centrocytes (small cleaved cells) in the follicles	Predominance of centrocytes (small cleaved cells) in the follicles
No follicles in the perinodal tissue (outside the node)	Follicles in the perinodal tissue (outside the node)
No atypical cells in the interfollicular region (centrocytes)	Atypical cells in the interfollicular region (centrocytes)
Immunostaining
Positive BCL-2 staining in the mantle zone and interfollicular region	Positive BCL-2 staining of the follicle centers
Dense CD3⁺ T cells in the interfollicular region with rare CD10⁺ cells	Dense CD20⁺, CD79⁺ B cells and CD10⁺ cells in the interfollicular region
Polytypic staining for Ig light chains	Light chain restriction in follicular center cells
Molecular studies
In situ hybridization for Ig mRNA shows polytypism	In situ hybridization for Ig mRNA shows monotypism
Genotypic studies (PCR): Ig gene rearrangement and BCL-2 gene rearrangements are absent	Genotypic studies (PCR): presence of Ig gene rearrangement and BCL-2 gene rearrangements

Ig: Immunoglobulin.

Table 4. Distinction between atypical lymphoid proliferations composed predominantly of B cells and B-cell lymphomas.
Aspects	Atypical lymphoid proliferation composed predominantly of B cells	B-cell lymphoma
Nodal architecture	Preserved or distorted lymph node architecture	Effaced architecture
Mass lesion	No mass lesions	Mass lesion
Neoplastic nodules	-	+
Reactive follicles	+	-/+
Cytologic atypia of the lymphoid cells	-	+
Angioinvasion and angiocentricity	-	+
Abnormal immunoarchitecture	-	+
Aberrant immunophenotype	-	+
Light chain restriction	-	+
Positivity for cyclin D1	-	+

+: Present; -: Absent.

Table 5. Distinction between atypical lymphoid proliferations composed predominantly of T cells and peripheral T-cell lymphoma.
Aspects	Atypical lymphoid proliferations composed predominantly of T cells	Peripheral T-cell lymphoma
Histologic features	Paracortical expansion with mottled appearance and hyperplastic follicles at the scanning magnification	Complete effacement of the nodal architecture with the presence of atrophic intervening follicles
Atypical CD3⁺/CD2⁺ lymphoid cells	-/+	+
Double-positive CD4⁺/CD8⁺ phenotype	-	+
Double-negative CD4^–/CD8^– phenotype	-	+
Deficiency or loss of pan-T-cell markers (CD2, CD5 and CD7)	-/+	+

+: Present; -: Absent.

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