B-cell lymphoma and lymphocytic leukemia

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Chapter 25

B-cell lymphoma and lymphocytic leukemia

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A summary table on ‘WHO Classification of B-cell Tumors of Hematopoietic and Lymphoid Tissues’ and a lymphoma atlas can be found in the on-line content for this book.

Cutaneous B-cell lymphoproliferative disorders

The primary cutaneous B-cell lymphomas share some histologic features with their nodal counterparts, but in many cases represent distinct clinicopathologic entities with significant clinical, immunophenotypic, molecular, and prognostic differences from their extracutaneous counterparts. In general, primary cutaneous B-cell lymphomas have a better prognosis than their nodal-based counterparts, and treatment strategies for them may be different. The classification system used in this chapter reflects the 2005 World Health Organization/European Organisation for Research and Treatment of Cancer combined consensus conference classification for lymphoproliferative diseases of the skin. Note that not all entities included here are necessarily of primary cutaneous origin (e.g. chronic lymphocytic leukemia/small lymphocytic lymphoma, mantle cell lymphoma, Burkitt lymphoma, intravascular large B-cell lymphoma, lymphomatoid granulomatosis) but may frequently involve the skin.

Primary cutaneous marginal zone lymphoma

Key features

• Patchy, nodular, or diffuse infiltrate of lymphoid cells in the dermis and superficial panniculus

• Characteristic “inverse” pattern of central darker benign reactive lymphocytes with surrounding neoplastic cells with paler abundant cytoplasm (marginal zone cells)

• Lack of epidermotropism

• Small lymphocytes may surround or invade eccrine coils

• Surrounding benign reactive follicles may be colonized by neoplastic cells

• Neoplastic marginal zone cells often comprise only a minority of lymphoid cells in the lesions

• CD20+, CD79+, CD5−, CD10−, CD43−, BCL-6−, BCL-2+

• Clonal rearrangement of immunoglobulin (Ig) H gene in >70% of cases

• t(14;18)(q32;q21) present in a minority of cases

• Intracytoplasmic monoclonal immunoglobulin (kappa or lambda) restriction

Primary cutaneous marginal zone B-cell lymphoma is an indolent lymphoma of small lymphocytes of B-cell origin, including centrocyte (marginal zone)-like cells with small to medium-sized slightly irregular nuclei with inconspicuous nucleoli, admixed with plasmacytoid lymphocytes and occasional centroblast-like cells. Marginal zone lymphoma is one of the most common types of cutaneous B-cell lymphoma. The prognosis is excellent, with 5-year survival rates approaching 100%. The lesions usually present as violaceous nodules or plaques preferentially on the trunk and extremities, with upper extremities more commonly involved than lower extremities. The lesions have a nodular or diffuse architecture, often with a characteristic “inverse” pattern relative to benign reactive lymphoid follicles, i.e. they show a dense, darker-staining central nodular portion of benign reactive lymphocytes, which may contain germinal centers, surrounded by neoplastic lymphoid cells with slightly irregular nuclei and more abundant paler cytoplasm (monocytoid or marginal zone B cells). Often, the neoplastic lymphoid population only represents a minority of the cells in the lesion. The epidermis is spared, without epidermotropism of lymphocytes. Surrounding benign reactive germinal centers may be present, and are often colonized by tumor cells. In some cases, the neoplastic cells may surround and infiltrate eccrine coils, similar to the lymphoepithelial lesions seen in extranodal marginal zone lymphomas of the gastrointestinal tract (MALTomas). Primary cutaneous marginal zone B-cell lymphoma includes cases designated primary cutaneous immunocytoma in earlier classification systems. Primary cutaneous immunocytomas are often associated with Borrelia and demonstrate high numbers of monotypic (i.e. they demonstrate monoclonal intracytoplasmic immunoglobulin) plasma cells and lymphoplasmacytoid lymphocytes, some of which may contain intranuclear immunoglobulin deposits (Dutcher bodies).

Primary cutaneous follicle center cell lymphoma

Key features

• Diffuse, nodular and diffuse, or nodular lymphoid proliferation

• If mixed architecture, lesions tend to have neoplastic follicles at the periphery of a central diffuse neoplastic infiltrate

• Follicles have reduced or absent mantle zones

• Follicles have decreased to absent tingible body macrophages

• Lack of polarity of follicles (i.e. absent light and darker zones of polarity in follicle germinal centers)

• CD20+, CD79+

• CD10+ (follicular pattern, most cases) or CD10− (diffuse pattern, most cases)

• BCL-6+, BCL-2−, CD5−, CD43−

• Reduced proliferative fraction by MIB-1 compared to benign reactive germinal centers

• Monoclonal rearrangement of immunoglobulin heavy chain J gene

• t(14;18) translocation is very uncommon in primary cutaneous follicle center cell lymphoma lesions

Primary cutaneous follicle center cell lymphoma is also an indolent mature B-cell lymphoma, which exhibits a predilection for the head and trunk. In contrast to its nodal counterpart (primary nodal follicle center cell lymphoma), primary cutaneous follicle center cell lymphoma has a more favorable prognosis, with 5-year survival rates >90%. As with their nodal counterparts, these lesions may have a follicular, follicular and diffuse, or diffuse architecture, most commonly diffuse. However, it must be emphasized again that, despite similar appearances by hematoxylin and eosin, these lesions have different immunohistochemical, genetic, and prognostic features from primary nodal follicle center cell lymphomas. Histology shows a nodular or diffuse proliferation of centrocyte-like lymphocytes with small, slightly irregular nuclei, and variable numbers of larger centroblast-like cells with larger, rounded vesicular nuclei and one or a few prominent nucleoli. In nodular lesions, the follicles appear monomorphous, with a loss of the normal polarity of light and dark zones of the germinal centers, an attenuated mantle zone around germinal centers, and lack of tingible body macrophages in the germinal centers. In larger lesions, the center may show a diffuse architecture, with residual monomorphous neoplastic follicles at the periphery.

Pearl

In primary cutaneous follicle center cell lymphoma, the BCL-6-positive cells typically stray outside of the follicle. BCL-2 expression is characteristic of follicle center cell lymphoma in lymph nodes, but is rare in the primary cutaneous variety. At cutaneous sites, BCL-2 positivity in a follicle center cell lymphoma should raise suspicion for a nodal primary with secondary involvement of the skin.

Cutaneous diffuse large B-cell lymphoma, leg type

Key features

• Predominantly affects older patients (>70), with a predilection for females

• Usual location is one or more red to brown nodules on one distal extremity, although lesions can present as multiple nodules and at other sites

• 5-year survival of approximately 50%

• Histology reveals a dense diffuse infiltrate of predominantly large round immunoblast-type cells with prominent nucleoli; occasional large cleaved, multilobated, or anaplastic cells may also be seen

• Centrocytes are largely absent

• Grenz zone may be present, and adnexal structures are often destroyed

• Epidermotropism of neoplastic lymphoid cells may closely simulate the epidermotropism characteristic of T-cell lymphomas

• CD20+, CD79a+, BCL-2+ in great majority; most cases also express BCL-6 and/or CD10

• MUM-1/IRF4 strong positive staining is very important to distinguish from diffuse form of follicle center cell lymphoma (MUM-1−), which may look similar by routine hematoxylin and eosin staining

• Rare variant is positive for CD30 and must not be mistaken for anaplastic large cell lymphoma

• Monoclonal rearrangement of J heavy gene is present; no specific chromosomal alterations

Intravascular large B-cell lymphoma

Lymphomatoid granulomatosis

Chronic lymphocytic leukemia/small lymphocytic lymphoma

Key features

Burkitt lymphoma

Key features

• Not a primary cutaneous entity but infrequently shows cutaneous involvement

• Various clinical forms recognized (endemic form in Africa and sporadic in other regions)

• Most common in first two decades, but can occur at any age

• Monomorphic, diffuse growth of medium-sized cells with round (non-cleaved) vesicular nuclei, multiple nucleoli, moderate amount of basophilic cytoplasm which often contains multiple clear (lipid-filled) vacuoles

• “Starry-sky” pattern due to abundant benign macrophages within tumor phagocytizing necrotic tumor cells/debris

• Extremely high proliferative/mitotic index, nearly 100% observed with MIB-1

• CD19+, CD20+, CD79a+, CD22+, CD10+, CD5−, CD23−, BCL-2−, terminal deoxyribonucleotidyl transferase (TdT)−

• Atypical variant (Burkitt-like lymphoma) shows greater cellular pleomorphism and heterogeneity than classic Burkitt lymphoma

B-cell lymphoblastic lymphoma/leukemia

Table 25-1

WHO classification of primary cutaneous B-cell lymphoma

Primary cutaneous follicle center lymphoma

Primary cutaneous marginal zone lymphoma (Cutaneous MALT-type lymphoma)

Primary cutaneous diffuse large B-cell lymphoma, leg type

Primary cutaneous diffuse large B-cell lymphoma, other

Adapted from World Health Organisation Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edition, 2008.

Table 25-2

WHO Classification of B-cell Tumors of Hematopoietic and Lymphoid Tissues

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Unified system accepted globally by hematopathologists, dermatopathologists, oncologists, other clinicians Formally incorporates previous 2004 WHO-EORTC classification scheme entities

Further reading

Baldassano, MF, Bailey, EM, Ferry, JA, et al. Cutaneous lymphoid hyperplasia and cutaneous marginal zone lymphoma: comparison of morphologic and immunophenotypic features. Am J Surg Pathol. 1999; 23(1):88–96.

Bradford, PT, Devessa, SS, Anderson, WF, et al. Cutaneous lymphoma incidence patterns in the United States: a population based study of 3884 cases. Blood. 2009; 113:5064–5073.

Caro, W, Helwig, E. Cutaneous lymphoid hyperplasia. Cancer. 1969; 24:487–502.

De Laval, L, Harris, NL, Longtine, J, et al. Cutaneous B-cell lymphomas of follicular and marginal zone types. Am J Surg Pathol. 2001; 25(6):732–741.

Demierre, M, Kerl, H, Willemze, R. Primary cutaneous B cell lymphomas: a practical approach. Hematol Oncol Clin North Am. 2003; 17:1333–1350.

Kiyohara, T, Kumakiri, M, Kobayashi, H, et al. Cutaneous marginal zone B cell lymphoma: a case accompanied by massive plasmacytoid cells. J Am Acad Dermatol. 2003; 48:S82–S85.

LeBoit, PE, McNutt, NS, Reed, JA, et al. Primary cutaneous immunocytoma: a B cell lymphoma that can easily be mistaken for cutaneous lymphoid hyperplasia. Am J Surg Pathol. 1994; 18:969–978.

Ritter, J, Adesokan, P, Fitzgibbon, J, et al. Paraffin section immunohistochemistry as an adjunct to morphologic analysis in the diagnosis of cutaneous lymphoid infiltrates. J Cutan Pathol. 1994; 21:481–493.

Roglin, J, Boer, A. Skin manifestations of intravascular lymphoma mimic inflammatory diseases of the skin. Br J Dermatol. 2007; 157:16–25.

Sander, C, Kaudewitz, P, Schirren, C, et al. Immunocytoma and marginal zone B cell lymphoma (MALT lymphoma) presenting in skin-different entities or a spectrum of disease? J Cutan Pathol. 1996; 23:59a.

Sokol, L, Naghashpour, M, Glass, F. Primary cutaneous B-cell lymphomas: recent advances in diagnosis and management. Cancer Control. 2012; 19(3):236–244.

Swerdlow, SH, Campo, E, Harris, NL, et al. World Health Organization (WHO) Classification of Tumors of Hematopoietic and Lymphoid Tissues. Lyon: World Health Organization; 2008.

Van Maldegem, F, van Dijk, R, Wormhoudt, TA, et al. The majority of cutaneous marginal zone B cell lymphomas express class-switched immunoglobulins and develop in a T-helper type 2 inflammatory environment. Blood. 2008; 112:3355–3361.

Willemze, R, Jaffe, ES, Burg, G, et al. WHO-EORTC Classification for cutaneous lymphomas. Blood. 2005; 105:3768–3785.

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