Lymphoid and Hematopoietic Tumors

Lymphoid and Hematopoietic Tumors

Judith A. Ferry


Primary lymphoma of the breast is defined as lymphoma involving one or both breasts with or without ipsilateral axillary lymph node involvement, without evidence of disease elsewhere at presentation, in a patient without a prior history of lymphoma (1). Some authorities also accept cases with more distant lymph node or bone marrow involvement, so long as clinically the primary or major manifestation of the lymphoma is the breast (2). The breast is a very uncommon primary site for lymphoma, accounting for 0.1% to 0.15% (2,3,4,5) of all malignant neoplasms of the breast, for 0.34% to 0.85% of all non-Hodgkin lymphomas (2,4,6,7,8) and for <2% of all extranodal non-Hodgkin lymphomas (2).

Establishing a diagnosis based on a needle biopsy specimen presents special challenges in the diagnosis of lymphoma. For high-grade lymphomas with obvious cytologic atypia, needle biopsies are often adequate to establish a diagnosis. For low-grade lymphomas such as follicular lymphoma and extranodal marginal zone lymphoma (MALT lymphoma) that often have features overlapping with those of reactive, chronic inflammatory lymphoid proliferations, establishing a diagnosis on a needle biopsy may be difficult. In such instances, ancillary studies play a key role in diagnosis. Obtaining a larger specimen may also be required.

Clinical Features

Most patients are middle-aged to elderly women, although occasionally younger females and rarely males are affected (1,3,4,5,6,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23). They typically present with a palpable breast mass, with or without ipsilateral axillary lymphadenopathy (4,6,15,17,20,21,23). A few patients have had the lymphoma detected by mammography; lymphomas detected initially by routine mammography are typically low-grade lymphomas (4,10,11,13). Constitutional symptoms are uncommon, being found in 0% (6,13,15,17,24) to 4% (19) of patients in different series. In some series, right-sided lymphoma was more common than left-sided lymphoma (23,25). Approximately 10% of primary breast lymphomas are bilateral (1,3,5,7,8,16,17,19,22,23,24,26). A few patients have a history of autoimmune disease, diabetes mellitus, mastitis (2,4,5,15), or HIV infection (27). However, most patients have no underlying illness, and specific factors predisposing to lymphoma of the breast are not identified (8,21,26). On physical examination, patients usually have discrete, mobile masses. The overlying skin is involved infrequently; it may be thickened (20), erythematous, or inflamed (3,28) mimicking inflammatory carcinoma. Skin retraction and nipple discharge are virtually never found. The proportion of cases with ipsilateral axillary lymphadenopathy varies widely among series from 11% (10) to about 50%.

Pathologic Features and Clinicopathologic Correlates

The specimen obtained must yield sufficient tissue to firmly establish a diagnosis (29). Excision is not required if a smaller biopsy is diagnostic. A diagnosis of lymphoma may be established by fine needle aspiration biopsy, but tissue for histopathology or at least a cell block is typically required to establish a complete diagnosis with subclassification (30). In most series, diffuse large B-cell lymphoma is the most common type, accounting for approximately 60% of the cases (3,4,5,6,7,12,13,17,18,21,31,32). The remainder are mainly low-grade lymphomas (MALT lymphoma or follicular lymphoma). Burkitt lymphoma is uncommon. T-cell lymphoma is very rare (11,21). The breast is rarely involved by post-transplant lymphoproliferative disorders, which are usually high-grade B-lineage lymphomas (33).

Diffuse Large B-cell Lymphoma

Diffuse large B-cell lymphoma affects women (and a few men) across a wide age range (4,12,15,19,22,29), with a median age in the sixth decade (32). Lesions range from 1 to 20 cm in greatest dimension, with a median size of 4 to 5 cm. A few patients have diffuse breast enlargement (7,8,15,17,19,22,32). The tumors have been described as discrete, hard, rubbery (16), soft or fleshy masses (3) that are sometimes rapidly enlarging (1,16,28).

The lymphomas are composed of a diffuse infiltrate of large lymphoid cells. Histologic and immunophenotypic features overlap with those seen in other sites (Table 21.1) (3,18,21,34). The lymphomas are CD45+, CD20+, with rare CD5+ cases

(22) and a relatively high proliferation index (60%-95% in one series) (22). The majority of cases has a nongerminal center B-cell (non-GCB) immunophenotype (CD10-, BCL6+, MUM1/IRF4+, or CD10-, BCL6-) (Fig. 21.1), while a minority has a germinal center B-cell (GCB) phenotype (CD10+, BCL6+ or CD10-, BCL6+, MUM1/IRF4-) (21,29). In recent large series, 77% of the cases (32) and 95% of the cases (35) had a non-GCB immunophenotype. Immunostaining for p50 and p65 has shown nuclear localization of p50 in a minority, suggesting NFκB activation in a subset of cases (34). In situ hybridization for Epstein-Barr virus (EBV) using a probe for EBER is typically negative (22). As is true of other nongerminal center/activated B-cell type diffuse large B-cell lymphomas, primary breast diffuse large B-cell lymphomas often have mutations of MYD88 (MYD88 L265) and CD79B, resulting in activation of the NFκB pathway, contributing to lymphomagenesis (36). Translocations of BCL2, BCL6, and MYC are absent or rare (36).

TABLE 21.1 Hematolymphoid Neoplasms of the Breast: Principal Features

Type of Neoplasm

Patients Affected


Neoplastic Cells, Usual Immunophenotype

Genetic, Cytogenetic Features

Clinical Behavior

Diffuse large B-cell lymphoma

Adults, females >> males, broad age range; few pregnant

Diffuse proliferation of large lymphoid cells; CB more common than IB

CD45+, CD20+, CD10 usually -, BCL6+/-, BCL2 and MUM1/IRF4 usually +, Ki67 high; non-GC > GC

Rare MALT1 rearrangements; trisomy 18 in some; NFκB activation in some

Aggressive; CNS, opposite breast: common sites of relapse; best outcomes with R-CHOP or R-CHOP-like chemo +/- RT

Extranodal marginal zone Lymphoma (MALT lymphoma)

Middle-aged and older adults; females >> males

Marginal zone B-cells, plasma cells variable, reactive follicles may be present. LELs often not prominent.

CD45+, CD20+, CD5-, CD10-, CD23-, CD43+/-, BCL2+/-, cyclin D1-, cIg+/-

Rare MALT1 rearrangements; minority of cases: trisomy 3, 12 and/or 18

Good prognosis. Localized extranodal relapses may occur. Few have large cell transformation. Few die of lymphoma.

Follicular lymphoma (FL)

Middle-aged and older women

Similar to lymph nodal follicular lymphoma

CD45+, CD20+, CD10+, BCL6+, CD5-, CD23-, CD43-, BCL2+, cyclin D1-, sIg+, occasionally BCL2-

Prognosis less good than MALT lymphoma. Behavior similar to nodal FL.

Burkitt Lymphoma

Young to middle-aged, few older women, some pregnant or lactating

Diffuse infiltrate of medium-sized round cells, many mitoses, starry sky

CD45+, CD20+, CD10+, BCL6+, BCL2-, Ki67 ˜ 100%a

Translocation of MYC with IGH [t(8;14)], less often with IGK or IGLa

Very aggressive; disease is often widespread

B- and T-lymphoblastic lymphoma/leukemia

Mostly adolescents and young adults, often with concurrent acute lymphoblastic leukemia

Diffuse infiltrate of small- to medium-sized cells with oval or irregular nuclei, fine chromatin, small nucleoli, and scant cytoplasm


CD19+, CD20-, CD10+, TdT+a


Variable expression of T-cell markers, but often CD3+, CD7+, CD4+/CD8+ (double+), CD1a+, TdT+a


Aggressive disease with relatively good prognosis depending on underlying genetic abnormalities, if optimally treated

Anaplastic large cell lymphoma, ALK-, associated with implant

Women with saline or silicone implants, for cosmetic purposes or following mastectomy; lymphoma occurs years after implant; seroma rather than discrete mass

Large atypical, pleomorphic cells in a background of fibrosis, debris, and sometimes chronic inflammation

CD30+, Alk1-, CD45+/-, CD4+/-, CD43+/-, CD3-/+, CD5-/+, CD8-, EMA+/-, TIA1+/-, granzyme B+/-, EBV-, HHV8-

TCR: clonal

IGH: polyclonal

Very good prognosis in absence of a discrete mass or spread beyond capsule

Chronic Hodgkin lymphoma (CHL)

Rare; breast involvement virtually always secondary to lymph nodal disease

Reed-Sternberg cells and variants in a reactive background

CD15+, CD30+, CD45-, Pax5 dim+, CD20-, CD3-, Alk1-

TCR: polyclonal

IGH: polyclonal

Outcome likely similar to other CHL of same stage


Rare; usually in setting of plasma cell myeloma; rarely isolated

Sheets of mature and/or immature plasma cells

CD138+, cIg+, EMA+/-, CD45-/+, Keratin-

Relatively poor in setting of myeloma

CB, centroblastic; cIg, monotypic cytoplasmic immunoglobulin; R-CHOP, rituximab-cytoxan, adriamycin, vincristine, prednisone; GC, germinal center immunophenotype; IB, immunoblastic; IGH, immunoglobulin heavy chain gene; IGK, immunoglobulin kappa light chain gene; IGL, immunoglobulin lambda light chain gene; LELs, lymphoepithelial lesions; non-GC, nongerminal center immunophenotype; RT, radiation therapy; sIg, monotypic surface immunoglobulin; TCR, T-cell receptor genes; CHL, chronic Hodgkin lymphoma.

a Based in part on data on same types of lymphoma in other sites.

Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue (MALT Lymphoma)

MALT lymphoma mainly affects middle-aged and older women and rarely men (2,3,4,6,10,25,31,37,38), with a median age of 68 years in one large series (39). Patients with MALT lymphoma of the breast typically have no recognized factors predisposing to lymphoma. Patients present with a lesion that is typically unilateral, and that may be detected by physical examination or by mammography. Constitutional symptoms are almost never present (39).

The lymphomas range from <1 to 20 cm, with a median size of approximately 3 cm (3,6,10,31,37,38,39). Their histologic features are similar to those of MALT lymphomas in other sites. The lymphomas have a vaguely nodular to diffuse appearance on low-power microscopic examination. They are composed of small- to medium-sized cells with slightly irregular nuclei and a scant-to-abundant quantity of pale cytoplasm. Reactive follicles, sometimes with follicular colonization (infiltration and partial-to-complete replacement by neoplastic marginal zone cells), and plasmacytic differentiation, sometimes accompanied by Dutcher bodies (intranuclear protrusions of cytoplasm containing immunoglobulin), are found in some cases. Mitotic activity is low, except in residual reactive follicles (Fig. 21.2). Necrosis and sclerosis are typically absent. Well-formed lymphoepithelial lesions are found less often than in MALT lymphomas involving some other sites (4,10,21,34). Rare MALT lymphomas with plasmacytic differentiation are associated with localized deposition of amyloid (3,40).

FIGURE 21.1 Diffuse Large B-cell Lymphoma. A: This needle core biopsy shows a dense, diffuse infiltrate of lymphoid cells. B: High power shows closely packed large atypical lymphoid cells surrounding lobular glands.

The neoplastic cells are typically CD45+, CD20+, CD5-, CD10-, CD23-, CD43+/-, BCL2+/-, and cyclin D1-, with monotypic cytoplasmic immunoglobulin in those cases with plasmacytic differentiation (5,25,37). The proliferation index is low. If there are remnants of reactive follicles, the germinal center cells are CD10+, BCL6+, and BCL2-, with a high proliferation index. Markers of follicular dendritic cells (CD21, CD23) typically show underlying follicular dendritic mesh-work, which are often expanded and disrupted. The presence of follicular dendritic cell meshwork tends to correlate with a vaguely nodular growth pattern in MALT lymphomas.

Chromosomal translocations that involve the MALT1 gene, including t(11;18), involving API2 and MALT1, and t(14;18) involving IGH and MALT1are rare (34,41,42). Trisomies of chromosomes 3, 12, and 18 are uncommon (41). The absence of nuclear p50 and p65 expression is reported, which suggests lack of NFκB activation (34). The genetic defects leading to the development of MALT lymphoma of the breast are not well understood.

Follicular Lymphoma

Follicular lymphoma mainly affects middle-aged and older women (6,10,31), and rarely men (39). Patients present with lesions that are unilateral in approximately 95% of the cases, typically unaccompanied by constitutional symptoms (39). The tumors appear to range from <1 to 9 cm, with a median size of about 2 to 3 cm (6,10,31,39). Histologic and immunophenotypic features are similar to those of nodal follicular lymphomas. The lymphomas are sometimes associated with
sclerosis. Follicular lymphomas of all grades (1,2,3) have been reported (Fig. 21.3) (10,11,15,17). Neoplastic follicles are typically CD45+, CD20+, CD10+, CD5-, CD23-, CD43-, BCL2+ or BCL2-, and cyclin D1-.

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Nov 17, 2018 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Lymphoid and Hematopoietic Tumors

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