Atypical Lymphoid Proliferations

The Pathologist's Viewpoint

Mahmoud Rezk Abdelwahed Hussein


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

In This Article

Lymphoproliferative Lesions

The histologic classifications of the lymphoid lesions are continuously developing as the authors understandings of the biology of the disease process continue to improve. Traditionally, the lymphoproliferative lesions can be separated into two categories; benign (reactive lymphoid hyperplasia and lymphadenitis) and neoplastic (malignant lymphoma) conditions.[11,12]

Benign Lymphoproliferative Lesions

The lymph node processes and presents various antigens to either B or T lymphocytes. Antigenic stimulation can result in proliferation of B or T cells, sinus histiocytes or specialized cells with the expansion of their corresponding anatomical compartments with subsequent nodal enlargement. Benign lymphoid lesions include both lymphoid hyperplasia and lymphadenitis. An infectious agent is usually present in lymphadenitis whereas lymphoid hyperplasia is secondary to antigenic stimulation without infectious etiology. Lymphoid hyperplasia includes follicular hyperplasia (stimulation of B-cell component), paracortical hyperplasia (stimulation of the T cells in the paracortex), histiocytic hyperplasia (mononuclear phagocyte system, including phagocytic histiocytes) and mixed pattern.[3,13] Other responses to antigenic stimuli include granulomatous reactions, deposition of interstitial substances, extensive necrosis, plasmacytosis, eosinophilia and formation of immunoblasts.[2,3] The benign conditions (reactive hyperplasia and lymphadenitis) are usually categorized by the various etiologic factors responsible for adenopathies. A summary of these reactions is presented in Figures 1 & 2.

Figure 2.

Lymph node with patterns of reactions to antigenic stimuli. Numerous immunoblasts (A–C) and paracortical expansion (D–F): distortion of the nodal architecture secondary to paracortical hyperplasia and the presence of numerous immunoblasts. Some reactive immunoblasts resemble Reed–Sternberg cells. Similar changes are seen in infectious mononucleosis. Plasmacytosis: distortion of the nodal architecture by distension of the interfollicular areas by numerous plasma cells and macrophages (G–I). Similar changes are seen in HIV-associated lymphadenopathy.

Malignant Lymphomas

Malignant lymphomas represent groups of heterogeneous disorders with relatively well-defined clinicopathologic and molecular features. They are classified into Hodgkin lymphomas and non-Hodgkin lymphomas[12] and their histological features of malignant lymphomas are shown in Figures 3 & 4. Some lymphoid markers useful for the evaluation of the lymphoproliferative lesions are listed in Table 1. At the molecular level, about 80% of the lymphomas with characteristic immunologic and clinical features have clonal immunoglobulin or T-cell receptor gene rearrangement.[14,15] Molecular analyses include determination of clonality, cell lineage as well as detection of oncogene and chromosomal translocation.[14,15] Demonstration of clonal lymphoid populations can support diagnosis of lymphomas and their absence favor benign conditions.[14,15] However, clonality does not always mean malignancy and sampling (i.e., very small samples) may give rise to 'pseudoclones'. Therefore, the results of the molecular studies must be correlated with the clinical and immunomorphological findings before a definitive diagnosis is rendered.[16,17]In situ malignancies including follicular lymphoma in situ and mantle cell lymphoma in situ have been recognized. The former usually occurs as an incidental finding in otherwise reactive lymph node, or coexists with overt follicular lymphoma, or with lymphomas other than follicular lymphoma or with other malignancies. The diagnosis of follicular lymphoma in situ depends on immunohistochemical (CD10, CD20, CD23, BCL2, BCL6 and Ki-67) and molecular studies, such as FISH analysis for t(14;18).[18] Immunohistologically, follicular lymphoma in situ is characterized by the presence of strongly BCL2-positive B cells in the germinal centers of morphologically inconspicuous lymph nodes.[19] In mantle cell lymphoma in situ scattered cyclin D1+ cells are present either within otherwise reactive germinal centers but not in the surrounding mantle zones[20] or reactive lymphoid follicles.[21] The prevalence, biological and clinical significance of these in situ malignancies are unknown.[19,22]

Figure 3.

Hodgkin lymphoma. A 40-year-old male patient presented with cervical lymphadenopathy, weight loss, fever and night sweating. Grossly, the specimen consisted of a lymph node (4.0 × 4.0 × 3.0 cm) with soft consistency and tan–white cut section. Histologically, there is effacement of the nodal architecture by neoplastic nodules composed of Reed–Sternberg cells (mononuclear, binucleated and multinucleated cells) amid a reactive cellular milieu (lymphocytes, histiocytes and plasma cells). The Reed–Sternberg cells are large and have water clear to eosinophilic cytoplasm and apparent nucleoli. Abnormal mitotic figures are noted (A–I). Immunostains were performed and Reed–Sternberg cells showed characteristic immunophenotype (positive for CD15 and CD30 and negative for CD45/45RB; results are not shown here).

Figure 4.

Follicular lymphoma, grade 1–2. A 61-year-old female patient presented with a mass lesion involving the left parotid gland. Grossly, the specimen consisted of an irregular portion of light-tan, soft salivary gland tissue measuring 4.0 × 3.5 × 3.0 cm. Histologic sections show involvement of the salivary gland tissue by a lymphoproliferative process with effacement of the normal salivary gland architecture and extension to the adjacent fibroconnective tissue. There are numerous indistinct, crowded, partially confluent lymphoid follicles. They lack the normal zoning pattern and efface the normal tissue architechture. The constituent cells of this lymphoid infiltrate are a mixture of centrocytes, some centroblasts and dendritic histiocytes. There is also brisk mitotic activity and scattered tangible body macrophages (A–D). The differential diagnosis was between atypical lymphoid proliferations and follicular lymphoma. Immunohistochemical evaluation was performed and the pertinent findings include follicles, which mark strongly with CD20 (E & F) but appear to be negative with BCL-2 (G & H). They are weakly positive with CD10 and BCL-6 (I & J). Other stains such as CD3 (K & L), CD5 (M & N) and CD43 (O & P) as well as κ and λ light changes are negative in the follicles. A flow cytometry report shows a reversal of the κ/λ ratio at 0.7, suggesting λ-restricted clonal B-cell population. With the immunomorphologic and flow cytometry findings taken into consideration, the diagnosis of follicular lymphoma was rendered.

AtLP (Equivocal Lymphoproliferative Lesions)

In the author's opinion, there are limitations for morphologic criteria-based diagnosis of some lymphoproliferative lesions. That is to say, there exist some difficult lesions with worrisome morphologic features that defy precise classification into one of these categories. The descriptive term 'AtLP' is suggested to label these equivocal lesions. Tumors appropriately placed in this descriptive category exhibit some features suggestive of possible lymphoma but in number or degree, the features are insufficient to justify a malignant diagnosis. In the author's opinion, the atypical lymphoid cells are nonmalignant lymphoid cells produced in a variety of disorders. They may represent a nonspecific response to stress from a variety of stimuli or perhaps precursor cells in the development of lymphoma. They comprise a heterogeneous mixture of cell types (small, medium and large cells). This is the result of a polyclonal immune response to antigenic stimulation. On histology, atypical lymphocytes are larger than the resting mature lymphocytes. The cells may have indentations or irregularities of the nuclear membrane. The cytoplasm may be scant, abundant or clear. The nucleus may be oval, round, kidney-shaped or divided. It has slightly finer chromatin compared with a small lymphocyte with inconspicuous or prominent nucleoli.[23–25]