Hematolymphoid tumors of the oral cavity

This occurs in the sixth and seventh decades, but may also be seen in younger adults.

Lesions present as an enlarging painless mass, frequently occur on the palatal mucosa, and may be ulcerated and painful.

B symptoms (fever, weight loss, and night sweats) are uncommon.

There is a diffuse proliferation of large lymphoid cells effacing underlying tissue architecture; multiple morphologic variants may be seen, including centroblastic (large cells with moderate amounts of cytoplasm, and large, open nuclei with multiple peripheral nucleoli), immunoblastic (large cells with abundant amphophilic cytoplasm, and large nuclei with large central nucleoli), and anaplastic; areas of frank necrosis may be present ( Fig. 18.2 A–B).

Lesional cells express B-cell markers CD19, CD20, and PAX5 ( Fig. 18.2 C); monotypic surface immunoglobulin light chain expression may be detected by flow cytometry.

The expression of CD10, BCL6, and MUM1 varies depending on subtype (GCB versus ABC) ( Fig. 18.2 D); several immunohistochemistry-based algorithms have been developed as a tool for assigning subtype.

In situ hybridization for Epstein-Barr virus (EBV)–encoded RNA (EBER) may be positive in some cases, particularly in older patients; however, EBER reactivity is not common and should prompt evaluation for lesions outlined in the Differential Diagnosis section later.

The proliferation index is variable and may be moderate to as high as 90% ( Fig. 18.2 E).

Burkitt lymphoma: There is a monotonous infiltrate of intermediate-sized B cells in a background of numerous macrophages containing cytoplasmic particles of cellular debris (“tingible-body macrophages”), which imparts a moth-eaten appearance at low-power known as a “starry sky” pattern; cells express CD10 and lack BCL2; the proliferation index is greater than 95%; endemic cases in particular may show reactivity for EBER; MYC translocation is detected (typically t(8;14)(q24;q32)) without concurrent BCL2 or BCL6 translocation.

Plasmablastic lymphoma: Cells are uniformly positive for CD138 and EBER and negative for CD20; oral lesions are most commonly seen in the setting of immunosuppression such as HIV/AIDS.

EBV-positive mucocutaneous ulcer: This ulcer contains cells that exhibit Hodgkin-like features in a polymorphous inflammatory background with strong expression of CD30 and EBER, and weak expression of CD20; it typically occurs in older patients, is self-limited, and runs an indolent course (see Chapter 4 ).

Myeloid sarcoma (acute myeloid leukemia): Given the morphologic overlap between the two entities, immunophenotyping is essential to confirm the B-cell origin of the infiltrate.

Extranodal NK/T-cell lymphoma, nasal type: This lymphoma tends to occur in those living in East Asia and South and Central America; a presenting symptom is an ulcerated, necrotic mass in the nasal and nasopharyngeal mucosa, and oral sites include Waldeyer ring and the palatal mucosa presenting as midline destructive disease; there is an infiltrate of large, irregular lymphoid cells with angiodestruction and abundant necrosis/apoptosis, and there is a high proliferation index; cells are typically positive for CD3 in a cytoplasmic pattern (but negative for surface CD3 by flow cytometry), CD2, CD56, and EBER, and negative for T-cell antigens CD5, CD4, and CD8; cells are also often positive for granzyme B and/or TIA-1.

High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements: Cases falling into this category are also known as “double-” or “triple-hit” lymphomas because they show a MYC rearrangement as well as BCL2 and/or BCL6 rearrangements. Cases that morphologically resemble DLBCL but show these genetic changes are placed into this category.

DLBCLs are aggressive but potentially curable with multiagent chemotherapy.

Multivariable analysis of patients with oral and maxillofacial DLBCL show age, clinical stage, and performance status to be significant prognostic factors.

PBL involving the oral cavity typically presents as a lesion of the gingiva or palatal mucosa, similar to other oral lymphomas; secondary bony involvement is uncommon.

Approximately 50% of patients present with advanced stage disease, although only a third demonstrate bone marrow involvement.

The presence of B symptoms is variable.

There is a diffuse proliferation of large lymphoid cells with variable appearance; some show typical immunoblastic features with prominent central nucleoli, whereas others resemble mature plasma cells or exhibit plasmablastic features (namely, vesicular chromatin, prominent nucleoli, and eccentrically placed nuclei) ( Fig. 18.3 A–C); there is a background of numerous apoptotic bodies and tingible-body macrophages.

Lesional cells express plasma cell markers including CD138, CD38, and MUM1; CD30 and epithelial membrane antigen (EMA) are frequently positive; cells are mostly negative for, or show weak expression of, CD45 and B-cell markers such as CD20 and PAX5; monotypic cytoplasmic immunoglobulin light chain is detected in 50% to 70% of cases; Ki67 proliferation index is usually very high (>90%); HHV8 and BCL6 are negative.

EBER is positive in almost all of the HIV-associated oral lesions, and in approximately 50% of the lesions occurring in the HIV-negative setting ( Fig. 18.3 D).

CD56 expression is more common in cases associated with HIV than in HIV-negative cases.

Anaplastic (plasmablastic) plasmacytoma: Correlation with clinical findings is essential; EBER positivity favors PBL, although rare cases of EBV-positive plasmacytoma in immunocompetent patients have been reported.

Burkitt lymphoma: Shared features include EBER positivity, high proliferation index, and tingible-body macrophages; unlike PBL, BL cells are intermediate in size without plasmacytoid features and are strongly positive for CD45, CD20, and BCL6.

Diffuse large B-cell lymphoma: Unlike PBL, DLBCL will show strong expression of CD45 and CD20 and typically a lower proliferation index.

Most are treated with multiagent chemotherapy, but PBL is an aggressive tumor and many patients die within the first year.

In one study, univariate analysis showed older age (60 years or older), advanced stage/bone marrow involvement, high Ki67 proliferation index (>80%), and HIV-negative status were associated with worse overall survival.

In the oral cavity, the mean age of presentation is in the eighth decade with a 3:1 male predominance; most cases involve the palatal mucosa (75% of cases).

Most lesions are low grade at presentation.

Most cases of FL have a predominantly follicular pattern with back-to-back follicles that replace the nodal architecture ( Fig. 18.4 A); the abnormal follicles exhibit attenuated mantle zones and are composed of a mixture of centrocytes (lymphoid cells with cleaved nuclei and condensed chromatin) and centroblasts.

CD21 highlights the follicular dendritic cell (FDC) meshwork underlying neoplastic follicles ( Fig. 18.4 B); diffuse areas demonstrate an absence of CD21 expression.

Grading of FL is based on the number of centroblasts present in neoplastic follicles: grade 1 = 0–5 centroblasts/high-powered field (hpf) ( Fig. 18.4 C–D); grade 2 = 6–15 centroblasts/hpf; grade 3 = greater than 15 centroblasts/hpf ( Fig. 18.4 E–F); grade 3 is subdivided into grade 3A (admixed centrocytes and centroblasts) and grade 3B (sheets of centroblasts); diffuse areas may be present as defined by an absence of underlying FDC meshworks; if grade 3 cytology is present in an architecturally diffuse area, this should be classified as DLBCL.

Lesional B cells express the B-cell markers CD19, CD20, and PAX5, and show coexpression of BCL2, BCL6, and CD10.

Grade 3 FL can be CD10− and lack BCL2 expression.

Monotypic surface immunoglobulin light chain expression is detected by flow cytometry.

The majority of FLs show a characteristic IGH-BCL2 translocation: t(14;18)(q32;q21).

Reactive follicular hyperplasia: Reactive follicles will show well-defined mantle zones and admixed tingible-body macrophages; germinal center cells will not coexpress BCL2, and molecular analysis will show a polyclonal pattern of immunoglobulin heavy chain gene rearrangements.

Marginal zone lymphoma: May show reactive follicles reminiscent of FL nodules, but the follicles in marginal zone lymphoma demonstrate reactive features as described earlier and are usually a minor component of the lesion; the majority of the marginal zone lymphoma infiltrate consists of neoplastic B cells in the interfollicular space.

Prognosis of FL is related to the extent of disease present at diagnosis; histologic grade also correlates with grade 1–2 cases being more indolent (but not curable), whereas grade 3 shows a more aggressive course.

Localized lesions may be treated with radiation, systemic disease may warrant chemotherapy, and these regimens will differ depending on grade.