Case 3 -

Parotid Gland Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue (MALT Lymphoma) Marsha C. Kinney and Steven H. Swerdlow

Clinical History 70 year old female with painless mobile mass in right parotid area for ~ 6 months. No facial paralysis. Diagnosis: Parotid Gland Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue (MALT Lymphoma) Case 3 - Figure 1 - Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type in parotid. Most of the salivary gland is replaced by a dense lymphoid infiltrate with large confluent pale areas seen at low magnification. Case 3 - Figure 2 - Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type in parotid. Note the lymphoepithelial lesions (LEL) with numerous pale lymphoid cells. These centrocyte-like/monocytoid-appearing cells extend beyond the LEL and form confluent sheets. Also see the hyperplastic follicular centers. Case 3 - Figure 3 - Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type in parotid. See the lymphoepithelial lesion associated with the neoplastic centrocyte-like/monocytoid-appearing lymphoid cells. Some transformed cells are also present. Discussion of Case 3 How to deal with lymphoid infiltrates in the salivary gland associated with lymphoepithelial lesions and what the diagnoses mean. Not all lymphoid infiltrates in the salivary gland, whether benign or malignant, are related to those associated with lymphoepithelial lesions. Salivary gland lymphoid infiltrates associated with lymphoepithelial lesions The salivary gland lymphoid infiltrates associated with lymphoepithelial lesions (LEL) include a broad spectrum of lympho(plasmacytic) proliferations that range from benign to small B-cell lymphomas to large B-cell lymphomas. [49, 155, 156, 157, 158, 159, 160] Depending on the author and precise type of proliferation, they go by a variety of different terms: benign lymphoepithelial lesion/myoepithelial sialadenitis/ lymphoepithelial sialadenitis/extranodal marginal zone B-cell lymphoma (MZL) of MALT type/high grade MALT lymphoma/diffuse large B-cell lymphoma. The use of eponymic terms such as Mikulicz's disease is strongly discouraged. About half of the cases are associated with Sjögren's syndrome or another autoimmune disorder such as rheumatoid arthritis. [157] Whereas most lesions with LEL in the past were considered benign, most are now considered MZL-MALT. Categorization of these lesions has become confusing due to varying criteria for lymphoma and recognition by some of borderline lesions or a "clonal disorder of uncertain malignant potential". [161] Histopathologic evaluation of salivary glands with lymphoepithelial lesions [156, 157] Salivary glands demonstrate variably dense lymphoid infiltration with destruction of the underlying parenchyma. The lymphoepithelial lesions (LEL) ("epimyoepithelial" islands) which represent lymphoid infiltration into the epithelium with resulting epithelial changes and sometime hyalinization are usually prominent. Cytokeratin stains can be very useful in highlighting the LEL. In most cases, the vast majority of the lymphoid cells are small with only scattered transformed cells. Germinal centers and variable numbers of plasma cells are frequently present. It is very important to assess the presence and distribution of pale "monocytoid" cells with more abundant pale cytoplasm in these salivary glands. In some cases they are not apparent. It is important in these cases to be sure that the lymphoid cells present do not suggest the presence of a non-MALT lymphoma as they are easily missed if one is fixated on only looking for a MALT lymphoma. For example, a marked proliferation of cleaved-appearing centrocyte-like cells should raise the possibility of follicular or mantle cell lymphoma. In other cases the pale cells are strictly within the LEL. Sometimes the pale cells extend beyond the LEL and form halos around them. Finally the pale cells may extend beyond the LEL and form confluent swaths and sheets. In some cases with LEL, there are many more numerous large transformed cells growing as sheets and sometimes present within the LEL. Immunophenotypic evaluation As discussed above, general immunophenotypic evaluation is very important in assessing the extent of the B-cell proliferation, the presence of a clonal population of B-cells and its precise phenotype (see above regarding the phenotype of typical MALT lymphomas). Because a moderate number of cases have plasmacytic differentiation and because it has been suggested that plasmacytic differentiation may be associated with more frequent extraglandular dissemination, immunohistochemistry/in-situ hybridization for kappa and lambda light chains can be very helpful. It is important to compare different areas to one another since some cases may have polyclonal plasma cells in areas of residual benign disease and monoclonal plasma cells in areas of lymphoma. Classification of salivary gland lymphoid proliferations with lymphoepithelial lesions [157] Diagnosis Histopathology Plasma cells Myoepithelial/Lymphoepithelial sialadenitis LEL with benign lymphoplasmacytic infiltrate Polyclonal (polyclonal B-cells) Myoepithelial/Lymphoepithelial sialadenitis with monocytoid halos LEL with nonconfluent monocytoid B-cell halos Polyclonal Marginal zone B-cell lymphoma of MALT type LEL with confluent monocytoid B-cell / "atypical" B-cells Polyclonal (monoclonal B-cells) Marginal zone B-cell lymphoma of MALT type with plasmacytic differentiation Marginal zone B-cell lymphoma of MALT type with monoclonal plasma cells Monoclonal Diffuse large B-cell lymphoma ("high grade" MALT)* Diffuse large B-cell areas with or without areas of marginal zone B-cell lymphoma of MALT type Polyclonal or monoclonal (monoclonal B-cells) * Although of uncertain significance, the additional presence of a "low grade" marginal zone B-cell lymphoma of MALT type should be mentioned. Other nonneoplastic lymphoid infiltrates in salivary glands Not all lymphoid infiltrates in salivary gland are associated with lymphoepithelial lesions, eg chronic sialadenitis. [162, 163] HIV-associated lymphoid hyperplasia associated with cyst formation and sometimes LEL. [164, 165, 166] Case 3: Summary of findings Case 3 demonstrates a marked dense lymphoplasmacytic infiltrate in the salivary gland with numerous small lymphoid cells, a moderate number of plasma cells, reactive germinal centers and prominent lymphoepithelial lesions. There are numerous "monocytoid" marginal zone cells that are within the LEL and extend beyond them forming confluent sheets. Immunohistologic stains demonstrate numerous B-cells with a moderate number of T-cells. The LEL are associated primarily with the B-cells. The plasma cells are polyclonal. Genotypic PCR studies performed using DNA obtained from suboptimal B5 fixed tissue demonstrated a faint clonal B-cell population on a polyclonal background (Dr. D. Bahler). This case fulfills the criteria for an extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type. Histologic/phenotypic-genotypic correlations [157] Diagnosis Original diagnosis benign Positive regional nodes at diagnosis Peri-glandular and/or perineural invasion Monoclonal by PCR and/or PSIP/ISH Myoepithelial/Lymphoepithelial sialadenitis 100% 0% 0% 42% Myoepithelial/Lymphoepithelial sialadenitis with monocytoid halos* 100% 0% 25% 63% Marginal zone B-cell lymphoma of MALT type 79% 50% 42% 77% Marginal zone B-cell lymphoma of MALT type with plasmacytic differentiation 50% 13% 67% 100% Diffuse large B-cell lymphoma ("high grade" MALT) 0% 100% 100% 100% * Diss, et al, report that this histologic pattern correlates with monoclonality and represents lymphoma. [155] Genotypic evidence of clonality is not equivalent to the diagnosis of lymphoma Clonal B-cells are found in circumstances not diagnostic of a lymphoma and in patients with no clinical evidence of concurrent or subsequent lymphoma. [157, 167, 168] Contralateral/subsequent biopsies may demonstrate the same clone (expected with a conventional lymphoma) or distinct unrelated clones. [155, 169, 170] Not all lymphomas "in" the salivary gland are MALT lymphomas Nodal lymphomas can involve the salivary glands and there are many lymph nodes in the region of the salivary glands. ML diagnosed in salivary gland biopsies [159] with MESA: 23 "immunocytoma"/0 germinal center derived without MESA: 2 "immunocytoma"/17 germinal center derived T-cell and NK/T-cell lymphomas also occur in the salivary glands and can be associated with lymphoepithelial lesions. [171] Most lymphomas arising in patients with Sjogren's syndrome are extranodal and marginal zone B-cell lymphomas but they do not necessarily arise in the salivary glands [158] 13/16 extranodal ± nodal involvement (parotid-7, lung-3, stomach-4, skin-3, buccal mucosa-1, thymus-1) 12/16 marginal zone B-cell lymphomas (9 of MALT type, 3 nodal) one developed a cutaneous T-cell lymphoma, one transformed to a diffuse large B-cell lymphoma. 4/16 diffuse large B-cell lymphomas (nodal, stomach, skin & parotid) two considered transformation of MALT lymphoma Clinical - Salivary gland MALT lymphomas Most patients do very well often without anti-neoplastic therapy; however, the disease can disseminate (especially cases with confluent "monocytoid" B-cell areas and/or monoclonal plasma cells). [49] late clonally-related recurrences are seen (supporting the neoplastic nature of these lymphomas). [172] some patients do die of lymphoma. [157, 159] Most optimal therapeutic approach remains to be determined. Clinical Follow-up in Case 3 Our patient was initially diagnosed with a nodular poorly differentiated lymphocytic lymphoma in 1984 and was alive at last known follow-up in 1997. Overview of salivary gland lymphoid infiltrates associated with lymphoepithelial lesions [157] Lympho(plasmacytic) infiltrates of the salivary gland associated with lymphoepithelial lesions# Benign Myoepithelial/lymphoepithelial sialadenitis, polyclonal Borderline Myoepithelial/lymphoepithelial sialadenitis, monoclonal Myoepithelial/lymphoepithelial sialadenitis, halos Indolent lymphoma * Extranodal marginal zone B-cell lymphoma of MALT type (with or without monoclonal plasma cells) Non-indolent lymphoma Diffuse large B-cell lymphoma ("high grade" MALT lymphoma) # Must exclude other lymphomas with LEL. * Therapeutic strategies must consider the special nature of these lymphomas. References 49. 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