Extranodal Marginal Zone B-cell Lymphoma of MALT Type, with Focal Transformation to Large Cell Lymphoma, of the Parotid Gland Dr. Christina MacMillan

Clinical History: 58-year-old female with swelling of the left parotid gland. FNA biopsy showed a lymphoid infiltrate, not otherwise specified. Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Diagnosis: Extranodal marginal zone B-cell lymphoma of MALT type, with focal transformation to large cell lymphoma, of the parotid gland. Treatment: Superficial left parotidectomy and partial excision of the deep lobe. Further Investigations: Post surgical diagnosis, the patient was referred to oncology. She had abnormal ANA and rheumatoid factor indices, heterogeneous parotid glands on CT scan compatible with Sjogren's syndrome, evidence of lymphoma in axillary lymph nodes and the lungs on CT of the chest. Bone marrow aspirate and biopsy showed a few clusters of atypical large lymphoid cells, but no definite evidence of lymphoma. Gross pathologic findings: On cut section, there were several fleshy nodules within the parenchyma, ranging in size from 0.4 cm up to 1.5 cm. Microscopic findings: Sections showed extensive infiltration by lymphocytes and numerous well-formed lymphoepithelial lesions (LEL's), with some preservation of the normal architecture. The infiltrated cells were predominantly small lymphocytes, marginal type cells and plasma cells. Halos of monocytoid cells around LEL's and broad bands of these cells along with centrocyte-like cells connecting LEL's were observed. Reactive lymphoid follicles colonized by centrocyte-like cells were also seen. In some areas there were clusters of large cells with dispersed chromatin and prominent nucleoli. Three separate lymph nodes were not involved. Immunophenotypic studies performed on paraffin sections demonstrated that the majority of cells were CD20+, CD3-, CD5-, CD10- and CD43-. Light chain restriction for kappa was demonstrated. The clusters of large cells were Bcl-6+. CD21 showed remnants of follicular dendritic cells meshwork, while MIB-1 showed a high proliferative rate. Discussion: General: Primary salivary gland non-Hodgkin's lymphomas (NHL) are uncommon, comprising about 5% of all primary extranodal lymphomas and 2% of all salivary gland tumors. The parotid gland is most commonly affected (80%), followed by submandibular gland (16%), sublingual gland (2%) and minor salivary glands (2%). Extranodal marginal B-cell lymphomas of MALT type are defined by the WHO classification as a low-grade B-cell lymphoma arising in mucosa-associated lymphoid tissue (MALT). Most occur in adults in the 55 to 65 year age range and with a much greater occurrence in women. Occasionally young adults and children may be affected. Patients typically present with a painless mass that may show episodic enlargement; a subset of patients may have facial nerve paresis or pain. The majority of patients have clinical or lab evidence of Sjogren's syndrome (SS). Multiple or bilateral involvement occurs in about 10% of cases. Head and neck is the second most common site of extranodal lymphomas after the gastrointestinal tract. [1, 2, 3] The most common histologic types in the salivary glands are extranodal marginal zone B-cell lymphoma (EMZBCL) of MALT type and diffuse large B-cell lymphoma (DBCL). The latter may arise from an EMZBCL or from a follicular lymphoma with transformation located in an intraparotid node and spreading into the adjacent gland. Lymphoepithelial sialadenitis (LESA), formerly known as myoepithelial sialadenitis (MESA) or benign lymphoepithelial lesion (BLEL) is a precursor lesion for EMZBCL of MALT type. LESA is usually associated with an underlying autoimmune disease, most commonly Sjogren's syndrome. The risk of developing malignant lymphoma in patients with LESA and SS has been estimated to be 43.8 X greater than that of general population. Extranodal marginal zone B-cell lymphoma of MALT type tends to remain localized for prolonged intervals and hence may be clinically confused with an inflammatory process. It has a predilection for involving other extranodal sites but a low frequency of bone marrow involvement. Due to the good prognosis, most patients can be followed closely without additional therapy. In the unusual event of transformation to a DBCL and extrasalivary gland involvement, additional localized or systemic therapy is usually administered. [1, 2, 3, 7, 8] DALT: The Duct-Associated Lymphoid Tissue (DALT) is poorly developed in normal human salivary glands and is present in 2 compartments; the interacinal interstitium, where IgA-secreting plasma cells are found and the periductal connective tissue, where lymphoid accumulations associate with the excretory duct epithelium. This DALT is considered to be a component of the Mucosa-Associated Lymphoid Tissue (MALT). In autoimmune diseases such as SS, organized lymphoid accumulations are formed around the ducts. [4] LESA Histology: LESA is usually associated with Sjogren's syndrome but can be seen outside the setting of autoimmune disorders. There is an extensive lymphoid infiltration with preservation of the underlying glandular architecture. Lymphoepithelial lesions (LEL's) previously known as epimyoepithelial islands are prominent. LEL's are islands of ductal epithelial cells infiltrated by small lymphoid cells. They were formerly thought to represent a proliferation of myoepithelial and ductal cells, but are now recognized to be a proliferation of the basal ductal cells. They contain hyaline basal lamina material and the associated ducts may be cystically dilated. Involved minor salivary glands show similar findings, however LEL's tend to be small or lacking. Over time, the lymphoid infiltrate replaces acinar tissue and is associated with reactive lymphoid follicles. LESA and lymphoepithelial cysts can also occur in HIV+ patients. [1, 2, 7, 8]. EMZBCL Histology: EMZBCL of the parotid gland almost always occurs in the background of LESA. It consists of a diffuse heterogeneous B-cell infiltrate that partially or completely effaces the normal gland architecture. There are 3 typical histologic findings: a population of small and irregular lymphoma cells, lymphoepithelial lesions and reactive lymphoid follicles. The lymphoid infiltrate is variably composed of small atypical cells, centrocyte-like (cleaved) cells, monocytoid cells, immunoblasts, lymphoplasmacytic cells and plasma cells. The neoplastic lymphoid cells are distinctive and were designated by Isaacson as centrocyte-like due to their resemblance to centrocytes or small-cleaved cells of the normal germinal center [15]. There may be a wide range of cytologic appearances. In many cases the neoplastic cells have abundant clear (monocytoid) cytoplasm resembling monocytoid B-cells seen in lymph node sinuses of reactive conditions. Occasional large lymphoid cells are scattered among the small lymphoma cells. When these large cells become numerous and form sheets, the neoplasm has transformed to a large B-cell lymphoma, however the boundary between low-grade and high-grade MALT-lymphoma (i.e. DLBCL) is poorly defined; a high mitotic rate and increased large cells (>10%) are helpful clues. The neoplastic cells infiltrate ductal epithelium, forming LEL's. At times, these may be difficult to recognize and keratin IHC may be required to identify them. Broad halos of centrocyte-like and monocytoid cells surrounding the LEL's and often forming interconnecting bands between LEL's are typically present. Reactive lymphoid follicles surrounded by the neoplastic cells are common. The lymphoma cells colonize or infiltrate the follicles, which can impart a nodular pattern sometimes resembling follicular lymphoma. Reactive plasma cells are often present. In addition, there may be true plasmacytoid differentiation. Some cases may appear biphasic with sheets of cytologically mature plasma cells and other areas of small lymphoid cells. Dutcher bodies (intranuclear pseudoinclusions) are common in MALT-lymphomas with plasmacytoid differentiation. Other findings that may be seen include small clusters of epithelioid histiocytes and areas of prominent fibrosis. [1, 2, 3, 7, 8] Immunohistochemical stains: The immunoprofile reflects the B-cell tumor lineage, showing immunoreactivity with CD20 and CD79a. The lymphocytes and monocytoid cells express surface immunoglobulin, and monotypic light chain expression is present (light chain restriction). Bcl-2 reactivity is in the neoplastic colonizing B-cells but not in the reactive germinal centre cells themselves. The neoplastic cells are negative with IgD, CD5, CD10, CD23 and Bcl-1 (Cyclin D1). Molecular studies: Clonal B-cell populations can be detected by PCR and Southern blot techniques in LESA without histologic evidence of lymphoma and in LESA with atypical features such as halos around the LEL's ("undetermined malignant potential"). There is controversy as to whether these represent malignant lymphomas. In the study by Bahler and Swerdlow, distinct B-cell clones in different biopsy specimens from the same patients were detected, and in 2 of these patients there was no evidence of lymphoma in the MESA-lesions. In addition, they found marked VH gene restriction suggesting binding to the same or similar antigens. They proposed that the growth of early MESA clones may be still dependent on antigen stimulation and an additional genetic event such as trisomy 3 or p53 mutation is required for the development of lymphoma. Recent studies have shown 4 apparently site specific chromosomal translocations that may occur in EMZBCL of MALT type: t(11;18) (q21;q21); t(14;18) (q32;q21); t(3;14) (p14.1;q32) and t(1:14) (p22;q32). Most of these are involved in activating the downstream nuclear factor K B (NF-KB) pathway. Numerical aberrations such as +3, +12 and +18 may occur isolated or in combination with a structural aberration. The most commonly detected genetic abnormalities in the salivary gland MALT lymphomas to date are t(14;18) and trisomy 3. [9, 11, 12, 13] Reactive versus MALT lymphoma? The distinction between LESA and EMZBCL may be very difficult. A large infiltrate, a relatively monotonous lymphoid population, cytologic atypia and numerous Dutcher bodies are supportive of a malignant diagnosis. The presence of halos around LEL's and broad interconnecting bands of atypical lymphoid cells (centrocyte-like or monocytoid B cells) are features supporting the diagnosis of lymphoma. Lymphoepithelial lesions are not helpful in distinguishing MESA from MALT-lymphoma since they can occur in both. With progression, the LEL's are destroyed, reactive follicles are infiltrated and replaced and the process extends outside the gland. Differential Diagnosis: Aside from LESA, it may also include chronic sclerosing sialadenitis (Kuttner tumor), inflammatory pseudotumor, Kimura disease, Rosai-Dorfman disease, mantle zone lymphoma and follicular lymphoma. A case of extranodal marginal zone B-cell lymphoma of MALT type arising in the background of chronic sclerosing sialadenitis (Kuttner Tumor) has also been described [10]. References: World Health Organization Classification of Tumours. Pathology & Genetics. Head and Neck Tumours. Edited by Leon Barnes, John W Eveson, Peter Reichart, David Sidransky. IARC Press: Lyon 2005. Vega F, Lin P, Medeiros J. Extranodal lymphomas of the head and neck. Ann Diagn Pathol. 2005;9(6): 340-350. Campo E, Chott A, Kinney MC, Leoncini L, Meijer CJLM, Papadimitriou CS, Piris MA, Stein H, Swerdlow SH. Update on extranodal lymphomas. Conclusions of the Workshop held by the EAHP and the SH in Thessaloniki, Greece. Histopathology. 2006;48(5): 481-504. Ciccone E, Truini M, Grossi CE. 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