Diagnosing Extranodal Lymphomas in the New Millennium
Case 3 -
Parotid Gland Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue (MALT Lymphoma)
Marsha C. Kinney and Steven H. Swerdlow
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
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. 
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".
Histopathologic evaluation of salivary glands with lymphoepithelial lesions
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.
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 
| 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.
|HIV-associated lymphoid hyperplasia associated with cyst formation and sometimes LEL.
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 
| 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
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.
|Contralateral/subsequent biopsies may demonstrate the same clone (expected with a conventional lymphoma) or distinct unrelated clones.
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 |
|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. |
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 
|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). |
|late clonally-related recurrences are seen (supporting the neoplastic nature of these lymphomas). |
|some patients do die of lymphoma.
|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 
Lympho(plasmacytic) infiltrates of the salivary gland associated with lymphoepithelial lesions#
| ||Myoepithelial/lymphoepithelial sialadenitis, polyclonal|
| ||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)|
| ||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.
|49.|| Alonsozana ELC, Stamberg J, Kumar D, Jaffe ES, Medeiros LJ, Frantz C, Schiffer CA, O'Connell BA, Kerman S, Stass SA, Abruzzo LV. Isochromosome 7q: the primary cytogenetic abnormality in hepatosplenic g d T cell lymphoma. Leukemia 11:1367-73, 1997.|
|155.|| Tomaszewski M-M, Lupton GP, Krishnan J, May DL. A comparison of clinical, morphological and immunohistochemical features of lymphomatoid papulosis and primary cutaneous CD30(Ki-1) positive anaplastic large cell lymphoma. J Cutan Pathol 22:310-18, 1995.|
|156.|| Willemze R, Beljaards RC. Spectrum of primary cutaneous CD30 (Ki-1)-positive lymphoproliferative disorders. A proposal for classification and guidelines for management and treatment. J Am Acad Dermatol 28:973-80, 1993.|
|157.|| Kadin M, Nasu K, Sako D, Said J, Vonderheid E. Lymphomatoid papulosis. A cutaneous proliferation of activated helper T cells expressing Hodgkin's disease-associated antigens. Am J Pathol 119:315-325, 1985?|
|158.|| Salhany KE, Cousar JB, Greer JP, Casey TT, Fields JP, Collins RD. Transformation of cutaneous T cell lymphoma to large cell lymphoma. A clinicopathologic and immunologic study. Am J Pathol 132:265-277, 1988.|
|159.|| Diamandidou E, Colome-Grimmer M, Fayad L, Duvic M, Kurzrock R. Transformation of mycosis fungoides/Sezary syndrome: clinical characteristics and prognosis. Blood 92:1150-1159, 1998.|
|160.|| Cerroni L, Rieger E, Hödl S, Kerl H. Clinicopathologic and immunologic features associated with transformation of mycosis fungoides to large-cell lymphoma. Am J Surg Pathol 16:543-52, 1992.|
|161.|| Kumar S, Kingma DW, Weiss WB, Raffeld M, Jaffe ES. Primary cutaneous Hodgkin's disease with evolution to systemic disease. Association with the Epstein-Barr virus. Am J Surg Pathol 20:754-759, 1996.|
|162.|| Sioutos N, Kerl H, Murphy SB, Kadin ME. Primary cutaneous Hodgkin's disease. Unique clinical, morphologic, and immunophenotypic findings. Am J Dermatopathol 16:2-8, 1996.|
|163.|| Guitart J, Fretzin D. Skin as the primary site of Hodgkin's disease: A case report of primary cutaneous Hodgkin's disease and review of its relationship with non-Hodgkin's lymphoma. Am J Dematopathol 20:218-222, 1998.|
|164.|| Su LD, Duncan LM. Lymphoma- and leukemia-associated cutaneous atypical CD30+ T-cell reactions. J Cutan Pathol 27:249-254, 2000.|
|165.|| Horn T, Lehmkuhle MA, Gore S, Hood A, Burke P. Systemic cytokine administration alters the histology of the eruption of lymphocyte recovery. J Cutan Pathol 23:242-246, 1996.|
|166.|| Nathan DL, Belsito DV. Carbamazepine-induced pseudolymphoma with CD30+ cells. J Am Acad Dermatol 38:806-809, 1998.|
|167.|| Crawford RI, McCalmont TH. The specificity of CD30 immunohistochemical staining in the diagnosis of cutaneous CD30-positive lymphoproliferative disease. J Cutan Pathol 24:92, 1997 (abstract).|
|168.|| Jaffe ES, Chan JKC, Su I-J, Frizzera G, Mori S, Feller AC, Ho FCS. Report of the workshop on nasal and related extranodal angiocentric T/natural killer cell lymphomas: definition, differential diagnosis, and epidemiology. Am J Surg Pathol 20:103-11, 1996.|
|169.|| Jaffe ES. Nasal and nasal-type T/NK cell lymphoma: a unique form of lymphoma associated with Epstein-Barr virus. Histopathology 27:581-83, 1995.|
|170.|| Kanavaros P, Lescs M-C, Brière J, Divine M, Galateau F, Joab I, Bosq J, Farcet J-P, Reyes F, Gaulard P. Nasal T-cell lymphoma: a clinicopathologic entity associated with peculiar phenotype and with Epstein-Barr virus. Blood 81:2688-95, 1993.|
|171.|| Van Gorp JV, De Bruin PC, Sie-go DMDS, Van Heerde P, Ossenkoppele GJ, Rademakers LHPM, Meijer CJLM, Van Den Tweel JG. Nasal T-cell lymphoma: a clinicopathological and immunophenotypic analysis of 13 cases. Histopathology 27:139-148, 1995.|
|172.|| Harabuchi Y,Imai S, Wakashima J, Hirao M, Kataura A, Osato T, Kon S. Nasal T-cell lymphoma causally associated with Epstein-Barr virus: clinicopathologic, phenotypic, and genotypic studies. Cancer 77:2137-49, 1996.|