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Inflammatory Pseudotumor of the Submandibular Gland: Report of a Case Presenting With Autoimmune Disease-like Clinical Manifestations.

Inflammatory pseudotumor (IPT) is an uncommon, benign, idiopathic lesion that has been described in various viscera and deep soft tissues, particularly the lung.[1-6] Inflammatory pseudotumors occasionally contain a heavy lymphoid and plasmacytic infiltrate, and the term plasma cell granuloma has been used interchangeably with the term IPT.[1-3,6] However, in marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type, plasma cell differentiation has been noted in various degrees, and sometimes dense infiltrate of monotypic plasma cells has been described.[7,8] Therefore, when IPTs contain numerous plasma cells, these lesions should be differentiated from MALT-type lymphomas in the lung, skin, oral cavity, and salivary glands.[1-4,6-9]

Inflammatory pseudotumors appear to be rare in the salivary glands.[10] Indeed, to our knowledge, only one study in the literature has given a detailed clinicopathologic and immunohistologic description of IPTs arising in the parotid glands.[10] We report an additional case of IPT containing numerous plasma cells and arising in the sub-mandibular glands, which presented with various autoimmune-like clinical manifestations, and discuss problems in making the differential diagnosis from primary MALT-type lymphoma of the salivary gland.

REPORT OF A CASE

A 70-year-old Japanese man presented with general fatigue and swelling in the bilateral submandibular gland region of 2 months' duration. The patient had no history of sialolithiasis or Sjogren syndrome. Physical examination on admission revealed anaphylactoid purpura. The patient's hemoglobin level was 100 g/L; white blood cell count, 6.7 x [10.sup.9]/L; and platelet count, 214 x [10.sup.9]/L. His total serum protein value was 106 g/L (albumin, 40 g/L; globulin, 66 g/L), and serum protein electrophoresis revealed a polyclonal pattern. Measurement of serum immunoglobulin (Ig) levels revealed the following values: IgG, 65.58 g/ L; IgA, 1.76 g/L; and IgM, 0.51 g/L. No Bence-Jones protein was detected in the urine. Although the antinuclear antibody titer was 1:1280 and the antithyroid test was positive, the patient did not have any symptoms of autoimmune disease, such as systemic lupus erythematosus.

The right submandibular gland mass was completely resected in June 1994, and it measured 3 cm in diameter. The lesion was tentatively diagnosed as MALT-type lymphoma, and the patient was given CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy. Twelve months after surgery, bilateral neck and intra-abdominal lymphadenopathy was observed. In July 1995, a left neck lymph node biopsy was performed. He was diagnosed with lymph node involvement of MALT-type lymphoma and received CHOP therapy again. He is currently alive and free of disease 72 months after surgery.

MATERIALS AND METHODS

We examined the right submandibular gland and lymph node biopsy specimens. Formalin-fixed, paraffin-embedded tissue was cut into 3-[micro]m sections and stained with hematoxylin-eosin and periodic acid-Schiff reagents and for acid-fast bacilli. In an immunohistochemical study, sections were stained by the streptavidin-biotin-peroxidase (SAB) method (ScyTek, Logan, Utah) using antibodies to the following: human immunoglobulin light chains (Novocastra, Newcastle, United Kingdom), L26 (CD20; Nichirei Co, Tokyo, Japan), KP-1 (CD68; Dako A/S, Glostrup, Denmark), cytokeratin (Immunotech, Marseille, France), vimentin (Immunotech), muscle-specific actin (HHF35; ScyTek), smooth muscle actin (1A4; Immunotech), and Bcl-2 oncoprotein (100; Immunotech). Microwave antigen retrieval was used with cytokeratin and Bcl-2 oncoprotein. In situ hybridization with Epstein-Barr virus (EBV)-encoded small RNA (EBER) oligonucleotides was used to test for the presence of EBV small RNAs in formalin-fixed, paraffin-embedded sections according to the manufacturer's instructions (Novocastra). Paraffin-embedded tissues from the resected right submandibular gland specimen for polymerase chain reaction were prepared, and the rearranged heavy-chain genes were amplified using the seminested polymerase chain reaction method according to Wan et al.[11]

RESULTS

Gross examination of the surgical specimen from the submandibular gland revealed firm, lobulated, yellow-gray nodules. No salivary calculi were detected.

At low magnification, multiple nodules separated by thick fibrous bands were observed. Except for scattered residual ductal structures, there was complete effacement of the lobular architecture. A few lymphoid follicles with an atrophic germinal center were found in the nodules (Figure 1). The nodules contained numerous mature plasma cells mixed with small lymphocytes, histiocytes, and spindle cells (Figures 2 and 3, a). Occasionally, the spindle cells were arranged in poorly formed fascicles and in a storiform pattern (Figure 3, a). No centrocyte-like cells or epimyoepithelial islands were observed in the lesions. No microlithiasis, excretory duct ectasia, squamous metaplasia of the ductal epithelium, or salivary extravasation were detected. Acid-fast bacilli and fungal stains were negative. The plasma cells were demonstrated to be polytypic with a [KappaL-[Lambda] ratio of 1:1. Most of the small lymphocytes were CD45RO-positive T cells, and there were a few scattered CD20-positive B cells. A few Bcl-2-positive small lymphocytes were identified in the negative-staining germinal centers. Spindle cells were usually reactive for vimentin. The majority were positive for muscle-specific actin and [Alpha]-smooth muscle actin (Figure 3, b), and only a minority were reactive for CD68. Based on these observations, most of the spindle cell population appeared to consist of myofibroblasts. No epimyoepithelial islands were detected, even by immunostaining for cytokeratin. No immunoglobulin deposition was detected in the fibrous bands. No EBER-positive cells were detected.

[ILLUSTRATIONS OMITTED]

The genotypic studies revealed only germline bands with the immunoglobulin heavy-chain probes.

The biopsy specimen of the lymph node lesion taken in July 1995 contained numerous lymphoid follicles with hyperplastic germinal centers. The interfollicular area and medullary cords were heavily infiltrated by mature plasma cells with a sheetlike arrangement in some areas. A few immature plasma cells and immunoblasts were intermingled with mature plasma cells. Immunohistochemical studies of light chain determinants for germinal center and interfollicular plasma cells revealed a polyclonal pattern.

COMMENT

The etiology of the IPT is still unknown. Hypotheses have suggested that the pathogenesis has infectious, autoimmune, and vascular origins. The presence of polyclonal plasma cells, lymphocytes, and histiocytes suggests an infectious or autoimmune origin.[2,4,6] Arber et al[12] recently detected EBV association in 7 of 18 cases of IPTs arising in the lymph node, spleen, and liver, and suggested that EBV might play a role in the pathogenesis of at least a subset of IPTs. In contrast, Ballesteros et al[6] failed to detect EBV genomes in the oral cavity by in situ hybridization. Our study also showed the absence of EBV genomes in IPT of the salivary gland. The distribution of EBV genomes in IPT appears to differ among organs affected, although the cases examined were too few in number to clarify this issue. In support of an autoimmune cause, splenic IPT occasionally occurred in idiopathic thrombocytopenic purpura.[4] The autoimmune disease-like clinical manifestation of the present case may further support an autoimmune cause of IPT

Mucosa-associated lymphoid tissue-type lymphoma appears to pose the most important problem in the differential diagnosis. Primary MALT lymphoma of the salivary gland has been frequently associated with autoimmune disease, mainly Sj6gren syndrome.[9,13,14] Plasma cell differentiation has been noted in various degrees in MALT lymphoma, and the plasma cells may occasionally obscure the centrocyte-like cells in the salivary gland.[8,9,14] The atrophic germinal centers seen in our cases resembled follicular colonization, and the thick fibrous bands could be misinterpreted as the extracellular immunoglobulin deposition occasionally seen in low-grade MALT lymphoma.[7] Hyjek et al[13] stated that the presence of a population of centrocyte-like cells around the epimyoepithelial islands was indicative of the emergence of B-cell monoclonalities. Diss et al[15] confirmed the suspicions of Hyjek et al on the basis of their histologic, immunologic, and genotypic findings. However, neither centrocyte-like cells nor epimyoepithelial islands were found in our lesion. Furthermore, the immunophenotypic and genotypic studies failed to provide any evidence of the presence of a monoclonal B-cell population.

In conclusion, IPTs arising in the submandibular glands can have clinical and pathologic features that mimic benign or malignant tumors, especially low-grade MALT lymphomas. It is therefore important to recognize them as such to avoid inappropriately aggressive therapy.

References

[1.] Bahadori M, Liebow AA. Plasma cell granulomas of the lung. Cancer. 1973; 31:191-208.

[2.] Spencer H. The pulmonary plasma cell/histiocytoma complex. Histopathology. 1984;8:903-916.

[3.] Hurt MA, Santa Cruz DJ. Cutaneous inflammatory pseudotumor lesions resembling "inflammatory pseudotumors" or "plasma cell granulomas" of extracutaneous sites. Am J Surg Pathol. 1990;14:764-773.

[4.] Thomas RM, Jaffe ES, Zaerate-Osorno A, Medeiros LJ. Inflammatory pseudotumor of the spleen. Arch Pathol Lab Med. 1993;117:921-926.

[5.] Coffin CM, Watterson J, Priest JR, Dehner LP. Extrapulmonary inflammatory myofibroblastic tumor (inflammatory pseudotumor): a clinicopathologic and immunohistochemical study of 84 cases. Am J Surg Pathol. 1995;19:859-872.

[6.] Ballesteros E, Osborne BM, Matsushima AY. Plasma cell granuloma of the oral cavity: a report of two cases and review of the literature. Mod Pathol. 1998; 11:60-64.

[7.] Isaacson PG, Norton Al. Extranodal Lymphomas. New York, NY: Churchill Livingstone; 1994.

[8.] Hussong JW, Perkins SL, Schnitzer B, Hargreaves H, Frizzera G. Extramedullary plasmacytoma: a form of marginal zone cell lymphoma? Am J Clin Pathol. 1999;111:111-116.

[9.] Schmid U, Helbron D, Lennert K. Development of malignant lymphoma in myoepithelial sialoadenitis (Sjogren's syndrome). Virchows Arch A Pathol Anat Histopathol. 1982;395:11-43.

[10.] Williams SB, Foss RD, Ellis GL. Inflammatory pseudotumors of the major salivary glands: clinicopathologic and immunohistochemical analysis of six cases. Am J Surg Pathol. 1992;16:896-902.

[11.] Wan JH, Trainor KJ, Brisco MJ, Morley AA. Monoclonality in B cell lymphoma detected in paraffin wax embedded sections using the polymerase chain reaction. J Clin Pathol. 1990;43:888-890.

[12.] Arber DA, Kamel OW, van De Rijn M, et al. Frequent presence of the Epstein-Barr virus in inflammatory pseudotumor. Hum Pathol. 1995;26:1093-1998.

[13.] Hyjek E, Smith WJ, Isaacson PG. Primary B-cell lymphoma of salivary glands and its relationship to myoepithelial sialoadenitis. Hum Pathol. 1988;19: 766-776.

[14.] Patsouris E, Noel H, Lennert K. Lymphoplasmacytic/lymphoplasmacytoid immunocytoma with a high content of epithelioid cells: histologic and immunohistochemical findings. Am J Surg Pathol. 1990;14:660-670.

[15.] Diss TC, Wotherspoon AC, Speight P, Pan L, Isaacson PG. B-cell monoclonality, Epstein-Barr virus, and t(14;18)in myoepithelial sialoadenitis and low-grade B-cell MALT lymphoma of the parotid gland. Am J Surg Pathol. 1995;19: 531-536.

Accepted for publication February 5, 2001.

From the Department of Pathology, Dokkyo University School of Medicine, Mibu, Japan (Drs Kojima and Masawa); the Department of Pathology and Genetics, Aichi Cancer Center Hospital, Nagoya, Japan (Drs Nakamura and Suchi); and the Department of Pathology and Clinical Laboratories, Maebashi Red Cross Hospital, Maebashi, Japan (Dr Itoh).

Reprints: Masaru Kojima, MD, First Department of Pathology, Dokkyo University School of Medicine, Mibu, Tochigi 321-0923, Japan (email: m-kojima@dokkyomed.ac.jp).
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Author:Kojima, Masaru; Nakamura, Shigeo; Itoh, Hideaki; Suchi, Taizan; Masawa, Nobuhide
Publication:Archives of Pathology & Laboratory Medicine
Geographic Code:1USA
Date:Aug 1, 2001
Words:1774
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