Published Ahead of Print on June 9, 2014 as 10.1200/JCO.2013.50.6501 The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2013.50.6501

JOURNAL OF CLINICAL ONCOLOGY

Extranodal Marginal Zone Lymphoma Presenting As Miliary Lung Disease Case Report The patient is an 83-year-old woman who had lung nodules incidentally identified on a shoulder x-ray performed for unrelated shoulder pain. A follow-up chest x-ray showed innumerable 2- to 3-mm pulmonary nodules in a miliary pattern diffusely throughout the lungs but predominating in the lung bases (Fig 1). The radiologic differential diagnosis included tuberculosis, fungal infection, collagen vascular disease, sarcoidosis, or diffuse metastatic disease. Though incidentally discovered, the patient endorsed diminishing appetite and energy as well as dyspnea on exertion that had slowly developed over many months. She reported a 15-pound weight loss over the prior 6 months. She also reported occasional night sweats beginning approximately 1 month before discovery of the lung nodules, but no fevers. She denied cough, hemoptysis, and other symptoms of infection. She had no known exposures to tuberculosis. Her medical history was notable for chronic Lyme disease over many years intermittently treated with doxycycline, most recently 1 year before presentation. She had multiple known thyroid nodules that had been aspirated in 1997 and found to be benign. Her only medications were hydrochlorothiazide and a multivitamin. She is a retired secretary but experienced exposures in her lifetime including saw dust, sheet rock

Fig 1. Journal of Clinical Oncology, Vol 32, 2014

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and other construction materials. She smoked one pack per day for 10 years from age 25 to age 35. On physical examination, she was well appearing, breathing comfortably, and had an oxygen saturation of 96% breathing ambient air. Her lungs were clear to auscultation. She had no lymphadenopathy or splenomegaly. Examination was otherwise unremarkable. A tuberculin skin test was placed and was negative. A chest computed tomography scan demonstrated innumerable diffuse pulmonary nodules in a perilymphatic distribution (Figs 2A and 2B). Modestly enlarged paratracheal lymph nodes were identified measuring up to 1.6 cm, as well as hilar lymph nodes measuring up to 2.9 cm on the right and 2.1 cm on the left (Fig 2C). The thyroid gland was diffusely enlarged and contained multiple nodules that measured up to 1.6 cm in diameter. She underwent bronchoscopy and cervical mediastinoscopy. The bronchial mucosa was edematous with submucosal thickening. No endobronchial lesions were identified. Bronchoalveolar lavage showed rare polys and normal flora on respiratory culture. No acid fast bacilli were identified, and fungal wet prep was negative. Mycobacterial and fungal cultures were both negative, as was a galactomannan antigen performed on the lavage fluid. Cytologic evaluation showed only bronchial columnar cells and pulmonary macrophages. Multiple paratracheal lymph nodes were biopsied on mediastinoscopy and showed normal lymphoid tissue without granulomas or malignancy. Pulmonary function testing showed a normal single-breath diffusion capacity. The FEV1 and FEV1/FVC ratio were normal. She was taken to video-assisted thoracoscopic surgery (VATS) for lung biopsy. Intraoperative photos showed numerous small lesions involving the visceral pleura of all visualized lung lobes (Fig 3). A wedge biopsy of the right middle lobe was performed. On sectioning, there were multiple tan-gray, 1- to 2-mm nodules scattered throughout the tissue (Fig 4A). Microscopic examination revealed numerous nodules of lymphoid cells, sometimes surrounding blood vessels (Fig 4B). The nodules were composed of small to mediumsized lymphoid cells with slightly irregular nuclei, coarse to finely dispersed dark chromatin, inconspicuous to absent nucleoli. and moderately abundant pale cytoplasm (Fig 4C). Occasional plasma cells and plasmacytoid cells were interspersed. Also seen within some nodules were poorly delineated aggregates of larger, mitotically active cells with interspersed tingible body macrophages suggesting remnants of reactive germinal centers. No granulomas were identified. Flow cytometric analysis revealed a predominant population of CD19dim, CD20-positive B cells lacking expression of CD5, CD10, and CD23, and expressing monotypic kappa immunoglobulin light chain. Immunohistochemical analysis revealed that the nodules of lymphoid cells were composed of CD20-positive B cells (Fig 4D) coexpressing bcl2, without expression of bcl6, CD43, or cyclin D1. With antibody to kappa and lambda, there was monotypic cytoplasmic kappa staining of scattered and clustered plasma cells. Remnants © 2014 by American Society of Clinical Oncology

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of reactive germinal centers were composed of bcl6-positive, bcl2negative B cells, most of which were Ki67 positive, with associated CD21-positive, expanded follicular dendritic meshworks. Scattered small T cells were detected with antibody to CD3 (Fig 4E). The proliferation marker Ki67 was positive in approximately 10% of neoplastic cells (Fig 4F). The histologic and immunophenotypic findings together supported a diagnosis of extranodal (pulmonary) marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), with plasmacytic differentiation. Fluorescent in situ hybridization analysis for a MALT1 rearrangement was negative; however, an abnormal hybridization pattern was observed, indicative of trisomy 18. Given the presence of pulmonary MALT lymphoma in the VATS biopsy, the previously sampled mediastinal lymph nodes were subsequently re-examined, and subtle involvement of MALT lymphoma was indeed identified. Complete blood count was completely normal without anemia, thrombocytopenia, or a lymphocytosis. LDH was normal at 177 U/L. B2 microglobulin was elevated at 3.93 ␮g/mL. Quantitative immunoglobulins showed a mildly elevated immunoglobulin M (IgM) of 443 mg/dL (upper limit of normal ⫽ 334). Immunofixation showed a 0.20 g/dL IgM kappa monoclonal paraprotein. Lyme serology showed a 2

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positive IgG and negative IgM, consistent with prior exposure. Serologies for Helicobacter pylori, hepatitis B, and hepatitis C were negative. The patient was treated with single-agent rituximab. She felt improved with therapy, and a restaging CT scan performed 2 months after her four weekly doses showed a dramatic response to therapy in both the parenchymal lung lesions and mediastinal adenopathy. (Fig 2D). The monoclonal IgM protein decreased to 0.04 g/dL. Discussion Extranodal marginal zone lymphomas account for approximately 5% of all newly diagnosed non-Hodgkin lymphomas, and typically follow an indolent natural history with a favorable prognosis.1 The most common site of MALT lymphoma is the stomach, where it is associated with H. pylori infection in the majority of cases, but other frequent sites of presentation include the lungs, ocular adnexa, thyroid gland, salivary glands, skin, small intestine, and others. Marginal zone lymphomas outside of the stomach have also been associated with antigen or autoantigen stimulation, including Chlamydophila psittaci in the ocular adnexa, Borrelia afzellii in the skin, autoimmune thyroiditis in the thyroid gland, Campylobacter jejuni in the small bowel, and Sjo¨gren syndrome in the salivary glands and lungs. The association of C. psittaci with MALT lymphomas of the JOURNAL OF CLINICAL ONCOLOGY

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Diagnosis in Oncology

Pulmonary MALT lymphoma, also called bronchiolarassociated lymphoid tissue (BALT) lymphoma, accounts for approximately 9% of all extranodal marginal zone lymphomas4 and presents most commonly in the seventh decade of life.4-6 Approximately 40% of patients are asymptomatic at presentation, with disease identified incidentally on imaging studies, as was the case in our patient.5,6 Among symptomatic patients, dyspnea and dry cough are most commonly reported, with systemic “B” symptoms, chest pain, or hemoptysis being uncommon. BALT lymphoma presents at stage 1AE in approximately half of cases.4-6 The stage IV miliary presentation in our patient is very unusual. In one study of 40 consecutive patients who presented with micronodular lung disease, lymphoma was the underlying diagnosis in only one case.7 More commonly, BALT lymphoma presents as multiple nonmiliary lung nodules confined to a single lobe, although about a quarter of patients will have bilateral disease. BALT may also manifest radiographically as single nodules, airspace consolidation, ground glass opacities, or diffuse interstitial lung disease.8,9 On laboratory examination, blood counts and LDH are usually normal. Paraproteins may be detected in patients with marginal zone lymphoma, most commonly IgM, as was observed in our patient. The 5-year overall survival for pulmonary MALT lymphoma based on SEER data is 73%,4 but is reported as 90% in multiple other published series.5,6,10 Fluorescent in situ hybridization analysis in our patient demonstrated a trisomy 18, but no rearrangement of MALT1. MALT1 rearrangements occur in approximately half of pulmonary MALT lymphomas, making the lungs the most common MALT site to harbor this genetic change.11 An additional copy of MALT1 in the context of trisomy 18 also occurs commonly in marginal zone lymphoma and has no known impact on response to therapy.12

Fig 3.

ocular adnexa has exhibited marked geographic variability, however, with most reported cases occurring in Italy compared with few associated cases in the United States and other regions.2 Recently, the Gram-negative bacteria Achromobacter xylosoxidans was identified in half of patients in a small series of pulmonary MALT lymphoma,3 but whether colonization or infection with this bacteria is specifically tied to lymphoma pathogenesis remains unknown. Our patient had a history of chronic Lyme disease, which was likely unrelated to her lymphoma diagnosis given that the association with Borrelia afzelii and MALT lymphoma has been limited to the skin, and has been found exclusively in Europe.

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For patients with localized BALT lymphoma, surgical resection alone is associated with an excellent outcome.5,6 Radiation is less commonly used for local control of pulmonary disease, though low doses (4 Gy) appear to offer encouraging efficacy with minimal toxicity.13 For patients with disease not amenable to local therapy, rituximab monotherapy for untreated MALT lymphoma produces an 87% response rate, with a median response duration of 10.5 months.14 The addition of single-agent or combination chemotherapy is also associated with high response rates and excellent outcomes, but at the expense of additional treatment-related toxicities.15,16 At relapse, encouraging responses have also been seen with novel agents, including the proteosome inhibitor bortezomib, which targets NFkB, as well as the immunomodulator lenalidomide.17,18 This case demonstrates that pulmonary MALT lymphoma should be considered in the differential diagnosis of miliary lung lesions. Unrevealing bronchoscopy and infectious disease work-up in this setting should warrant tissue sampling for diagnosis.

Jeremy S. Abramson, Judith A. Ferry, Victorine V. Muse, and Michael Lanuti Massachusetts General Hospital, Boston, MA

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest. REFERENCES 1. Armitage JO, Weisenburger DD: New approach to classifying nonHodgkin’s lymphomas: Clinical features of the major histologic subtypes. NonHodgkin’s Lymphoma Classification Project. J Clin Oncol 16:2780-2795, 1998 2. Husain A, Roberts D, Pro B, et al: Meta-analyses of the association between Chlamydia psittaci and ocular adnexal lymphoma and the response of ocular adnexal lymphoma to antibiotics. Cancer 110:809-815, 2007 3. Sammassimo S, Pruneri G, Adam P, et al: Potential pathogenetic role of Achromobacter (Alcaligenes) xylosoxidans in primary extranodal marginal zone lymphoma of the lung (BALT-lymphoma): Update of the results of a retrospective analysis on behalf of IELSG. ASH Annual Meeting Abstracts 118:880, 2011 4. Olszewski AJ, Castillo JJ: Survival of patients with marginal zone lymphoma: Analysis of the Surveillance, Epidemiology, and End Results database. Cancer 119:629-638, 2013 5. Oh SY, Kim WS, Kim JS, et al: Pulmonary marginal zone B-cell lymphoma of MALT type–what is a prognostic factor and which is the optimal treatment,

operation, or chemotherapy?: Consortium for Improving Survival of Lymphoma (CISL) study. Ann Hematol 89:563-568, 2010 6. Borie R, Wislez M, Thabut G, et al: Clinical characteristics and prognostic factors of pulmonary MALT lymphoma. Eur Respir J 34:1408-1416, 2009 7. Lee KS, Kim TS, Han J, et al: Diffuse micronodular lung disease: HRCT and pathologic findings. J Comput Assist Tomogr 23:99-106, 1999 8. Bae YA, Lee KS, Han J, et al: Marginal zone B-cell lymphoma of bronchusassociated lymphoid tissue: Imaging findings in 21 patients. Chest 133:433-440, 2008 9. Zhang WD, Guan YB, Li CX, et al: Pulmonary mucosa-associated lymphoid tissue lymphoma: Computed tomography and (1)(8)F fluorodeoxyglucosepositron emission tomography/computed tomography imaging findings and follow-up. J Comput Assist Tomogr 35:608-613, 2011 10. Zucca E, Conconi A, Pedrinis E, et al: Nongastric marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue. Blood 101:2489-2495, 2003 11. Streubel B, Simonitsch-Klupp I, Mu¨llauer L, et al: Variable frequencies of MALT lymphoma-associated genetic aberrations in MALT lymphomas of different sites. Leukemia 18:1722-1726, 2004 12. Dierlamm J, Pittaluga S, Wlodarska I, et al: Marginal zone B-cell lymphomas of different sites share similar cytogenetic and morphologic features. Blood 87:299-307, 1996 13. Girinsky T, Paumier A, Ferme C, et al: Low-dose radiation treatment in pulmonary mucosa-associated lymphoid tissue lymphoma: A plausible approach? A single-institution experience in 10 patients. Int J Radiat Oncol Biol Phys 83:e385-9, 2012 14. Conconi A, Martinelli G, Thie´blemont C, et al: Clinical activity of rituximab in extranodal marginal zone B-cell lymphoma of MALT type. Blood 102:27412745, 2003 15. Zinzani PL, Pellegrini C, Gandolfi L, et al: Extranodal marginal zone B-cell lymphoma of the lung: Experience with fludarabine and mitoxantrone-containing regimens. Hematol Oncol 31:183-188, 2012 16. Rummel MJ, Niederle N, Maschmeyer G, et al: Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent and mantle cell lymphomas (MCL): Updated results from the StiL NHL1 study. J Clin Oncol 30:6s, 2012 (suppl; abstr 3) 17. Conconi A, Martinelli G, Lopez-Guillermo A, et al: Clinical activity of bortezomib in relapsed/refractory MALT lymphomas: Results of a phase II study of the International Extranodal Lymphoma Study Group (IELSG). Ann Oncol 22:689-695, 2011 18. Kiesewetter B, Troch M, Dolak W, et al: A phase II study of lenalidomide in patients with extranodal marginal zone B-cell lymphoma of the mucosa associated lymphoid tissue (MALT-lymphoma). Haematologica 98:353-356, 2012

DOI: 10.1200/JCO.2013.50.6501; published online ahead of print at www.jco.org on June 9, 2014

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Extranodal Marginal Zone Lymphoma Presenting As Miliary Lung Disease.

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