Case 4 -

Extranodal Marginal Zone B-cell Lymphoma of Mucosa Associated Lymphoid Tissue (MALT)-type with Light Chain Deposition. Non-necrotizing Granulomatous Inflammation Suggestive of Sarcoid. Anja C. Roden, Mayo Clinic, Rochester, MN

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Clinical History This 42 year old man presented to the Emergency Department with sudden onset of sharp, non-exertional anterior chest pain. He denied any fever. The patient had a 25-pack year smoking history and also smoked marijuana for 20 years. Otherwise, his past medical history and family history were unremarkable. Physical examination revealed diminished bilateral breath sounds, bilateral coarse crackles, and markedly hyperinflated chest. He was treated with antibiotics for one week without clinical improvement. A chest X-ray was performed followed by a CT scan. Subsequently, the patient underwent wedge biopsy of the right middle and lower lung lobes. Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: CT imaging (Figure 1) shows large cysts in both lower lungs with basilar predominance in a background of bilateral scattered infiltrates and focal consolidation in the left base. Sections from the right middle lobe mass, at low magnification, reveal a nodular cellular infiltrate focally involving overlying visceral pleura in a background of stromal fibrosis and cysts of variable size (Figures 2 & 3). The infiltrate is composed of plasma cells and lymphocytes some of which are forming follicles. These cells also infiltrate cyst walls (Figure 4). While some cysts are lined by respiratory epithelium, others are lined by cuboidal epithelioid cells. Many lymphocytes and plasma cells involve bronchiolar epithelium to form lymphoepithelial lesions. The lymphocytes are small and focally of monotonous appearance with clear cytoplasm (Figure 5). Immunostains confirm a predominance of CD138 positive plasma cells (Figure 6) and clusters of small CD20 positive B-cells (Figure 7). CD3 highlights scattered small T-cells. Stains for immunoglobulin light chains reveal kappa restriction in many lymphocytes and plasma cells (Figures 8), although some plasma cells and many B-cells, especially those forming reactive follicles, are polytypic. Amorphous deposits in the right middle lobe are associated with occasional multinucleated giant cells (Figures 9 & 10). Congo red stain does not reveal birefringence under polarized light. The amorphous material is positive for albumin and prealbumin with a monotypic pattern of kappa immunoglobulin light chain reaction. Figures 11 & 12 show well formed non-necrotizing granulomas in a lymphangitic distribution within and away from the lymphocytic infiltrate, identified in both, the right middle and lower lobe lung. Stains for microorganisms (GMS, AFB) were negative. Case 4 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 4 - Figure 1 CT shows multiple bilateral cysts in the lower lung lobes in addition to nodular infiltrates in the left lung base. Case 4 - Figure 2 Low power view showing a nodular cellular infiltrate in a background of fibrosis and cysts (x 20). Case 4 - Figure 3 Higher power view showing lymphocytic infiltrate of cyst walls (x 40). Case 4 - Figure 4 The cellular infiltrate is comprised of monotonous appearing lymphocytes with focal clear cytoplasm involving a cyst wall lined by cuboidal epithelium (x 200). Case 4 - Figure 5 High power view showing an infiltrate that is composed of small lymphocytes and plasma cells (x 400). Case 4 - Figure 6 The cellular nodules are predominantly comprised of CD138 positive plasma cells (x 200). Case 4 - Figure 7 CD20 positive B cells form clusters (x 200). Case 4 - Figure 8 Immunostain for immunoglobulin kappa light chain highlights monotypic plasma cells (x 200). Case 4 - Figure 9 Amorphous material is present surrounded by chronic inflammation and organization (x 40). Case 4 - Figure 10 The amorphous material is focally bordered by multinucleated giant cells (x 400). Case 4 - Figure 11 Well-formed non-necrotizing granuloma with a small chronic inflammatory cuff are distributed in a lymphangitic pattern (x 40). Case 4 - Figure 12 High power view of non-necrotizing granuloma. Differential Diagnoses: On imaging, the differential diagnosis of cystic lung disease includes emphysema, pulmonary Langerhans cell histiocytosis (PLCH), lymphangioleiomyomatosis (LAM), and cystic bronchiectasis. Less commonly, cystic lung disease can be found in pulmonary lymphoma and/or amyloid, lymphoid interstitial pneumonia (LIP), sarcoidosis, Birt-Hogg-Dubé syndrome, interstitial pulmonary fibrosis, autoimmune diseases, infections, embolic disease, and cancer [14]. Cystic lung disease with lower lobe predominance and ground glass infiltrates raises the possibility of LIP; if consolidations are also present, low grade lymphoma might be suspected. Birt-Hogg-Dubé syndrome can present with parenchymal cysts predominantly in the basilar lung zones, however, consolidations are not typical in that disease. A lower lobe predominance of cystic lung disease would be unusual for PLCH and LAM. Moreover, LAM occurs almost exclusively in women. While centrilobular emphysema is an upper lobe predominant disease, panacinar emphysema tends to involve the entire lung with more severe destruction in the lower lobes. The microscopic differential diagnosis includes low grade lymphoma, LIP, and nodular lymphoid hyperplasia. Well- formed non-necrotizing granulomas in a lymphangitic distribution raise the possibility of sarcoid after an infectious process has been excluded. Final Diagnosis: Extranodal Marginal Zone B-cell Lymphoma of Mucosa Associated Lymphoid Tissue (MALT)-type with Light Chain Deposition. Non-necrotizing Granulomatous Inflammation Suggestive of Sarcoid. Case Discussion: Given the predominant lower lobe distribution of the cystic lung disease on imaging, clinically, the possibility of alpha-1-antitrypsin deficiency was raised. However, serology was negative. To establish a diagnosis, the patient underwent thoracotomy with resection of a right middle lobe mass and wedge biopsy of the right lower lobe. The biopsy from the right middle lobe revealed a dense lymphoplasmacytic infiltrate in a background of fibrosis, cysts and numerous lymphoid follicles. Lymphoepithelial lesions were also noted. To distinguish a lymphoproliferative disease from a reactive process immunostains were performed. Although some of the B-cells and plasma cells were polytypic, many revealed a monotypic staining pattern for kappa immunoglobulin light chain. In addition, the amorphous material was negative for Congo Red but stained with kappa immunoglobulin light chain antibody, features suggestive of light chain deposition. Overall, the morphologic findings together with the immunophenotype led to a diagnosis of extranodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue (MALT)-type with light chain deposition. The wedge biopsy of the lower lobe lung was not involved by the lymphoplasmacytic infiltrate. The non-necrotizing granulomas were identified in the vicinity but also away from the neoplastic process. In the absence of stainable microorganisms together with the histopathologic features, sarcoid was considered. There were no morphologic features to suggest LAM given the lack of smooth muscle proliferations in the interstitium. Furthermore, the absence of bronchiolocentric infiltrates of Langerhans cells and eosinophils or stellate scars argued against PLCH. In panacinar emphysema, acini are uniformly enlarged and eventually destroyed and there might be mild chronic inflammation of the airway walls. Birt-Hogg- Dubé syndrome is morphologically characterized by intraparenchymal collections of air surrounded by normal lung parenchyma [3]. However, both, panacinar emphysema and Birt-Hogg-Dubé syndrome lack the dense lymphoplasmacytic infiltrate. Lymphoproliferative disease, LIP, amyloid, and sarcoid have all been associated with cystic lung disease. In the present biopsy, lymphoplasmacytic infiltrates, reactive lymphoid follicles, and light chain deposition are identified narrowing and obstructing small airways conceivably leading to air-trapping with subsequent cyst formation. The non-necrotizing granulomas are in a bronchiolocentric distribution and likely contributed to the cystic lung disease. Further workup of the patient included a bone marrow biopsy which was negative and imaging did not reveal lymphadenopathy elsewhere. Therefore, the lymphoma was clinically staged as Stage I-EA. The patient received Rituximab-CHOP therapy. Although he tolerated the treatment well, his chest pain did not resolve. The patient was followed by his local physician. A CT scan 10 months after initial treatment revealed a residual right lung lesion of app. 2 cm; cysts and infiltrates were essentially unchanged. Reportedly, the patient developed shortness of breath and died 5 years after his diagnosis with an "emphysema-like picture". Review of the Literature/Treatment Options: Pulmonary extranodal marginal zone B-cell lymphomas of MALT type represent app. 14% of all extranodal MALT lymphomas. These lymphomas are thought to arise from bronchial mucosa- associated lymphoid tissue and although they comprise 70- 90% of primary pulmonary lymphomas, they constitute less than 0.5% of all primary lung neoplasms. In some patients, pulmonary extranodal marginal zone B-cell lymphomas of MALT type might be associated with Sjoegren' syndrome, AIDS, dysgammaglobulinemia, or collagen vascular disease. Microscopically, pulmonary extranodal marginal zone B-cell lymphomas of MALT type are characterized by a diffuse infiltrate of small lymphoid cells, which may surround or overrun reactive lymphoid follicles. Plasma cells might be numerous. Amyloid or light chain deposition can be seen. The neoplastic cells form lymphoepithelial lesions and express B-cell markers including CD20 and CD79a and usually show aberrant expression of Bcl2, CD21, CD35 and maybe CD43 but are negative for CD5, CD10, CD23, Bcl6, and cyclin D1. This immunophenotype helps to distinguish the disease from other small B-cell lymphomas. Reactive T cells are scattered throughout the lesion. Light chain restriction of the neoplastic B cells and plasma cells helps to differentiate lymphoma from LIP or nodular lymphoid hyperplasia, but sometimes RT-PCR for B-cell gene rearrangement might be necessary to show clonality. Cystic lung disease has been reported in patients with pulmonary lymphoma, most of which were pulmonary extranodal marginal zone B-cell lymphomas of MALT type. 8 such cases are reported in the literature [7, 8, 9, 11, 12, 16]. The median age of the patients is 49 years (range, 35 – 77 years) and there appears no gender predilection. Clinical presentation is similar to the pulmonary extranodal marginal zone B-cell lymphomas of MALT type without cystic lung disease. In addition, one patient presented with throat discomfort, fever and several bouts of pneumonia. In 2 patients, nodules or a "shadow" were incidentally identified at a chest X-ray. Pulmonary function tests were only available in 3 patients and showed mild to moderate restriction (n=2) or mild non-reversible obstruction. Chest X-rays revealed bilateral ground glass infiltrates in middle and lower lung fields, ill-defined masses, and only in 1 patient an upper lobe infiltrate. CT scans usually were described as multifocal cystic changes, micronodules or poorly circumscribed nodules, throughout both lungs with a middle and lower lobe predominance. The majority of the patients underwent wedge biopsy. Histology often revealed diffuse lymphocytic infiltrates, multiple cystic lesions with significant lymphocytic infiltrate in cyst walls, monotonous small lymphocytes invading epithelial structures and narrowing bronchioles. The immunophenotype of the neoplastic cells resembled that of pulmonary extranodal marginal zone B-cell lymphomas of MALT type. In 3 cases amyloid was also identified, in two of which amyloid was infiltrating bronchioles. In another case, prominent follicular bronchiolitis was described. In 2 patients the disease was localized to the lung and 1 had stage IV disease with involvement of stomach, bone marrow and lung. Patients with available follow up (n=3) were treated with Rituximab or a combination of steroids and Rituximab, lobectomy, and/or bone marrow transplant. In one patient, despite treatment of lymphoma, bullous disease progressed and the patient died while awaiting a transplant. Another patient tolerated treatment well but did not improve radiologically. A third patient was alive and well 17 months after diagnosis. In addition to pulmonary extranodal marginal zone B-cell lymphomas of MALT type, 1 case of classical Hodgkin lymphoma, nodular sclerosing type [5], and 1 case of adult T- cell leukemia/lymphoma [15] were also reported to be associated with multiple cystic structures in the lung. Given that several bronchioles are either stenotic or obstructed by peribronchiolar neoplastic lymphocytic infiltrates, reactive lymphoid follicles and/or amyloid, it has been postulated, that partial obstruction of small airways might lead to a 'ball-valve effect' with subsequent air trapping in the distal airways and cyst formation [6]. Furthermore, an ischemic process has been hypothesized due to obstruction and/or infiltration of bronchioloalveolar structures and alveolar capillaries [13]. An association between lymphoma and sarcoidosis as noted in the present case was first suggested by Bichek and Brincker in 1965 [1], describing 46 cases of sarcoid coexisting with malignant tumors. The authors showed that patients with sarcoid had a 5.5 relative risk of developing lymphoma and coined the term 'sarcoidosis-lymphoma syndrome' (SLS). Evidence also suggests that the greatest risk of developing SLS might be during chemotherapy or 1 year after lymphoma treatment [2]. Furthermore, an increase in risk of non- Hodgkin lymphoma was observed in patients with history of sarcoidosis [10]. Recently, Goswami T et al [4] summarized 79 published case reports of SLS, and found that sarcoid has been associated with orbital lymphoma, follicular and low- grade lymphomas, Hodgkin lymphoma, and aggressive lymphoma including diffuse large B-cell lymphoma. Patients have been diagnosed with lymphoma before and after the diagnosis of sarcoid, with intervals ranging from months to 27 years. Although 2 studies have failed to confirm an association between sarcoid and lymphoma, overall, the authors felt the published data support a relationship between the two diseases. Furthermore, because both sarcoid and lymphoma are FDG avid, imaging studies should be interpreted with caution and it might be possible that at the time of the initial diagnosis of 1 condition, clinicians may not recognize the coexistence of the other. Conclusion(s): Pulmonary extranodal marginal zone B-cell lymphomas of MALT type can present as cystic lung disease. The cysts involve predominantly the lower lung zones and are thought to occur because of a ball valve mechanism. The differential diagnosis of cystic lung disease with lower lobe predominance includes panacinar emphysema and LIP.Although the lymphoma might be treated similar to non-cystic pulmonary extranodal marginal zone B-cell lymphoma of MALT type, in some cases the cystic lung disease might not respond to treatment. There appears to be an association between lymphoma and sarcoid, however, an infectious process needs to be excluded. References: Bichel J, Brincker H. Treatment of Pruritus in Hodgkin's Disease and in Reticulum Cell Sarcoma. Scandinavian journal of haematology. 1965;2:85-90. Brincker H. Coexistence of sarcoidosis and malignant disease: causality or coincidence? Sarcoidosis. 1989;6:31-43. 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Pulmonary localized AA type amyloidosis with cyst-like structures and marginal zone B-cell lymphoma of the MALT type coexisting independently in the left upper lung. Intern Med. 2008;47:1529-1533.