Pulmonary Involvement of IgG4-Related Sclerosing Disease Andrea Valeria Arrossi Cleveland Clinic Cleveland, OH

Clinical History A 50 year old woman, ex-smoker, presents with weakness and shortness of breath. The patient had a past medical history of medically controlled diabetes mellitus type 2, hypothyroidism and hypertension. She has a five-pack-year smoking history, quitting 8 years ago, and works in a factory making ceramic jet engine parts. Initial laboratory tests revealed severe anemia (hemoglobin of 5.6g/dL). An esophagogastric duodenal endoscopy showed features consistent with celiac sprue, confirmed with elevated titers of gliadin IgG and IgA and transglutaminase IgA antibodies. Colonoscopy and camera endoscopy were normal. Her symptoms slightly improved on a gluten-free diet. However, she continued to have weakness, and developed abdominal pain. A subsequent abdominal CT scan showed an infiltrative retroperitoneal soft tissue mass that encased and involved the pancreas and a chest CT scan showed several lung nodules ranging from 0.3 to 3.3 cm, in the right upper, middle and lower lobes. No pleural effusions or lymphadenopathies were seen. Two pancreatic percutaneous biopsies, a percutaneous biopsy of the right middle lobe nodule and a bone marrow biopsy were performed for suspected pancreatic malignancy or lymphoma with pulmonary involvement. The biopsies were non-diagnostic and the patient underwent a video assisted thoracoscopic biopsy (slides and pictures provided). Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Figure 1 Thin-section chest CT scan demonstrating a well defined 2.7 cm solid mass in the right lower lobe, abutting the major fissure with focal pleural thickening Figure 2 Low magnification of the lesion showing extensive sclerosing fibrosis and scattered chronic inflammatory infiltrates Figure 3 Chronic inflammatory infiltrates obliterating the lumen of a vascular structure Figure 4 Chronic inflammatory infiltrates showing numerous plasma cells Figure 5 Chronic inflammatory infiltrates showing numerous plasma cells Figure 6 Chronic inflammatory infiltrates showing numerous plasma cells Figure 7 Dense sclerosis and diffuse lymphoplasmacytic infiltrates involving fibrotic tissue Figure 8 Movat stain highlighting two vessels with obliterative inflammation in the same field in Figure 7 Figure 9 High magnification of IgG4 immunostain showing greater than 10 IgG4-positive plasma cells Figure 10 CT images of the retroperitoneal mass pre (left) and post (right) treatment, showing a decrease in size after steroid therapy Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: The pancreatic biopsy showed dense hyalinizing collagenous fibrosis with chronic inflammatory infiltrates. No epithelial malignancy was present. The bone marrow was normal. The pulmonary wedge excisions of both nodules in the right lower lobe and right upper lobe demonstrated subpleural well-circumscribed firm tan-white masses that measured 3.2 x 2.9 x 1.6 cm and 5.4 x 3.1 x 2.8 cm respectively. Two smaller separate nodules in the pericardial fat and diaphragm were also biopsied. All nodules showed dense sclerosing fibrosis alternating with inflammatory infiltrates, predominantly composed of lymphocytes and plasma cells. The vessels, veins as well as arteries, showed extensive obliterative inflammation and sclerosis. Additional histochemical and immunohistochemical stains were performed. The results were as follows: Congo red and thioflavin: negative CD34: negative Chromogenic in-situ hybridization (CISH) for Epstein Barr virus encoded RNA: negative Kappa light chain (immunohistochemistry and chromogenic in- situ hybridization) and Lambda light chain (immunohistochemistry and chromogenic in-situ hybridization): polytypic plasma cell population. IgG4 immunohistochemistry: Positive in scattered aggregates of plasma cells, (greater than 10 positive plasma cells in the higher density areas). Differential Diagnoses: Pulmonary hyalinizing granuloma Nodular amyloidosis Lymphoproliferative disorder Solitary fibrous tumor Inflammatory pseudotumor Final Diagnosis: Pulmonary Involvement of IgG4-Related Sclerosing Disease Case Discussion: Our patient underwent VATS biopsy in the setting of a large retroperitoneal infiltrative soft tissue mass that had its epicenter in the pancreas and several nodular lesions in the right lung. Previous needle biopsies from the pancreas were "non-diagnostic". The clinical differential diagnoses were those of a pancreatic malignancy with metastasis to the lung or a lymphoma with pulmonary involvement. Histologically the pulmonary lesions showed distinctive features, including prominent sclerosis, lymphoplasmacytic infiltrates and obliterative vasculitis. The histological differential diagnoses were as listed above. Pulmonary hyalinizing granuloma (PHG) is a lesion that can be associated with other sclerosing diseases such as sclerosing mediastinitis or retroperitoneal fibrosis. It is composed of thick dense collagen, arranged in lamellae in a concentric fashion around the vessels, features not seen in IgG4-related sclerosing disease. Plasma cells and lymphocytic infiltrates are also present, but these are more pronounced at the periphery of the nodules, in contrast to the diffuse infiltrate in our case. Nodular amyloidosis consists of deposits of amorphous, eosinophilic, extracellular material with perivascular predisposition. The background in our case appeared to be collagen rather than the amorphous waxy material of amyloidosis. Further, in amyloidosis, lymphocytes, plasma cells, and multinucleated giant cells can be also seen throughout the deposits, more prominently at the periphery of the nodules. Special stains with Congo red and thioflavin confirmed the lack of amyloid deposition. Due to the lymphoplasmacytic infiltrates and the clinical suspicion of lymphoma, lymphoproliferative disorders were in the differential diagnosis. A plasma cell dyscrasia was excluded with the demonstration of a normal ratio of kappa and lambda light chains by immunohistochemistry and CISH studies. Lymphomatoid granulomatosis (LYG) was also considered because of the perivascular infiltrates, but excluded due to the absence of infiltrative atypical neoplastic large lymphoid cells or necrosis, and negative CISH for Epstein Barr encoded RNA. Spindle cell lesions are also in the differential diagnosis. Solitary fibrous tumor usually shows a CD34 positive-spindle cell proliferation in association with thick "ropey" bands of dense collagen, not present in our lesions. Inflammatory myofibroblastic tumor (inflammatory pseudotumor) is a lesion composed of a myofibroblastic proliferation intermixed with varying degrees of chronic inflammatory cells, including plasma cells, lymphocytes, histiocytes with or without giant cells, and foamy histiocytes. A subset of these lesions can present areas of sclerosing fibrosis, similar to our case; however, the mixed inflammatory infiltrates including histiocytes and foamy histiocytes were lacking. Lastly, IgG4-related sclerosing disease was confirmed with the laboratory results, showing elevated serum titers of total IgG and IgG1 and IgGg4 subclasses. The patient's response to corticosteroid therapy, demonstrated with the follow-up CT images, also supported this diagnosis. Review of the Literature/Treatment Options (if applicable): IgG4-related sclerosing disease is characterized by mass- forming lesions with dense lymphoplasmacytic infiltrates and stromal sclerosis, increased tissue IgG4-positive plasma cells, obliterative phlebitis and usually elevated serum IgG4 titer [1]. It affects adults with male predominance. The disease was initially described affecting the pancreas, as autoimmune pancreatitis [1, 2], but it can affect extrapancreatic sites, including the hepatobiliary system, lacrimal and salivary glands, thyroid and retroperitoneum [3], among a large list of reported organs involved that continues to grow. The disease can also demonstrate an infiltrative growth and clinically be overlooked and mistaken for a malignant process, resulting in unnecessary resections. Involvement of extrapancreatic organs can also occur in the absence of pancreatitis. Pulmonary involvement associated with autoimmune pancreatitis was first reported in 2004 [4], a case of interstitial pneumonia with increased IgG4 positive plasma cells. Since thus initial case, several case reports or small case series have been published. The two largest were published in 2009. The study from UK and Japan, which included 21 patients, classified the pulmonary and pleural lesions based on radiologic findings. Five main patterns were observed, which included pleural, pulmonary solid nodular, bronchovascular, round-shaped ground-glass- opacities (GGO), and alveolar interstitial patterns [5]. Histologically, most cases of the nodular pattern and the pleural lesions showed diffuse sclerosing inflammation with lymphoplasmacytic infiltration distorting the alveolar architecture, and obliterative vasculitis. The bronchovascular, alveolar interstitial and GGO patterns showed lymphoplasmacytic infiltrates that predominantly affected the bronchovascular bundles, alveolar interstitium, interlobular septa and pleura in the former, and the alveolar interstitium, resembling non-specific interstitial pneumonia (NSIP), in the two latter [6]. Shrestha et al. compiled lung biopsies from 6 autoimmune pancreatitis patients with pulmonary lesions and 12 lung biopsies with similar histologic findings from patients without autoimmune pancreatitis. Additional cases of other lung diseases, including examples of interstitial lung disease, Rosai Dorfman, inflammatory myofibroblastic tumor, Erdheim-Chester disease and pulmonary Sjogren, were also evaluated for comparison. In this study, lymphangitic distribution of plasma cell-rich inflammatory infiltrates, active fibrosis and intimal inflammation involving both pulmonary veins and arteries were the most consistent findings in the biopsies from autoimmune pancreatitis patients. Rosai Dorfman-like features, organizing pneumonia and non-specific interstitial pneumonia patterns of injury were also observed. All biopsies from autoimmune pancreatitis patients and the biopsies with similar histologic features without autoimmune pancreatitis showed increased IgG4-positive plasma cells. IgG4 quantification demonstrated 11-30 IgG4 positive plasma cells per high power field in 12 cases and >30 IgG4 positive plasma cells per high power field in 6 cases. Five of these six cases were in the setting of autoimmune pancreatitis. These data suggest the need of >30 IgG4-positive plasma cells per high power field for the diagnosis of IgG4 related lung disease [7]. However, other studies have suggested different numbers for different organs. In the pancreas, greater than 10, 20, 30 or 50 IgG4-positive plasma cells per high power field were proposed for the diagnosis of autoimmune pancreatitis [8, 9, 10, 11] but a defined value has not been standardized. Of note, cases of IPT with a predominant fascicular arrangement of the myofibroblastic cells, admixed with numerous plasma cells, the so-called plasma cell granuloma pattern, have been reported to demonstrate increased IgG4- positive plasma cells, and were suggested to represent the nodular pattern of IgG4-related sclerosing lung disease [6, 12]. Treatment of autoimmune pancreatitis is based on corticosteroids and the effective response to steroid therapy might be used as one (optional) diagnostic criteria [13, 14]. Likewise, several of the reported cases of pulmonary IgG4 related disease have been shown to respond to steroid therapy [4, 6, 14]. Conclusion(s): This is a case of IgG 4-related sclerosing disease with nodular pattern of pulmonary involvement diagnosed during the work up for a suspected pancreatic malignancy. IgG4 related disease is a relatively "new" entity that is rapidly evolving. Autoimmune pancreatitis is the prototype of this steroid responsive disease, but it can affect several other extrapancreatic organs. Different histopathologic patterns of the pulmonary lesions have been described, including nodular and interstitial lymphoplasmacytic infiltrates with increased IgG4-positive plasma cells, with or without sclerosing fibrosis or obliterative vasculitis, and lymphangitic distribution of plasma cell-rich inflammatory infiltrates. Pulmonary lesions in the setting of autoimmune pancreatitis usually show greater than 30 IgG4-positive plasma cells; however, a cut-off has not been standardized. References: Kamisawa T, Funata N, Hayashi Y, et al. 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