IgG4-related sclerosing disease

IgG4-related sclerosing disease (IgG4-RSD) is a systemic one in which IgG4-positive plasma cells and T lymphocytes extensively infiltrate various organs. The clinical manifestations of the disease include autoimmune pancreatitis, sclerosing cholangitis, cholecystitis, sialodenitis, retroperitoneal fibrosis, tubulointestitial nephritis, interstitial pneumonia, prostatitis, inflammatory pseudotumors and lymphadenopathy, all related with significantly elevated serum IgG4 levels. Tissue fibrosis with obliterative phlebitis of the affected organs is pathologically induced. The disease occurs predominantly in elderly men and responds well to steroid therapy. Since malignant tumors are frequently suspected on initial presentation, IgG4-RSD should be considered in the differential diagnosis to avoid unnecessary surgery.     

IgG4-related inflammatory abdominal aortic aneurysm associated with autoimmune pancreatitis

An association between autoimmune pancreatitis (AIP) and inflammatory abdominal aortic aneurysm (AAA) has never been reported. Reported herein is a case of IgG4-related inflammatory AAA accompanying metachronous AIP. A 77-year-old man presented with malaise and intermittent lower abdominal pain. Radiological examination showed inflammatory AAA and right hydronephrosis caused by retroperitoneal fibrosis. Surgical correction of the AAA was performed, but high levels of systemic inflammatory markers persisted. Four months after surgery, the patient presented with epigastric pain, backache, and jaundice. His serum IgG4 concentration was high (571 mg/mL), and he was diagnosed with AIP, based on clinical and radiological findings. Corticosteroid therapy resulted in improvement of the clinical findings and lowered his serum IgG4 levels. Subsequent histological examination of a specimen from the aortic wall showed irregular proliferation of fibroblastic and myofibroblastic cells, severe lymphoplasmacytic infiltration, and obliterative phlebitis in the adventitia. Furthermore, on immunohistochemistry many plasma cells within the lesion were found to be positive for IgG4. These findings suggest that inflammatory AAA has a pathological process similar to that of AIP, and that some cases of inflammatory AAA and retroperitoneal fibrosis may be aortic and periaortic lesions of an IgG4-related sclerosing disease.     

IgG4-associated inflammatory pseudotumor of ureter: clinicopathologic and immunohistochemical study of 3 cases

Inflammatory pseudotumors are lesions characterized by proliferation of fibroblasts/myofibroblasts with variable chronic inflammatory cell infiltration. Recent studies have suggested that inflammatory pseudotumor with abundant IgG4-positive plasma cells may be a unique entity associated with systemic IgG4-related sclerosing disease and should be distinguished from other similar lesions such as inflammatory myofibroblastic tumor and fibrohistiocytic-type inflammatory pseudotumor. Localized inflammatory pseudotumor has been rarely reported in the ureter, and IgG4-associated inflammatory pseudotumor of ureter has not been described. We describe herein 3 cases of ureteral inflammatory pseudotumor of IgG4-associated lymphoplasmacytic type, focusing on density of IgG4-positive plasma cells; infiltration pattern of eosinophils and histiocytes; presence of obliterative phlebitis; and immunohistochemical profiles of smooth muscle actin, anaplastic lymphoma kinase, and CD68. Three patients, 45- and 47-year-old men and 84-year-old woman, all presented with flank pain and ureteral narrowing by a mass effect. Microscopic examination of the resected ureters showed suburothelial masslike lesions with fibroblasts/myofibroblasts without atypia, abundant plasma cells, and scattered eosinophils and histiocytes. The lesion of the 47-year-old man showed obliterative phlebitis in addition to the above findings. The lesion of the 84-year-old woman was accompanied by urothelial carcinoma in situ in the overlying urothelium. Spindle cells were diffusely or focally positive for smooth muscle actin but negative for anaplastic lymphoma kinase in all 3 cases. For each case, respectively, an average of 154, 112, and 50 plasma cells per high-power fields were immunoreactive for IgG4, a diagnostic feature of IgG4 inflammatory pseudotumor. We described 3 cases of IgG4-associated inflammatory pseudotumor of ureter with pathologic and immunohistochemical features that are compatible for lymphoplasmacytic type of inflammatory pseudotumor. Further study is needed to characterize any relationship between this entity and systemic sclerosing disease and/or urothelial carcinogenesis.     

IgG4-related periureteral fibrosis presenting as a unilateral ureteral mass

IgG4-related sclerosing disease is a rare disease characterized by fibrosis and lymphoplasmacytic infiltration in various organs. Here, we report a rare case of IgG4-related fibrosis that presented as a unilateral ureteral mass in a 39-year-old man who presented with abdominal pain. Left hydronephrosis and a mass measuring 3× 1.1 cm in the lower portion of the left ureter were found. As a ureteral malignancy could not be ruled out, the left ureter was resected partially. Pathologically, severe fibrosis and infiltration of plasma cells, lymphocytes, and eosinophils were found. No malignancy was found. Immunohistochemically, most of the plasma cells were IgG4-positive. The serum IgG4 level was also elevated (233 mg/dl). The histological characteristics were similar to those of retroperitoneal fibrosis, inflammatory pseudotumor, or idiopathic segmental ureteritis. It is important to consider IgG4-related sclerosing disease in the differential diagnosis of a unilateral ureteral mass.     

Tissue eosinophilia and eosinophil degranulation in syndromes associated with fibrosis.

Eosinophilia has long been associated with endomyocardial fibrosis, but the involvement of the eosinophilia in fibrosis of other organs is unclear. To investigate this question, the authors tested whether tissue eosinophilia and eosinophil degranulation are present in syndromes associated with fibrosis. The authors used an indirect immunofluorescent technique to localize eosinophil granule major basic protein (MBP) in formalin-fixed, paraffin-embedded tissue specimens from 50 patients. Thirty-four specimens were obtained from patients with inflammatory fibrosis: 12 with idiopathic retroperitoneal fibrosis, seven with sclerosing mediastinitis, four with sclerosing cholangitis, and 11 with pulmonary fibrosis. The remaining 16 specimens were obtained from patients with noninflammatory fibrous proliferations: four with keloids, six with scars, three with Dupuytren's contracture and three with dense stromal fibrosis of the breast. Eosinophil infiltration and/or extracellular MBP deposition were observed in 28 of the 34 specimens (82%) from patients with inflammatory fibrosis, including 11 of the 12 cases of retroperitoneal fibrosis, five of the seven cases of sclerosing mediastinitis, all four cases of sclerosing cholangitis, and 8 of the 11 cases of pulmonary fibrosis. In contrast, eosinophil infiltration and MBP deposition were not observed in specimens from the 16 patients with noninflammatory fibrous proliferation (P less than 0.001). These results indicate that eosinophil infiltration and release of a granule protein, namely MBP, commonly occur in inflammatory fibrotic lesions.     

Chronic sclerosing sialadenitis of the submandibular gland associated with idiopathic retroperitoneal fibrosis

We report a case of a 57-year-old man who developed a fibrosclerosing lesion in the submandibular gland and idiopathic retroperitoneal fibrosis (IRF) involving the unilateral periureteral region within a year. Both lesions were resected surgically because of the suspicion of neoplasm. Pathologic examination revealed similar histologic and immunohistochemical features for both lesions, namely, fibrosclerosis with prominent hyalinizing collagen bundles and proliferation of myofibroblastic cells, and a non-neoplastic reactive nature. There was infiltration by lymphocytes with prominent lymph follicles, plasma cells and macrophages. The histologic and immunohistochemical findings suggest that the two lesions were of a similar pathogenesis, which was possibly mediated by macrophages. We think that the present case may be an unusual form of multifocal fibrosclerosis. Although sialolithiasis is thought to be a major pathogenic factor for chronic sclerosing sialadenitis of the submandibular gland, the present case suggests that certain cases might have an etiology similar to IRF.     

A mathematical model of atherogenesis as an inflammatory response.

We construct a mathematical model of the early formation of an atherosclerotic lesion based on a simplification of Russell Ross' paradigm of atherosclerosis as a chronic inflammatory response. Atherosclerosis is a disease characterized by the accumulation of lipid-laden cells in the arterial wall. This disease results in lesions within the artery that may grow into the lumen restricting blood flow and, in critical cases, can rupture causing complete, sudden occlusion of the artery resulting in heart attack, stroke and possibly death. It is now understood that when chemically modified low-density lipoproteins (LDL cholesterol) enter into the wall of the human artery, they can trigger an immune response mediated by biochemical signals sent and received by immune and other cells indigenous to the vasculature. The presence of modified LDL can also corrupt the normal immune function triggering further immune response and ultimately chronic inflammation. In the construction of our mathematical model, we focus on the inflammatory component of the pathogenesis of cardiovascular disease (CVD). Because this study centres on the interplay between chemical and cellular species in the human artery and bloodstream, we employ a model of chemotaxis first given by E. F. Keller and Lee Segel in 1970 and present our model as a coupled system of non-linear reaction diffusion equations describing the state of the various species involved in the disease process. We perform numerical simulations demonstrating that our model captures certain observed features of CVD such as the localization of immune cells, the build-up of lipids and debris and the isolation of a lesion by smooth muscle cells.     

Lymphocyte ‘homing’ and chronic inflammation

Chronic inflammation is a response to prolonged exposure to injurious stimuli that harm and destroy tissues and promote lymphocyte infiltration into inflamed sites. Following progressive accumulation of lymphocytes, the histology of inflamed tissue begins to resemble that of peripheral lymphoid organs, which can be referred to as lymphoid neogenesis or formation of tertiary lymphoid tissues. Lymphocyte recruitment to inflamed tissues is also reminiscent of lymphocyte homing to peripheral lymphoid organs. In the latter, under physiological conditions, homing receptors expressed on lymphocytes adhere to vascular addressin expressed on high endothelial venules (HEVs), initiating a lymphocyte migration process composed of sequential adhesive interactions. Intriguingly, in chronic inflammation, HEV‐like vessels are induced de novo, despite the fact that the inflamed site is not originally lymphoid tissue, and these vessels contribute to lymphocyte recruitment in a manner similar to physiological lymphocyte homing. In this review, we first describe physiological lymphocyte homing mechanisms focusing on vascular addressins. We then describe HEV‐like vessel‐mediated pathogenesis seen in various chronic inflammatory disorders such as Helicobacter pylori gastritis, inflammatory bowel disease (IBD), autoimmune pancreatitis and sclerosing sialadenitis, as well as chronic inflammatory cell neoplasm MALT lymphoma, with reference to our work and that of others.     

Lymphoplasmacytic sclerosing pancreatitis with cholangitis: a variant of primary sclerosing cholangitis extensively involving pancreas

Pancreatic involvement in primary sclerosing cholangitis (PSC) is an extremely rare condition, and its pathologic features are poorly documented. We report two cases of an unusual lymphoplasmacytic sclerosing inflammatory disease involving the total pancreas, common bile duct, gallbladder, and, in one patient, the lip. Two elderly men presented with waxing and waning obstructive jaundice, and exhibited radiologic and ultrasonographic findings highly suggestive of pancreatic carcinoma. Gross appearance of the pancreas showed firm and mass-like enlargement with regional lymph node swelling. Histologic findings were characterized by diffuse lymphoplasmacytic infiltration with marked interstitial fibrosis and acinar atrophy, obliterated phlebitis of the pancreatic veins, and involvement of the portal vein. Similar inflammatory processes involved the bile duct and the gallbladder. Lymphoplasmacytic sclerosing pancreatitis with cholangitis is thought to be a more appropriate term for this condition, of which a similar lesion has been previously noted in a single case of "PSC involving pancreas". Differences in age, radiologic appearance, and the negative history of ulcerative colitis exist, but the two cases in this study could be considered as a variant of PSC extensively involving pancreas, which can readily be mistaken for pancreatic carcinoma.     

Hyper-IgG4 disease: report and characterisation of a new disease

Background

We highlight a chronic inflammatory disease we call 'hyper-IgG4 disease', which has many synonyms depending on the organ involved, the country of origin and the year of the report. It is characterized histologically by a lymphoplasmacytic inflammation with IgG4-positive cells and exuberant fibrosis, which leaves dense fibrosis on resolution. A typical example is idiopathic retroperitoneal fibrosis, but the initial report in 2001 was of sclerosing pancreatitis.

Methods

We report an index case with fever and severe systemic disease. We have also reviewed the histology of 11 further patients with idiopathic retroperitoneal fibrosis for evidence of IgG4-expressing plasma cells, and examined a wide range of other inflammatory conditions and fibrotic diseases as organ-specific controls. We have reviewed the published literature for disease associations with idiopathic, systemic fibrosing conditions and the synonyms: pseudotumour, myofibroblastic tumour, plasma cell granuloma, systemic fibrosis, xanthofibrogranulomatosis, and multifocal fibrosclerosis.

Results

Histology from all 12 patients showed, to varying degrees, fibrosis, intense inflammatory cell infiltration with lymphocytes, plasma cells, scattered neutrophils, and sometimes eosinophilic aggregates, with venulitis and obliterative arteritis. The majority of lymphocytes were T cells that expressed CD8 and CD4, with scattered B-cell-rich small lymphoid follicles. In all cases, there was a significant increase in IgG4-positive plasma cells compared with controls. In two cases, biopsies before and after steroid treatment were available, and only scattered plasma cells were seen after treatment, none of them expressing IgG4. Review of the literature shows that although pathology commonly appears confined to one organ, patients can have systemic symptoms and fever. In the active period, there is an acute phase response with a high serum concentration of IgG, and during this phase, there is a rapid clinical response to glucocorticoid steroid treatment.

Conclusion

We believe that hyper-IgG4 disease is an important condition to recognise, as the diagnosis can be readily verified and the outcome with treatment is very good.     

Sclerosing variant of epithelioid angiomyolipoma

Presented herein are two unusual epithelioid angiomyolipomas (AML) displaying prominent stromal sclerosis. Both patients were middle-aged women without a clinical history of tuberous sclerosis. One patient (case 1) had a 2 cm lesion arising in the renal cortex, and another (case 2) had a pararenal retroperitoneal tumor measuring 13 cm. Both tumors were composed of sheets or nests of polygonal epithelioid or short spindle cells having uniform round to oval nuclei and eosinophilic cytoplasm with cords of hyalinized sclerotic stroma between them. The tumor in case 2 had small areas of mature-looking fat cells. Immunohistochemically, epithelioid tumor cells were diffusely positive for actins and desmin in both cases, and melanoma antigen recognized by T cells (MART)-1 was positive in patient 2. Scattered HMB-45-immunoreactive cells were identified in the sclerotic cords of both tumors, but epithelioid tumor cells were essentially negative for HMB-45. The characteristic clinicopathological and immunohistochemical features of the present cases are analogous to a subset of epithelioid AML or sclerosing perivascular epithelioid cell tumors previously reported.     

Chronic coronary periarteritis in two patients with chronic periaortitis

Two cases of chronic coronary periarteritis associated with chronic periaortitis are described. In one, the chronic periaortitis took the form of perianeurysmal fibrosis around a thoracic atherosclerotic aneurysm; in the other it resembled idiopathic retroperitoneal fibrosis. The findings in the two subjects support the unifying concept of chronic periaortitis, to include conditions previously known as idiopathic retroperitoneal or mediastinal fibrosis, perianeurysmal retroperitoneal fibrosis and inflammatory aneurysms of the aorta. The observations are also compatible with the view that the disease is due to hypersensitivity to atheroma.     

Idiopathic segmental ureteritis, misdiagnosed as ureteral cancer preoperatively: a case report with literature review

A 53-year-old man presented with right flank pain for 6 days. Computerized tomography revealed a 3 cm long segment of ureteral narrowing with wall thickening and hydronephrosis, suspicious for ureteral cancer. Under the clinical diagnosis of ureteral carcinoma a right nephroureterectomy was performed. The wall of the distal ureter, 2.5 cm from the bladder cuff, had a luminal-narrowing, firm mass-forming lesion with abrupt transition from the adjacent ureter. Histologically, the resected ureteral mass showed transmural fibrosing, chronic inflammation with numerous plasma cells, epithelioid granulomas, and obliterative phlebitis. Histological findings were consistent with idiopathic segmental ureteritis (ISU) with differential diagnoses of IgG4-related sclerosing disease, including lymphoplasmacytic inflammatory pseudotumor (IPT) and idiopathic retroperitoneal fibrosis. IgG4 immunostaining in this case was barely positive, excluding the possibility of IgG4-related IPT. Although the majority of luminal obliterated segmental lesions of the ureter are neoplastic in nature, non-neoplastic inflammatory processes as seen in this case may occur in the ureter, causing diagnostic confusion with true neoplasms. Herein we report a rare case of ISU that was clinically misdiagnosed as malignancy preoperatively. ISU of the current case may be an IgG4-unrelated subtype of IPT.     

Metaplastic carcinoma of the breast arising within complex sclerosing lesion: a report of five cases

AIMS: This study presents a series of five cases in which metaplastic carcinoma, predominantly low-grade adenosquamous carcinoma, of the breast is seen arising within a background of a complex sclerosing lesion. This association has been recognized previously but has not been documented in detail. This study describes the characteristics of the components present in each case and discusses the existing literature. This observation adds further evidence to support an association between some types of invasive breast carcinoma and sclerosing lesions of the breast. METHODS AND RESULTS: Four of these cases were received as referral cases for opinion. The fifth was received as part of the routine surgical workload within our own institution. Two patients presented following mammographic screening and three symptomatically; their mean age was 62 years (range 49-68). The mean lesion size was 16 mm (range 7-24). All five lesions showed features of a complex sclerosing lesion/radial scar in the form of central sclerosis with elastosis and radiating benign entrapped tubules. One had associated benign papillary structures and two had focal benign squamous metaplasia. Four cases showed coexisting but distinct areas of low-grade adenosquamous carcinoma with glandular and squamous epithelial differentiation in a spindle cell background. One case had associated undifferentiated spindle cell carcinoma. Detailed immunophenotypic characteristics of two cases are presented. CONCLUSIONS: This series illustrates a postulated but previously unconfirmed association between an unusual form of metaplastic breast carcinoma (adenosquamous carcinoma) and complex sclerosing lesions. The mechanisms of induction of breast carcinoma are poorly understood but these observations further emphasize the potential for sclerosing lesion of the breast to be associated with, and possibly give rise to, invasive carcinoma of different types. The precise nature of the interaction between the pathological processes remains unclear.     

p63 expression in adamantinoma

Paratesticular fibrous pseudotumor (nodular periorchitis, inflammatory pseudotumor of the spermatic cord) is a rare, benign condition of unknown etiology characterized by solitary or multiple intrascrotal nodules composed of dense fibrous tissue with a variable, sometimes sparse inflammatory infiltrate. Based on certain similarities to other fibroinflammatory disorders characterized by infiltrates of IgG4-expressing plasma cells and recently subsumed under the heading of IgG4-mediated diseases, we investigated the plasma cell distribution and immunoglobulin isotypes in three cases of paratesticular fibrous and inflammatory pseudotumor. All three cases showed a high number of IgG4-positive plasma cells with an IgG4 to IgG ratio of 44–48%. This finding indicates that paratesticular fibrous pseudotumor might belong to the growing list of IgG4-related diseases, which by now includes such diverse entities as retroperitoneal fibrosis, sclerosing pancreatitis and cholangitis, Riedel’s thyroiditis, or sclerosing sialadenitis.     

Multiple IgG4-related sclerosing lesions in the maxillary sinus, parotid gland and nasal septum

IgG4-related sclerosing disease is recognized as a distinct clinicopathological entity. It is well known that this disease can occur in the salivary, lacrimal and pituitary glands, in the head and neck region. The nasal cavity is an extremely rare site of involvement of IgG4-related sclerosing disease. Herein is reported a case of multiple IgG4-related sclerosing lesions in the maxillary sinus, parotid gland and nasal septum. A 73-year-old Japanese man presented with nasal obstruction and tumors of the right maxillary sinus and parotid gland were detected, after which resections of these tumors were performed. One year after the last surgery, he noted swelling of the nasal septum, and the tumor was resected. These three tumors had similar histopathology, such as conspicuous fibrosclerotic changes with dense lymphoplasmacytic infiltration and occasional obliterative phlebitis. Immunohistochemistry indicated abundant IgG4-positive plasma cell infiltration and high ratios of IgG4-positive/IgG-positive plasma cells (>70%) in all three lesions. The diagnosis of multiple IgG4-related sclerosing lesions was made. The present case suggests that IgG4-related sclerosing lesion can occur in the maxillary sinus and nasal septum, and represents an extension of the spectrum of IgG4-related sclerosing disease.     

Idiopathic retroperitoneal fibrosis (sclerosing retroperitonitis)

Three cases of idiopathic retroperitoneal fibrosis, one of which was localized to the perirenal area, are presented. The predominance of plasma cells, which may be difficult to recognize because of distortion unless methyl green-pyronine staining is done, and the character of the fibrous tissue indicated the non-neoplastic nature of the processes. This diagnosis was confirmed by immunoperoxidase studies that demonstrated polyclonality of the lymphoplasmacytic component. Immunologic studies, which may be performed on paraffin-embedded tissue, are helpful in differentiating this lesion from the sclerosing lymphomas that also occur in the retroperitoneal area.     

Hepatobiliary manifestations of IgG4-related disease

IgG4-related disease involving the liver and biliary tree exhibits variable morphological changes. The most common manifestation is sclerosing cholangitis characterized by pipe stem-like fibrosis of the wall and extensive inflammation. IgG4-related sclerosing cholangitis sometimes exhibits pseudo-tumourous exuberance around the hilar bile duct (inflammatory pseudotumour), radiological features of which are reminiscent of hilar cholangiocarcinoma. Another minor manifestation is IgG4-related chronic active hepatitis. Consistent with other manifestations of IgG4-related disease, pathological features include diffuse lymphoplasmacytic infiltration, irregular fibrosis typically in a storiform pattern, and moderate tissue eosinophilia. On immunostaining, not only the absolute number of IgG4-positive plasma cells but also the IgG4/IgG-positive ratio is dramatically increased. Pathologists need to be aware of this condition, as the diagnosis requires a multi-disciplinary approach, in which pathological examination has a critical role.     

Sclerosing lipogranuloma of male genitalia. Review of 23 cases

In 1950 the term "sclerosing lipogranuloma" was introduced to designate a praticular subcutaneous granulomatous reaction that was believed to be a "local reactive process following injury to adipose tissue." Subsequent reports have shown that exogenous lipid injections probably are responsible for this lesion. We have studied 23 cases involving penis, scrotum, spermatic cord, and perineum, nine of which had been previously reported. We have been able to identify paraffin hydrocarbons by means of infrared-absorption spectrophotometry in 21 of these cases. We belive this entity should be redefined as a "local reactive process following injection of exogenous lipids into the subcutaneous tissues." In conventional microscopical sections, the lesion must be differentiated from adenomatoid tumor, sclerosing liposarcoma, and lymphangioma.     

Hemosiderotic fibrohistiocytic lipomatous lesion: Early pleomorphic hyalinizing angiectatic tumor?

Hemosiderotic fibrohistiocytic lipomatous lesion (HFLL) and early pleomorphic hyalinizing angiectatic tumor (PHAT) are characterized histologically by an admixture of fat, moderately cellular fascicles of hemosiderin-laden spindle cells growing in a perivascular, periadipocytic and septal pattern, as well as the presence of macrophages and chronic inflammatory cells. In contrast to a suggested reactive nature of HFLL, PHAT is regarded as a non-metastasizing tumor of uncertain lineage in the recent World Health Organization classification of soft tissue tumors. Reported herein is the case of a 47-year-old woman with an unencapsulated and irregularly circumscribed recurring lesion in the ankle/foot region that developed following ankle distortion and that fulfills histological criteria for both HFLL and early PHAT. In summary, the present case suggests a reactive over-neoplastic nature of HFLL and confirms profound histological similarities with early PHAT. Until more data become available on the biological potential of HFLL/early PHAT, radical surgical excision and follow up of the patient remains the best treatment option.