We report on the histological features of 16 biopsy specimens from 12 patients seen at the Middlesex hospital with a primary diagnosis of RPF, for whom we have now been able to review the histology and examine sections for evidence of IgG4-expressing plasma cells. Only archival paraffin wax-embedded material was used for this study. All the biopsies were taken for diagnostic reasons with the informed consent of patients.

All the samples were routinely fixed in formalin and embedded in paraffin wax. Dewaxed sections (μm) were stained with haematoxylin and eosin. Immunohistochemical analysis was performed using antibodies (all Dako UK Ltd, Cambridgeshire, UK) against CD3, CD4, CD8, CD20, and CD138, and the kappa and lambda light chains of immunoglobulins, by the standard streptavidin-biotin-peroxidase method. For IgG4, a mouse human IgG4 monoclonal antibody was used (1:100 dilution, MC011; The Binding Site, Birmingham, UK). Negative controls were created by substituting the primary antibody with similarly diluted non-immunized mouse serum.

We examined a wide variety of other inflammatory conditions and fibrotic diseases as organ-specific controls, which included liver (autoimmune hepatitis, chronic hepatitis C), pancreas (chronic and alcoholic pancreatitis), salivary gland (chronic sialadenitis), gallbladder (chronic cholecystitis), kidney (tubulointerstitial nephritis), duodenum (chronic duodenitis), colon (non-specific colitis), and other fibrotic processes (Dupuytren's, keloid scars). Because an association between RPF and asbestos exposure has been reported 11, we also included cases of malignant mesotheliomas. In addition, specimens from cases of "benign pleural plaques" were stained as controls.

Positive controls comprised tissue obtained from pancreas, salivary gland and liver from patients seen in our gastroenterological department who had sclerosing pancreatitis and chronic inflammation associated with IgG4-expressing plasma cells, details of which have been reported previously 34.

The degree of inflammation was assessed as severe [>100 inflammatory cells per high power field (), moderate (30–100 cells/HPF) and mild (30–10 cells/HPF). The presence of lymphoid-follicle formation, eosinophilic infiltration, venulitis and obliterative arteritis (on elastic van Gieson-stained sections) was also recorded. The number of IgG4-positive cells was estimated by counting 10 HPF, and scoring as follows: 0 (no IgG4 plasma cells/HPF), 1 (≤ 20 cells/HPF), 2 (20–50 cells/HPF) or 3 (≥ 50 cells/HPF) [12]. Fibrosis was assessed as - (no fibrosis), + (mild), ++ (moderate) or +++ (severe).

We reviewed the published literature for disease associations with idiopathic, systemic fibrosing conditions using the following synonyms: pseudotumour, myofibroblastic tumour, plasma cell granuloma, systemic fibrosis, xanthofibrogranulomatosis and multifocal fibrosclerosis. We also looked for reports associating these conditions with organ-specific conditions, particularly sclerosing pancreatitis (see Table 2 for other synonyms), RPF, Reidel's thyroiditis, panniculitis, Weber-Christian syndrome and retro-orbital tumour, and with a range of autoimmune diseases (Table 3).

Many of these reports are case reports. We have not attempted to list every report but rather to draw up a comprehensive list of all possible associations with at least one citation.

A 39-year-old Moroccan steel fitter had lived in the UK for 31 years. He presented in May 2003 with abdominal pain, weight loss, sweating, generalized lymphadenopathy, and severe anaemia and thrombocytosis. Investigations showed haemoglobin of 6.7 g/dL (normal range 13.0–17.0 g/dL), platelets 1031 × 10⁹/L (150–400 × 10⁹/L), erythrocyte sedimentation rate (ESR) 120 mm/h (0–15 mm/h), IgG 21.4 g/L (8.0–18.0 g/L), IgA 2.9 g/L (0.9–4.5 g/L), IgM 0.6 g/L (0.6–2.8 g/L) and C-reactive protein (CRP) 289 mg/L (normal 0–5 mg/L). Biochemistry was normal. Chest X-ray showed apical pleural thickening. An intravenous urogram (IVU) showed left hydronephrosis; an ultrasound scan (USS) confirmed this, and showed dilatation of the bile and pancreatic ducts and the gallbladder. Computed tomography (CT) showed multifocal upper zone and patchy nodular airspace shadowing, with right posterior pleural thickening and subcarinal lymphadenopathy. Biopsies of pleural, ileal and colonic tissue, bone marrow, and left inguinal lymph node were all either normal or showed reactive change. Cultures of blood, urine and sputum were all negative. The patient was also negative for human immunodeficiency virus types 1 and 2, hepatitis B and C, human T-lymphotropic virus, toxoplasmosis and treponemal disease. Mantoux test was weakly positive, and although bronchoalveolar lavage was smear-negative, there was one positive culture for a mycobacterium after 3 weeks.

The patient was commenced on quadruple therapy for tuberculosis (TB) in July 2003, for an organism that was strongly isoniazid-resistant. The patient presented again in November with fatigue, weight loss and fever, which was thought to be medication-related. He was given prednisolone 20 mg for 6 weeks of, taken off all TB therapy, and after 2 months was feeling so well that he was told his TB had been cured.

He re-presented 3 months later (March 2004) with a 6-week history of night sweats, low-grade fever, lethargy, weight loss, left pleuritic chest pain and axillary lymphadenopathy. Blood tests again showed microcytic anaemia, and the same acute phase response. Antinuclear antibody (ANA), antineutrophil cytoplasmic antibodies, mitochondrial antibodies and smooth-muscle antibodies were all negative. CT showed many of the previous changes but with a right hydronephrosis that was confirmed on IVU (left hydronephrosis was no longer present). A repeat bone-marrow biopsy, inguinal lymph node and transjugular liver biopsies, endoscopy, colonoscopy, peritoneal fluid aspiration and bone scan were all either normal or non-specific. The patient was treated with quintuple anti-TB therapy in order to cover his original mycobacterium infection as well as an infection with Mycobacterium fortuitum that had been cultured from sputum on this occasion. He was also treated with steroids, initially 60 mg of prednisolone, tapered down to 20 mg over 3 months.

The patient was readmitted 6 months later with generalized abdominal pain and vomiting. He had stopped his steroids 11 days earlier because of side effects. Investigations showed only a marked inflammatory response. CT scan revealed no hydronephrosis, but now showed dilated, thick-walled small bowel in the left iliac fossa. During an exploratory laparotomy (October 2004), an inflamed omental mass adherent to the small-bowel mesentery was removed. Histology was reported as showing only some fibrosis with a mild chronic inflammatory cell infiltrate of lymphocytes and plasma cells. The patient was recommenced on steroids and quadruple anti-TB therapy.

He remained well for some months, but then presented (March 2005) with a 6-week history of pain in the right upper quadrant of the abdomen. His blood tests showed the same inflammatory response and a USS showed prominent intrahepatic ducts only. The histology of the omental mass was reviewed and showed a large number of IgG4-positve plasma cells throughout the fibroinflammatory reaction (Table 4). The patient's serum IgG concentration was 21.4 g/l and IgG4 2.4 (normal range 0–1.3 g/l). A diagnosis of hyper-IgG4 disease was made, all microbial therapy was stopped, and the patient was treated with prednisolone 20 mg/day with immediate improvement in his illness. He remains on azathioprine and 5 mg prednisolone.

We reviewed the histology and examined sections for evidence of IgG4-expressing plasma cells of 16 biopsies from 12 patients with a clinical diagnosis of idiopathic RPF seen at our hospital in the past 10 years. Biopsies comprised nine samples of retroperitoneal tissue, two of liver, and one each from kidney, colon and omentum. In addition, there were two further samples of retroperitoneal tissue taken from two patients after steroid therapy.

The results are shown in Table 4. All patients showed, to varying degrees, fibrosis, intense inflammatory cell infiltration with lymphocytes, plasma cells, scattered neutrophils and in some cases eosinophilic aggregates. The majority of lymphocytes expressed CD8 and CD4 positivity (T-cell markers), with B cells present to a lesser degree and with scattered B-cell-rich small lymphoid follicles. In addition, we saw vasculitis affecting small veins, and evidence of obliterative arteritis (Figures 1, 2, 3). In all cases, there was a significant increase in IgG4-positive plasma cells compared with controls (Figure 4). Even when few plasma cells were seen (patients 10–12) the majority expressed IgG4 (Figure 5). In two cases, biopsies before and after steroid treatment were available; only scattered plasma cells were seen after treatment, none of which expressed IgG4 (Fig 3). In all of our patients, the kappa and lambda light chains showed a polytypic pattern. We used PCR to look for evidence of oligoclonal infiltrates for IgH in one case (patient 1), as has been reported from Japan 13, but found none. None of the wide range of control sections showed significantly increased numbers of IgG4-positive cells.

We also examined biopsy specimens from liver (two patients), large bowel (one) and renal tissue (one). In all of them, we found mild fibrosis and a small increase in lymphoplasmacytic inflammatory cell infiltrate, although IgG4-positive plasma cells were not seen in one liver biopsy, nor in the colon biopsy (Table 4).

In summary, raised numbers of IgG4-positive plasma cells are seen in both peritoneal and non-peritoneal tissues in patients with hyper-IgG4 disease. The degree of IgG4-positive staining did not necessarily correlate with elevated serum IgG. Our clinical impression was that the number of IgG4-positive plasma cells was associated with disease activity.

Idiopathic RPF generally presents in a non-specific manner with malaise, fatigue, fever and weight loss 11141516. Pain in the back (lumbosacral) region, flank or lower abdomen is most common. The pathognomonic feature of RPF is a thick retroperitoneal fibrotic mass covering the abdominal aorta and compressing the ureters. The process of fibrosis can result in obstruction of the ureters and renal failure, or signs and symptoms may be related to the encasement or entrapment of other structures by the inflammatory mass, such as hydrocoeles or unilateral leg oedema. With renal involvement, severe hypertension is common.

The disease presents typically between the ages of 50 and 70 years, and men are affected 2–3 times more commonly than women 14. The inflammatory nature of idiopathic RPF is demonstrated by elevated ESR and CRP, reduced haemoglobin and elevated gammaglobulins at presentation. An autoimmune nature is suggested by the finding of ANA in 10–20% of cases, an occasional association with different autoimmune diseases and good response to glucocorticosteroids. In one series of RPF associated with periaortitis, 10 of 16 patients were ANA-positive 17.

Although there are no randomised studies of treatment for RPF, patients who present during the acute inflammatory phase respond quickly to glucocorticosteroids. Patients with late presentation and dense fibrosis will not respond to medical treatment and surgery is often necessary11.

Part of the spectrum of disease in patients with hyper-IgG4 disease is parenchymal lung pathology, often described as either bronchiolitis obliterans with organizing pneumonia or cryptogenic organizing pneumonia 50. This is seen typically as migratory pulmonary infiltrates, and is steroid-responsive. Nevertheless, there are at present no studies that have looked for evidence of IgG4 plasma cells in these conditions 51. Other conditions associated with migratory pulmonary infiltrates that may be related, but not yet investigated, include pulmonary eosinophilia, hypersensitivity to drugs, parasitic infection, allergic bronchopulmonary aspergillosis and Churg-Strauss vasculitis 52. Pleural thickening, with and without calcification, is well described 323253. There are also reports of calcifying pseudo-tumour of the pleura 5455 and peritoneum 56.

Fever of unknown origin (FUO) in an immunocompetent patient is defined as an illness of more than 3 weeks' duration with fever higher than 38.3°C (101°F) on several occasions, and with an uncertain diagnosis after 1 week of investigation 57. Infection accounts for about one-third of cases (25–32%) of FUO, followed by non-infectious inflammatory disease (21–31%) and neoplasm (12–17%) 5859606162. Although many patients with FUO will be found to have bacterial infection, rarer diagnoses will be considered with time and extensive investigation. Nevertheless, at the end of all investigations, 18–30% of patients will have no diagnosis, although the majority of this idiopathic group will improve spontaneously 60. We propose that hyper-IgG4 disease can be added to this list of systemic inflammatory diseases.