Degree of IgG4+ plasma cell infiltration in retroperitoneal fibrosis with or without multifocal fibrosclerosis. 404 Correspondence

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1 404 Correspondence CD34, c-kit and CD21. Immunohistochemistry for epithelial markers highlighted small clusters of chief cells trapped within the ASCLs. Transitional-type cells in the ASCL in the upper right gland showed some positivity for AE1 AE3 (Figure 2E) and CAM5.2. Cyclin D1 immunohistochemistry showed nuclear staining of 30 40% of the cells in both the ASCLs and that of 20% of the cells in several chief cell nodules other than those with ASCLs. The MIB-1 labelling index was 10% in the ASCL of the lower right gland and 7% in that of the upper right gland, whereas MIB-1 staining was rarely found in the surrounding area. Several features associated with malignancy of the parathyroid gland 3 were identified in the present case, including readily identifiable mitotic figures, coagulative tumour necrosis and macronucleoli present in many tumour cells. MIB-1 expression is higher in carcinoma than in adenoma or hyperplasia. 4 MIB-1 indices in the ASCLs in the present case were similar to those in carcinoma. Although overexpression of cyclin D1 has been identified in parathyroid adenoma and carcinoma and is thought to be involved in the pathogenesis of some types of parathyroid neoplasia, it has also been detected in secondary hyperplasia. 5 In the present case, overexpression of cyclin D1 was detected in the ASCLs as well as in other hyperplastic nodules. Vimentin has been shown to be positive only in stromal cells of normal, hyperplastic and adenomatous parathyroid glands. 6 However, we identified glandular cells positive for vimentin in hyperplastic nodular lesions other than the ASCLs in the present case. Our preliminary immunohistochemistry of nine cases of secondary hyperparathyroidism with no ASCLs showed positive glandular cells in all cases. Since the introduction of antigen retrieval methods, more cell types, even cells of epithelial origin, have been reported to be positive for vimentin. The vimentin positivity of ASCLs may be compatible with a glandular cell origin of the lesions. The positivity of some transitional-type cells for epithelial markers in the present case also suggests an epithelial origin of the spindle cells. In the case reported by Alpers and Clark, 2 the presence of similar transitional-type cells in the ASCLs was also described; they stated that the lesions were suggestive of parathyroid carcinoma, but there was insufficient evidence for this diagnosis. Secondary hyperparathyroidism is generally present in patients with uraemia. Neoplasia may emerge from nodular hyperplasia. Clonal analysis has suggested that in renal hyperparathyroidism, parathyroid glands initially grow diffusely and polyclonally, and that the cells within the nodules later become monoclonal and proliferate aggressively. 7 It has been suggested that monoclonal tumours are more common than previously thought in both primary and secondary hyperparathyroidism. 8 Although the cause of the ASCLs in the present case, and their malignant or benign nature, are uncertain at the present time, they may reflect malignant transformation with metaplastic changes. A Masuda T Nishikawa T Yamamoto M Aiba 1 M Kobayashi Department of Surgical Pathology, Tokyo Women s Medical University, and 1 Department of Surgical Pathology, Tokyo Women s Medical University Medical Centre East, Tokyo, Japan 1. Bondeson L, Sandelin K, Grimelius L. Histopathological variables and DNA cytometry in parathyroid carcinoma. Am. J. Surg. Pathol. 1993; 17; Alpers CE, Clark OH. Atypical spindle cell pattern (?Carcinoma) arising in a parathyroid adenoma. Surg. Pathol. 1989; 2; Chan JKC. Tumor of the thyroid and parathyroid glands. In Fletcher CDM ed. Diagnostic histopathology of tumors. Edinburgh: Churchill Livingstone, 2000; Abbona GC, Papotti M, Gasparri G, Bussolati G. Proliferative activity in parathyroid tumors as detected by Ki-67 immunostaining. Hum. Pathol. 1995; 26; Vasef MA, Brynes RK, Sturm M, Bromley C, Robinson RA. Expression of cyclin D1 in parathyroid carcinomas, adenomas, and hyperplasias: a paraffin immunohistochemical study. Mod. Pathol. 1999; 12; Miettinen M, Clark R, Lehto VP, Virtanen I, Damjanov I. Intermediate-filament proteins in parathyroid glands and parathyroid adenomas. Arch. Pathol. Lab. Med. 1985; 109; Tominaga Y, Kohara S, Namii Y et al. Clonal analysis of nodular parathyroid hyperplasia in renal hyperparathyroidism. World J. Surg. 1996; 20; Shan L, Nakamura M, Nakamura Y et al. Comparative analysis of clonality and pathology in primary and secondary hyperparathyroidism. Virchows Arch. 1997; 430; Degree of IgG4+ plasma cell infiltration in retroperitoneal fibrosis with or without multifocal fibrosclerosis DOI: /j x Sir: Retroperitoneal fibrosis (RF) is a rare disease characterized by fibrosis of the retroperitoneal tissue with chronic inflammation, resulting in local pain and hydronephrosis. Histological recognition of RF is important, as the lesions show a favourable response

2 Correspondence 405 to steroid therapy, whereas clinically they often mimic malignancy. RF is seen in isolated form or as part of multifocal fibrosclerosis (MFS), which causes mass lesions in the pancreas, liver, lungs, salivary glands and other organs. 1 Recently, MFS has been reported to be associated with increased serum levels of IgG4 and IgG4+ plasma cell infiltration. 2,3 Most studies on MFS and IgG4, however, have concentrated on pancreatic lesions. Here, we focus on the degree of IgG4+ plasma cell infiltration in RF in association with MFS. From the pathology database of Kyoto University, 29 patients with retroperitoneal lesions were selected and divided into three groups: patients with RF and MFS (group A, n = 5), RF regarded as idiopathic and isolated (group B, n = 10), and secondary fibrosis of retroperitoneal tissue of known aetiology (group C, n = 14; Table 1). For one patient in group A, a specimen of autoimmune pancreatitis, or pancreatic lesion of MFS, was also available. In addition, three patients with MFS without RF were selected, and six fibrosclerotic lesions from these patients were also evaluated. Conventional histology was evaluated for the presence of lamellar collagen bundles, obliterative phlebitis, lymphoid follicles and prominent eosinophilic infiltration [>5 eosinophils per high-power field (0.307 mm 2 area) (HPF)]. 4 Immunohistochemistry was performed with polyclonal antibodies against IgG (NCL-lgGp, dilution 1:20; NovoCastra, Newcastle, UK) and monoclonal antibodies against IgG4 (clone HP6025, dilution 1:500; Serotec, Oxford, UK) using an autoimmunostainer (Ventana XT System Benchmark; Ventana Medical System, Inc., Tucson, AZ, USA). Two typical areas for each lesion were photographed with a 20 objective lens (Nikon ECLIPSE E800). The numbers of IgG+ and IgG4+ plasma cells were counted manually and presented as the numbers of IgG4+ cells in one HPF and the ratios of IgG4+ to IgG+ plasma Table 1. Patients characteristics and results of immunohistochemistry for IgG and IgG4 Group Case Age Sex IgG4 HPF IgG4 IgG, % Procedure Clinical diagnosis other than retroperitoneal fibrosis A 1* 69 M Right nephroureterectomy Autoimmune pancreatitis, sclerosing cholangitis, Sjögren s syndrome 2 66 M Left nephroureterectomy Autoimmune pancreatitis, hypothyroidism 3* 61 M Left ureterolysis Autoimmune pancreatitis 4* 76 M Left ureterolysis Autoimmune pancreatitis 5 72 M Distal pancreatectomy, left nephroureterectomy Autoimmune pancreatitis, chronic renal failure B 6 69 M 3 7 Right ureterolysis 7 63 M Bilateral ureterolysis Hypertrophic cardiomyopathy 8 76 M 2 9 Left ureterolysis 9 73 F Right ureterolysis Hypertension, arthritis, ectopic pregnancy M Open biopsy Hypertension F Right nephroureterectomy Uterine leiomyoma M 1 4 Graft replacement of AAA, bilateral ureterolysis AAA, chronic renal failure, hypertension, F 6 1 Percutaneous needle biopsy M Bilateral ureterolysis Asthma 15* 78 M 0 0 Ureterointestinoneocystostomy

3 406 Correspondence Table 1. (Continued) Group Case Age Sex IgG4 HPF IgG4 IgG, % Procedure Clinical diagnosis other than retroperitoneal fibrosis C M 13 4 Right nephroureterectomy Right ureteropelvic junction stenosis M 0 0 Left nephroureterectomy Urothelial carcinoma M 2 7 Bilateral nephrectomy Bilateral nephrostomy due to ureteropelvic junction steatosis, F 0 0 Tumour excision Undifferentiated pleomorphic sarcoma F 2 5 Hysterectomy, bilateral salpingo-oophorectomy Endometrioid adenocarcinoma of left ovary M Tumour excision Well-differentiated liposarcoma F Left nephroureterectomy Xanthogranulomatous pyelonephritis and ureteritis F 0 0 Hysterectomy, bilateral salpingo-oophorectomy Clear cell adenocarcinoma of right ovary F 7 6 Bilateral salpingo-oophorectomy Serous adenocarcinoma of left ovary F 3 3 Hysterectomy, bilateral salpingo-oophorectomy Endometrioid adenocarcinoma of uterine corpus M 28 4 Right nephroureterectomy Right chronic ureteritis F 0 0 Right hemicolectomy Tubular adenocarcinoma of ascending colon M Distal pancreatectomy Tubular adenocarcinoma of pancreas F 9 3 Right nephrectomy Xanthogranulomatous pyelonephritis *After steroid therapy. AAA, Abdominal aortic aneurysm. Table 2. Histological findings Group A, % (n = 5) Group B, % (n = 10) Group C % (n = 14) Lamellar collagen bundles 60 (case 1, 2, 5) 60 (case 6, 7, 9, 10, 11, 14) 7 (case 21) Obliterative phlebitis 60 (case 1, 2, 3) 50 (case 6, 7, 9, 10, 14) 29 (case 19, 20, 27, 28) Lymphoid follicles 60 (case 1, 2, 5) 20 (case 10, 14) 14 (case 28, 29) Prominent eosinophilic infiltration 0 40 (case 6, 9, 13, 15) 7 (case 19) cells (IgG4:IgG). The Kruskal Wallis test was employed for statistical analysis, followed by the Mann Whitney U-test with Bonferroni correction. Histologically, lamellar collagen bundles were the most common finding in group A and group B (group A, 60%; group B, 60%; group C, 7%), but

4 Correspondence 407 Figure 1. Representative histology of retroperitoneal lesions. Lymph follicle formation (A), lamellar collagen bundles interspersed with inflammatory cells (B), obliterative phlebitis (C), eosinophilic infiltration (D). E G, Representative images of immunopositivity for IgG4 in groups A, B and C, respectively. The same areas immunostained with IgG are shown in (H), (I) and (J), respectively. In these images, the ratios of IgG4+ cells to IgG+ cells in groups A, B, and C were 80%, 25% and 3%, respectively.

5 408 Correspondence none of the findings was specific in group A (Table 2 and Figure 1A D). Representative patterns of immunoreactivity are shown in Figure 1E J. In group A IgG4 IgG were significantly higher than in both groups B and C (P < 0.05), and the numbers of IgG4+ cells were also significantly greater than in group C (P < 0.05), but did not show significant differences compared with group B (Table 1 and Figure 2). In group A, there were >300 IgG4+ cells HPF, except for two patients after steroid therapy, and IgG4 IgG was >60% in all five cases. In all extraretroperitoneal fibrous lesions of MFS, there were >300 IgG4+ cells HPF and IgG4 IgG was >60% (Table 3). There was no significant difference between groups B and C in the numbers of IgG4+ cells (P = 0.75), but in four patients (40%) in group B there were more than in any patients in group C, and were within the range of cells HPF. Similarly, IgG4 IgG of the four patients in group B were between 20 and 60%, which was higher than any patients in group C. In all cases in group C, there were <30 IgG4+ cells HPF, and IgG4 IgG was <20%. In patients after steroid therapy, both the numbers and IgG4 IgG tended to be less than in other patients in the same group (Table 1). Figure 2. Numbers of IgG4+ plasma cells per high-power field (left) and ratio of IgG4+ plasma cells to IgG-positive plasma cells (right). Horizontal bars denote median values. Table 3. Results of immunohistochemistry for IgG and IgG4 in multifocal fibrosclerosis Case Age Sex IgG4 HPF IgG4 IgG, % Organ Diagnosis 5 72 M Pancreas Autoimmune pancreatitis M Orbit Bilateral relapsing pseudotumours of orbits, hilar lymphadenopathy M Liver Sclerosing cholangitis M Subcutis Subcutaneous nodule (tumefactive fibroinflammatory lesion) M Orbit Bilateral relapsing pseudotumors of orbits, hypopituitarism (post radiation) M Abdominal aorta Abdominal aortic aneurysm (inflammatory aneurysm) M Pancreas Autoimmune pancreatitis, sclerosing cholangitis, bilateral submandibular gland swelling, asthma

6 Correspondence 409 It could be hypothesized that those four patients in group B had IgG4-related isolated RF rather than idiopathic RF, but the number of IgG4+ cells in those patients was still lower than that of MFS. The pathogenesis of isolated RF remains unknown in patients with few IgG4+ cells. In reported cases of autoimmune pancreatitis, serum IgG4 concentration has reflected disease activity 5 and the levels of serum IgG4 have been significantly higher in patients with systemic extrapancreatic lesions than in those without. 6 In our study also, there were fewer IgG4+ cells in cases after steroid therapy than in other cases. It is assumed that the number of IgG4+ cells may reflect inflammatory activity of retroperitoneal fibrosis. In conclusion, all patients with RF in MFS and some with isolated RF were characterized by increased IgG4+ cell infiltration. Isolated IgG4-related RF may show fewer IgG4+ plasma cells than MFS because of the lower activity of inflammation. acknowledgements We thank Ms I Koyanagi, Ms S Yamane and Ms C Tanaka for technical assistance with immunohistochemistry. K Yamashita H Haga Y Mikami A Kanematsu 1 Y Nakashima H Kotani O Ogawa 1 T Manabe Departments of Diagnostic Pathology and 1 Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan 6. Hamano H, Arakura N, Muraki T, Ozaki Y, Kiyosawa K, Kawa S. Prevalence and distribution of extrapancreatic lesions complicating autoimmune pancreatitis. J. Gastroenterol. 2006; 41; Sarcomatoid carcinoma of the thymus arising in metaplastic thymoma DOI: /j x Sir: Metaplastic thymoma is a newly defined rare thymic epithelial tumour that usually has a benign clinical course. 1 No association with malignant thymic tumours has been reported. We describe a hitherto unreported type of thymic tumour characterized by combined features of metaplastic thymoma and sarcomatoid carcinoma. A routine chest X-ray of a 43-year-old asymptomatic Japanese man revealed an anterior mediastinal mass that had increased in size at 1-year follow-up. A computed tomography scan revealed a well-circumscribed anterior mediastinal mass with heterogeneous density measuring 65 mm in greatest diameter (Figure 1). He had no signs or symptoms of myasthenia gravis. The peripheral blood count and serum biochemistry were within normal limits. Tumour markers were not elevated and autoantibodies were not detected. The tumour was completely excised by a right hemithymectomy with partial resection of the pleura. The postoperative clinical course has been uneventful at 13 months after surgery without chemotherapy or radiation. The resected mass measured mm and was grossly well encapsulated. The cut surface 1. Oguz KK, Kiratli H, Oguz O, Cila A, Oto A, Gokoz A. Multifocal fibrosclerosis: a new case report and review of the literature. Eur. Radiol. 2002; 12; Hamano H, Kawa S, Horiuchi A et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N. Engl. J. Med. 2001; 344; Kamisawa T, Okamoto A. Autoimmune pancreatitis: proposal of IgG4-related sclerosing disease. J. Gastroenterol. 2006; 41; Zamboni G, Luttges J, Capelli P et al. Histopathological features of diagnostic and clinical relevance in autoimmune pancreatitis: a study on 53 resection specimens and 9 biopsy specimens. Virchows Arch. 2004; 445; Aoki S, Nakazawa T, Ohara H et al. Immunohistochemical study of autoimmune pancreatitis using anti-igg4 antibody and patients sera. Histopathology 2005; 47; Figure 1. Computed tomography scan of the chest. A well-circumscribed mass with heterogeneous density is located in the anterior mediastium.