[A Case of Solitary Inguinal Lymph Node Metastasis 15 Years after Colorectal Cancer Surgery].

The patient is a 69-year-old man. 17 years ago, a colectomy was performed for colorectal cancer, and a disseminated nodule was found during the operation, so the disseminated nodule was also resected. After the surgery, 12 courses of FOLFOX4 were administered, and there was no recurrence thereafter. He was diagnosed with hepatocellular carcinoma 12 years after the colectomy and underwent liver resection. Fifteen years after the colectomy, a mass shadow appeared in the right inguinal region, and inguinal lymph node metastasis of hepatocellular carcinoma or colorectal cancer was suspected. In the same year, he underwent the tumor resection and histopathological diagnosis revealed colon cancer inguinal lymph node metastasis. After the lymph node resection, he has been followed up for 2 years with no recurrence of colorectal cancer. It is extremely rare to have a solitary inguinal lymph node recurrence 15 years after colon surgery.

Lanthanum Deposition in the Gastroduodenal Mucosa of Dialysis Patients.

Lanthanum (La) carbonate (LC) is one of the most popular phosphate binders used in dialysis patients with end-stage renal disease. Only a small amount of LC is believed to be absorbed from the gastrointestinal (GI) tract because LC strongly binds to dietary phosphate and forms insoluble complexes. La deposition in the gastroduodenal mucosa has been recently identified. Endoscopically, La deposition is demonstrated as whitish lesions of varying sizes and shapes in the gastroduodenal mucosa. Microscopically, La deposition is characterized by histiocytic reaction or small foreign body granulomas containing gray or brown materials mainly in the lamina propria of the GI mucosa. Some histiocytes containing La can migrate into regional lymph nodes via the lymphatic flow. The amount of La deposition in the gastroduodenal mucosa is correlated with the total dose of LC administration, and La deposition is almost consistently observed in LC-treated dialysis patients. Although the detailed mechanism of La deposition in the GI tract is still unclear, several factors, such as gastric pH and metaplastic change of the mucosal epithelium, may be involved in the La deposition in the gastroduodenal mucosa. Here we present an overview of the feature of La deposition in the GI tract.

MUC4 expression in meningiomas: under-recognized immunophenotype particularly in meningothelial and angiomatous subtypes.

AIMS: MUC4 is a transmembrane glycoprotein that plays a role in cell growth signalling and is expressed in various epithelial tissues. Gene expression profiling and immunohistochemical analyses revealed that MUC4 is also constantly and specifically expressed in low-grade fibromyxoid sarcomas and sclerosing epithelioid fibrosarcomas among the mesenchymal tumours, and immunohistochemical detection of MUC4 is extremely useful for their diagnoses. In our routine pathological practice, we noticed that meningiomas are also often positive for MUC4, which has not yet been reported previously, despite the extensive scrutiny of its expression in soft tissue tumours. METHODS AND RESULTS: We examined immunohistochemically the expression of MUC4, progesterone receptor (PgR) and somatostatin receptor 2A (SSTR2A) in 140 meningiomas of various histological subtypes and 123 other mesenchymal tumours, including intracranial or sinonasal tumours and peripheral nerve sheath tumours. MUC4 was expressed in 130 meningiomas (92.9%). MUC4 expression was constant and almost diffuse in meningothelial and angiomatous subtypes, whereas it was limited in 5% or fewer tumour cells or absent in 26 of 28 fibrous meningiomas. All other mesenchymal tumours examined were negative for MUC4. PgR and SSTR2A were expressed in 94 (67.1%) and 134 (95.7%) meningiomas, respectively. Five of six SSTR2A-negative meningiomas focally expressed MUC4. CONCLUSIONS: MUC4 is expressed variably but almost consistently in meningiomas, particularly in meningothelial or angiomatous subtypes. Its immunohistochemical detection is useful to distinguish meningiomas from other intracranial or head and neck mesenchymal tumours, particularly those with epithelioid features. Our study could expand a variety of MUC4-positive mesenchymal tumours.

Lanthanum-Induced Mucosal Alterations in the Stomach (Lanthanum Gastropathy): a Comparative Study Using an Animal Model.

Lanthanum (La) carbonate (LC) is one of the most potent phosphate binders that prevents the elevation of serum phosphate levels in patients with end-stage renal diseases undergoing dialysis. LC binds strongly to dietary phosphate and forms insoluble complexes that pass through the gastrointestinal tract. La deposition in patients treated with LC is a recently documented finding particularly observed in gastric mucosa. We herein describe the detailed gastric mucosal lesions in 45 LC-treated patients and address the potential underlying pathologic mechanism using oral LC administration in rats. Microscopically, La deposition, as shown by subepithelial collections of plump eosinophilic histiocytes or small foreign body granulomas containing coarse granular or amorphous inclusion bodies, was found in the gastric mucosa of 44 (97.8%) of the 45 dialysis patients in the study cohort, which was most frequently associated with foveolar hyperplasia (37.8%). Using oral administration of rats with 1000 mg/day LC for 2 or more weeks, La deposition was consistently detectable in the gastric mucosa but not in other organs examined. In addition, various histologic alterations such as glandular atrophy, stromal fibrosis, proliferation of mucous neck cells, intestinal metaplasia, squamous cell papilloma, erosion, and ulcer were demonstrated in the rat model. Thus, orally administered LC can induce mucosal injury, designated here as La gastropathy, which may alter the local environment and result in La deposition in the gastric mucosa, thereby potentially inducing abnormal cell proliferation or neoplastic lesions.

Lanthanum deposition in the gastrointestinal mucosa and regional lymph nodes in dialysis patients: Analysis of surgically excised specimens and review of the literature.

Lanthanum carbonate (LC) is one of the most potent phosphate binders currently used to reduce serum phosphate levels in dialysis patients with end-stage renal disease (ESRD). LC forms insoluble complexes with dietary phosphate that pass through the gastrointestinal (GI) tract with little absorption. GI lesions due to lanthanum deposition in biopsy specimens or those in endoscopic submucosal dissection (ESD) in dialysis patients have been recently identified. Here, we describe more detailed histopathological findings in the gastroduodenal mucosa and regional lymph nodes in three patients with gastric cancer. Three patients with ESRD, two elderly women and one man, underwent dialysis and were treated with LC for 3-36 months. The patients underwent laparoscopic distal gastrectomy and lymph node dissection due to gastric cancer. Many subepithelial histiocyte aggregates or small foreign body granulomas, which contained gray or brown pigments or crystal-like structures, were mostly present in non-neoplastic areas of the upper GI. Lanthanum accumulation was noted in the duodenal mucosa and the antral and body mucosae of the gastric lesser curvature. Lanthanum was also deposited in the regional lymph nodes of the three patients. Electron microscopy with energy dispersive X-ray spectroscopy confirmed lanthanum and phosphorus deposits in histiocytes. Long-term prognosis of patients and the excretion or the metabolic pathway of accumulated lanthanum remain unclear.

Peculiar histiocytic lesions with massive lanthanum deposition in dialysis patients treated with lanthanum carbonate.

Pathologic lesions caused by lanthanum carbonate (LC), a recently developed phosphate-binding agent, have not been recorded. A peculiar gastroduodenal histiocytic lesion associated with a mucosal lanthanum overload was reported. Our routine gastrointestinal biopsy series included 6 cases with heavy lanthanum burden in the gastroduodenal mucosa. In addition to routine histopathologic examinations, a series of immunohistochemical analysis and electron microscopic examinations associated with x-ray diffraction and elemental analysis were performed. Six cases, 3 of male and 3 of female individuals with ages from 59 to 69 years, were all patients of end-stage renal diseases managed under dialysis and treated with LC for >21 months. Endoscopic examinations demonstrated gastric erosions in 3, gastric polyps in 2, and duodenal ulcer in 1. In the mucosal layer, there were numerous non-Langerhans cell histiocytes, stained with CD68 but not S100 protein, engulfing a large amount of mineral-like materials. An electron microscopic and elemental analysis revealed a similar distribution of lanthanum and phosphorus in the histiocytes. Long-standing LC administration can cause massive mucosal accumulation of lanthanum in the tissue histiocytes associated with several forms of gastroduodenal lesions. A long-standing outcome is not clear at present; hence, careful follow-up studies of these patients may be needed.

Long-term survival of a patient with multiple myeloma-associated severe cardiac AL amyloidosis after implantation of a cardioverter-defibrillator.

Cardiac involvement is by far the most relevant factor impacting poor outcomes of patients with systemic light-chain (AL) amyloidosis. Median survival of patients with symptomatic cardiac AL amyloidosis is less than 6 months. Approximately two-thirds of these patients die suddenly due to ventricular arrhythmias and electromechanical dissociation. We report a 56-year-old female with very severe cardiac AL amyloidosis (NT-proBNP 13,355 ng/l, troponin T 0.16 µg/l, and systolic blood pressure 100 mmHg), who was successfully treated with diuretics and an implantable cardioverter-defibrillator (ICD) and has survived for more than 4 years, to date. During the 4-year period after receiving the ICD, she experienced several episodes of sustained ventricular tachycardia and ventricular fibrillation, all successfully terminated by anti-tachycardia pacing or electrical shock. The benefit of ICD for cardiac AL amyloidosis is unclear since there have been only a few reports of successful use of this therapy for patients with cardiac AL amyloidosis. Recently, new treatment options for AL amyloidosis, such as bortezomib and lenalidomide, have shown high response rates and improved outcomes. It is important to identify those cardiac amyloidosis patients who might be more likely to benefit from ICD implantation.

A comparison of epidermal growth factor receptor expression in malignant peritoneal and pleural mesothelioma.

An evaluation of epidermal growth factor receptor (EGFR) phenotypic expression in malignant pleural and peritoneal mesothelioma was undertaken, using immunohistochemical (IHC) and fluorescence in situ hybridization (FISH) analysis. Thirty-eight malignant mesothelioma (MM) specimens were subjected to IHC staining and FISH to evaluate the expression of EGFR protein and gene status. Overall positive IHC reaction was detected in 20/38 (53%) cases, in 11/22 (50%) pleural MM, and in 9/16 (56%) peritoneal MM. Our study confirmed that EGFR membranous expression is a common feature in MM, but not in benign mesothelial lesion. Thirty-seven cases did not show a gene copy number gain. Only one case showed a copy number gain. The protein overexpression of EGFR was not related to a gene copy number gain.

Epidermal growth factor receptor mutations in malignant pleural and peritoneal mesothelioma.

BACKGROUND: Epidermal growth factor receptor (EGFR) gene mutation at the kinase domain and EGFR gene amplification are reported to be predictors of the response to EGFR tyrosine kinase inhibitors in lung cancer cases. In malignant mesothelioma (MM), the role of EGFR is less clear. METHODS: Thirty-eight MM specimens were submitted to EGFR mutation evaluation, and compared with the results of immunohistochemical staining and fluorescence in situ hybridization (FISH) analysis. DNA was extracted from paraffin blocks and PCR was performed to amplify exon regions 18-21 of the EGFR gene. Direct sequencing of the purified PCR products was performed. RESULTS: Five EGFR missense mutations were detected in six of the 38 patients (16%); two of these mutations were novel, two were originally detected in non-small cell lung carcinoma, and one resembled a location previously noted for malignant peritoneal mesothelioma. CONCLUSION: As far as the authors are aware there has been no report of the EGFR mutation of MM in Japanese cases, but in this study EGFR missense mutations were detected in some cases. EGFR mutation results were not related to immunohistochemical and FISH analysis.

IgG4-related disorder of the retroperitoneum resembling Castleman's disease plasma cell type: a report of 2 cases.

This study reports 2 cases of IgG4-related disorder of the retroperitoneum resembling plasma cell type of Castleman's disease. A single lesion was located in the renal hilum and ureter, respectively, in these 2 cases. Histologically, both lesions were characterized by reactive follicular hyperplasia with active germinal centers and a sheet of polyclonal mature plasma cells in the interfollicular area. The prominent sclerosis and/or fibrosis, which were characteristic histological findings of IgG4-related disorders, were absent. However, immunohistochemical study demonstrated numerous IgG4+ plasma cells accounting for more than 50% of IgG+ cells. The phlebitis that occurs with early lesions of obliterative phlebitis is one of the characteristic histological findings of IgG4-related disorders and was noted in one case. Serum IgG4 concentration was increased in one case. The serum interleukin-6 level was within the normal range in one case that was examined. From a therapeutic perspective, it is important to discriminate IgG4-related disorder from plasma cell type of Castleman's disease.

Castleman's disease of the retroperitoneum: with special reference to IgG4-related disorder.

Localized Castleman's disease (CD) has been divided two types, the classical hyaline vascular (HV) type and the rare plasma cell (PC) type. Recently, we have reported two cases of IgG4-related disorder of the retroperitoneum showing PC type of CD. To further clarify the clinicopathological findings of CD of the retroperitoneum, eight such cases have been studied. A single lesion was located in the retroperitoneum (n=3), ureter (n=2) and renal hilum (n=2). One case had bilateral ureter lesions. The HV type of CD accounts for approximately 90% of cases. However, 50% (n=4) of our cases were the PC type of CD. Three of the four lesions of HV type had lymph node lesions, whereas all four PC type of CD were soft tissue masses. These clinicopathologic findings appear quite different from previous descriptions. Immunohistochemical study demonstrated numerous IgG4(+) plasma cells accounting for more that 50% of IgG4(+) cells in three cases of the four PC type of CD. Moreover, serum IgG4 concentration was increased in two of the four cases of PC type of CD that were examined. The serum interleukin-6 levels were within the normal range in two cases of PC type that were examined. The present study suggests that a majority of the PC type of CD arising in the retroperitoneum appears to be an IgG4-related disorder.

Application of a new histological staging and grading system for primary biliary cirrhosis to liver biopsy specimens: Interobserver agreement.

Recently the authors proposed a new staging and grading system for primary biliary cirrhosis (PBC) that takes into account necroinflammatory activity and histological heterogeneity. Herein is proposed a convenient version of this system. Scores for fibrosis, bile duct loss, and chronic cholestasis were combined for staging: stage 1, total score of 0; stage 2, score 1-3; stage 3, score 4-6; and stage 4, score 7-9. Cholangitis activity (CA) and hepatitis activity (HA) were graded as CA0-3, and HA0-3, respectively. Analysis of interobserver agreement was then conducted. Digital images of 62 needle liver biopsy specimens of PBC were recorded as virtual slides on DVDs that were sent to 28 pathologists, including five located overseas. All participants were able to apply this version in all 62 cases. For staging, kappa was 0.385 (fair agreement) and the concordance rate was 63.9%. For necroinflammatory activity, the kappa and concordance rate were 0.110 (slight agreement) and 36.9% for CA, and 0.197 (slight agreement) and 47% for HA, respectively. In conclusion, this new staging and grading system for PBC seems to be more convenient and practical than those used at present, but more instruction and guidance are recommended for the grading of necroinflammatory activity in practice.

Abundant IgG4-positive plasma cell infiltration characterizes chronic sclerosing sialadenitis (Küttner's tumor).

Chronic sclerosing sialadenitis (CSS) is a cryptogenic tumor-like condition of the salivary gland(s). While immune-mediated processes are suspected in its pathogenesis, and CSS is occasionally reported to be associated with sclerosing pancreatitis, an IgG4-related disease, the exact immunopathologic processes of CSS remain speculative. In this study, we examined the clinicopathologic findings of CSS (12 cases) in comparison with sialolithiasis (8 cases) and Sjogren's syndrome (13 cases), and tried to clarify whether CSS is an IgG4-related disease or not. Submandibular gland(s) were affected in all cases of CSS. CSS cases could be divided into two types: 5 cases were associated with sclerosing lesions in extrasalivary glandular tissue (systemic type), while only salivary gland(s) were affected in the remaining 7 cases (localized type). In the former type, which showed male predominance, bilateral salivary glands were frequently affected, and eosinophilia and elevations of gamma-globulin and IgG in serum were frequently found. Histologically, all cases of CSS showed marked lymphoplasmacytic infiltration admixed with fibrosis and the destruction of glandular lobules. Obliterative phlebitis was found in the affected salivary glands in all cases of CSS. Immunohistochemically, the proportion of IgG4/IgG-positive plasma cells was more than 45% in CSS, while it was less than 5% in controls. The resemblance of the clinicopathologic features of CSS with those of sclerosing pancreatitis suggests the participation of a similar immunopathologic process with IgG4 disturbance in CSS. The abundance of IgG4-positive plasma cells in the lesions would be useful for distinguishing CSS from other forms of sialadenitis.

Proposal of histological criteria for intraepithelial atypical/proliferative biliary epithelial lesions of the bile duct in hepatolithiasis with respect to cholangiocarcinoma: preliminary report based on interobserver agreement.

Biliary lining epithelia of the bile ducts in biliary diseases are known to have intraepithelial atypical/proliferative lesions related to the development of cholangiocarcinoma. The purpose of the present study was to determine the histological criteria for these lesions based on interobserver agreement. Digital images of 30 intraepithelial atypical/proliferative lesions in the stone-containing intrahepatic bile ducts of hepatolithiasis (30 cases) were sent to 10 pathologists. At first, 10 pathologists made a diagnosis (either of reactive/regenerative change, low-grade or high-grade biliary intraepithelial neoplasia (BilIN-1 and BilIN-2), or in situ carcinoma (BilIN-3)) based on their own criteria. The histological criteria for these four lesions were then determined, and the digital images of the same lesions with proposed criteria were re-distributed. Interobserver agreement on these four lesions was slightly improved (kappa = 0.44, first diagnosis; 0.49, second diagnosis) and intraobserver agreement was 'almost perfect' (kappa = 0.82 at both first and second diagnosis). Interobserver agreement between BilIN-1 and BilIN-2 and that between BilIN-2 and BilIN-3 were 'moderate', although the agreement between regenerative/reactive change and BilIN-1 was 'fair'. In this report, we propose histological criteria for reactive/regenerative change, BilIN-1, BilIN-2 and BilIN-3. Improvement of interobserver agreement suggests their applicability in diagnostic and research fields.

IgG4-related sclerosing cholangitis with and without hepatic inflammatory pseudotumor, and sclerosing pancreatitis-associated sclerosing cholangitis: do they belong to a spectrum of sclerosing pancreatitis?

Sclerosing cholangitis (SC) is a heterogeneous disease entity. Different etiologies such as choledocholithiasis, biliary tumor, or pericholangitis can manifest as SC. Hepatic inflammatory pseudotumor (IP) is rarely associated with SC (sclerosing cholangitis associated with hepatic inflammatory pseudotumor; SC-hepatic IP), but sclerosing pancreatitis (SP) is not infrequently associated with bile duct lesions (sclerosing pancreatitis-associated sclerosing cholangitis; SP-SC). In this study, we compared the histologic changes of hepatic hilar and extrahepatic bile duct lesions of SC (7 cases), SC-hepatic IP (5 cases), SP-SC (5 cases), and typical primary sclerosing cholangitis (PSC) (5 cases). Histologically, all SP-SC cases showed extensive and dense fibrosis with marked lymphoplasmacytic infiltration, many eosinophils, and obliterative phlebitis. Four cases of SC showed bile duct lesions similar to those of SP-SC, whereas other three cases of SC showed milder lymphoplasmacytic infiltration, scant eosinophilic cell infiltration, and no obliterative phlebitis. All SC-hepatic IP cases showed bile duct lesions identical to those of SP-SC. Immunohistochemically, many IgG4-positive plasma cells were found in the bile duct lesions of all SP-SC cases, 4 SC cases with marked lymphoplasmacytic infiltration, and all SC-hepatic IP cases. By contrast, IgG4-positive plasma cells were scarce or hardly found in the remaining 3 SC cases and all PSC cases. In conclusion, 4 SC cases and all SC-hepatic IP cases showed bile duct lesions identical to those of SP-SC, suggesting that these three conditions may be a single disease entity. Their pathogenesis may be similar or closely related to that of SP, and in that respect they may represent an IgG4-related biliary disease. They may respond to steroid therapy as SP does.

Results of wedge resection for focal bronchioloalveolar carcinoma showing pure ground-glass attenuation on computed tomography.

BACKGROUND: Focal bronchioloalveolar carcinoma (BAC) showing pure ground-glass attenuation (GGA) on thin-section computed tomography (CT), which is considered to be an early-stage adenocarcinoma, has been diagnosed with increasing frequency due to the development and spread of the helical CT scanner. We discussed the appropriateness of limited resection for this type of lesion. METHODS: Between July 1996 and June 2001, 17 patients with localized BAC showing "pure GGA" (GGA without central scar formation) on thin-section CT underwent limited pulmonary resections. The mean patient age was 57.2 +/- 10.5 years old. Among these patients, four tumors were detected in a CT mass-screening program and the others were incidentally detected on CT during follow-up for other diseases. Fourteen patients underwent thoracoscopic wedge resection, and 3 underwent segmentectomy because of tumor location. RESULTS: The mean tumor diameter was 7.9 +/- 1.9 mm. On pathological examination, all tumors showed a pure bronchioloalveolar growth pattern and no evidence of stromal, vascular, or pleural invasion. The median follow-up time was 32.0 months, with no cancer death or relapse to date. CONCLUSIONS: Focal BAC showing pure GGA on thin-section CT is peripheral in situ adenocarcinoma. Wedge resection by VATS is considered to be an appropriate treatment for this type of lung cancer. It can be a minimally invasive complete resection for this type of early cancer, and offer the best chance for long-term survival and good quality of life.

Reasons for the delays in the definitive diagnosis of lung cancer for more than one year from the recognition of abnormal chest shadows.

OBJECTIVE: Primary lung cancer generally has a poor prognosis if not diagnosed at an early stage. But some lung cancers grow very slowly. In particular, adenocarcinoma is sometimes observed for years with no change of tumor size. In this study, we examined the reasons for the delays in reaching a definitive diagnosis of lung cancer. METHODS: We retrospectively reviewed primary lung cancer cases between January 1995 and December 1999 and examined those whose definitive diagnoses were delayed for more than a year. RESULTS: A total of 222 primary lung cancers were diagnosed. Of those, 19 patients (group A, 8.6%) were diagnosed after more than a year, and the other 203 (group B, 91.4%) were diagnosed within one year. The proportion of women in group A was significantly higher than that in group B (p<0.05). The mean age of group A was significantly younger than that of group B (p<0.05). The Brinkman Index of group A was significantly lower than that of group B (p<0.05). The histologic types were significantly different between the two groups (p<0.05). In group A, 18 patients (94.7%) had adenocarcinomas. Five primary reasons for the delays in group A were identified: 1) Four patients were tentatively diagnosed as inflammation or benign tumor on CT and were consequently not followed-up. 2) The chest CT shadows in 6 patients were suspected lung cancers but transbronchial lung biopsy findings did not show malignancy. 3) Four patients were tentatively diagnosed as inflammation or benign tumor on CT, but the tumors showed only very slow growth or no change at all. 4) The chest CT shadows of 2 patients were suspected lung cancer, but the patients refused to undergo video-assisted thoracic surgery (VATS) or closer examination. 5) Three patients did not consult medical facilities for a second examination. CONCLUSIONS: Many of the adenocarcinomas reviewed in our study grew slowly or remained unchanged for years. Doctors are mainly responsible for the delays in the definitive diagnosis and should aggressively perform VATS or closer examinations without hesitation.

Diffuse mucosal carcinoma of intrahepatic and extrahepatic bile ducts including gallbladder.

An autopsy case with a widespread mucosal carcinoma of the biliary tree was reported. A biochemical profile of the bile duct damage was noticed in a woman in her seventies during a gastric examination. Imaging procedures depicted irregular dilatations of intrahepatic bile ducts with a bead-like appearance. Elevated levels of serum alkaline phosphatase and gamma-glutamyltransferase with a negative antimitochondrial antibody persisted. The patient was diagnosed as primary sclerosing cholangitis, she was followed up for 4 years under preservative therapies, and died of anasarca and heart failure. Post-mortem examination showed a diffuse mucosal carcinoma of both intrahepatic and extrahepatic biliary passages including the gallbladder with a minimal invasion and scattered foci of adenoma-like area in part. There was no evidence of gallstones or pre-existing sclerosing cholangitis. The striking features of the tumor were extensive papillary growth, mucus secretion and irregular dilatation of bile ducts. The tumor may bear biological and morphological homology with intraductal papillary mucinous tumor of the pancreas.