Appearance of large scavenger receptor A-positive cells in peripheral blood: A potential risk factor for severe exacerbation of chronic obstructive pulmonary disease.

Fresh peripheral blood (PB) samples from 432 outpatients with stable chronic obstructive pulmonary disease (COPD) were examined. Patients were classified into Group A (large SRA+ cells were undetected) and Group B (large SRA+ cells were detected) and followed-up for 1 year. Patients were further subdivided according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage. Cox proportional hazard model had shown that Gold, Group, home oxygen therapy (HOT), and treatment were significant predictors of severe exacerbation. Six of 353 patients in Group A and 29 of 79 in Group B developed severe exacerbation. The rates of severe exacerbation were significantly higher in Group B patients, GOLD stage 2 than Group A, GOLD stage 2; in Group B, GOLD stage 3 than Group A, GOLD stage 3; and in all of Group B compared with in all of Group A. The Kaplan-Meier curves of Group B, GOLD stages 1-4, and of all of Group B showed significantly worse rates of severe exacerbation than those of Group A, Gold 1-4, and all of Group A, respectively. The appearance of large SRA+ cells in the PB of patients with stable COPD may represent a useful biomarker for severe COPD exacerbation.

Acute exacerbation of IPF has systemic consequences with multiple organ injury, with SRA+ and TNF-α+ cells in the systemic circulation playing central roles in multiple organ injury.

BACKGROUND: The pathophysiologic mechanisms underlying acute exacerbation of idiopathic pulmonary fibrosis (IPF) are not fully understood. Few studies have examined autopsy findings in patients who have died from an acute exacerbation of IPF. The pathologic findings in systemic organs have not been described. METHODS: We retrospectively reviewed the autopsy findings in 12 patients who had died from an acute exacerbation of IPF and two of connective tissue disease- associated interstitial lung disease between 2005 and 2015. We recorded demographic and clinical characteristics, autopsy findings and cytologic findings in peripheral blood. RESULTS: The median age at autopsy was 68 years (range 45-87 years); 11 subjects (78.5 %) were men. High-dose corticosteroid, cyclophosphamide and oxygen therapy had been administered to all patients. Underlying lesions had the usual interstitial pneumonia pattern; diffuse alveolar damage and contraction band necrosis were observed in all cases. Large cells expressing scavenger receptor A (SRA+) had been observed in the systemic circulation of 11 of the 14 cases (78.6 %) before acute exacerbation, and cells expressing tumor necrosis factor-α (TNF-α+) were detected after its diagnosis in nine (64.3 %). Both were detected in all cases at autopsy. There was neutrophil and platelet accumulation predominantly in capillaries, and extensive capillary endothelial cells injury. CONCLUSIONS: Our findings suggest that acute exacerbation of IPF has systemic consequences with multiple organ injury, with SRA+ and TNF-α+ cells in the systemic circulation playing central roles in multiple organ injury.

Minute lesions of alveolar damage in lungs of patients with stable idiopathic pulmonary fibrosis.

AIMS: To investigate the mechanisms underlying the acute exacerbation of idiopathic pulmonary fibrosis, and in particular the role of minute lesions of alveolar damage. METHODS AND RESULTS: We examined surgical lung biopsy samples from 38 patients with stable idiopathic pulmonary fibrosis, and evaluated the association between the foci and development of acute exacerbation. Mild extravasation, probably resulting from lung injury and intra-alveolar oedema fluid, were observed in narrow areas of architecturally intact lung tissue. Minute lesions of alveolar damage were detected in these areas. Alveolar epithelial cells in these lesions were injured. Hypoxia-inducible factor-2α-positive macrophages, tumour necrosis factor-α-positive macrophages and neutrophils had accumulated in alveolar spaces in and around these lesions. Cases were classified into patients without (17) and with (21) minute lesions of alveolar damage. Development to acute exacerbation (five cases) occurred only in patients with minute lesions of alveolar damage (P = 0.03). CONCLUSIONS: The formation of minute lesions of alveolar damage may be initiated by hypoxia, and such lesions play important roles in the development of acute exacerbation.

Malignant peripheral nerve sheath tumor of the trigeminal nerve: clinicopathologic features in a young adult patient.

Malignant peripheral nerve sheath tumors (MPNSTs) arising from cranial nerves are rare and usually affect adults. Here we report the clinicopathologic features of a young adult patient with a trigeminal nerve MPNST, in whom another tumor involving the oculomotor nerve on the contralateral side was evident. The patient, an 18-year-old woman, had suffered recurrent paroxysmal sharp stabbing pain over her cheek and forehead on the right side for 1 month. A brain MRI study disclosed a mass, 35 mm in diameter, in the right Meckel's cave, and another mass, 10 mm in diameter, involving the intracranial portion of the left oculomotor nerve. Following gadolinium administration, the former and latter tumors exhibited strong and weak enhancement, respectively. The patient had no clinical stigmata characteristic of neurofibromatosis type 1. Following a tentative diagnosis of schwannoma, total resection of the trigeminal nerve tumor was performed. Histologically, the tumor consisted of highly cellular, spindle-shaped cells arranged in a fascicular pattern, with occasional mitotic figures, nuclear pleomorphism and necrosis. Immunohistochemically, the tumor cells showed variable intensities and frequencies of reactivity for S-100 protein, myelin basic protein, CD34, podoplanin and p53, but no reactivity for Smarcb1. Thus, the tumor exhibited features of MPNST. This case appears to provide information that is useful for accurate diagnosis and surgical planning in patients with bilateral or multiple cranial nerve tumors.

A case of aseptic abscesses syndrome treated with corticosteroids and TNF-alpha blockade.

Aseptic abscesses syndrome (AA) is an emerging clinicopathological entity characterized by visceral sterile collections of mature neutrophils that do not respond to antibiotics but regress quickly when treated with corticosteroids. Although most previous case reports of AA have been restricted to Europe, we present here a Japanese woman with AA showing recurrence of splenic abscesses, ileocolitis, pyoderma gangrenosum, and arthritis. Although both steroid therapy and tumor necrosis factor (TNF)-alpha blockade were effective, relapses remained frequent.

Apoptotic cells in peripheral blood and multiple organ injury.

To evaluate the roles of apoptotic cells in peripheral blood (PB) on multiple organ injury, five patients with hematopoietic stem cell transplantation (HSCT) and one with refractory anemia were examined. The following findings were confirmed. 1) High-dose alkylating agents were administrated as conditioning regimens to all HSCT patients. 2) Many organs were injured in all cases. 3) Neutrophils accumulated in the capillaries of injured organs, and endothelial cells were extensively injured. 4) Large numbers of apoptotic cells and γH2AX(+) cells were observed in the foci of large cells with hyperchromatic nuclei. 5) Increased numbers of apoptotic cells (6/6), γH2AX(+) cells (6/6), scavenger receptor A positive (SRA(+) ) cells (6/6), and tumor necrosis factor (TNF)-α(+) cells (5/6) were observed in PB smear preparations. 6) Cytokines exceeded the normal levels in most patients. From these findings, apoptotic cells were considered to be produced by the administration of high-dose alkylating agents in HSCT patients, and apoptotic cells and SRA(+) cells in PB were thought to play important roles in the development of multiple organ injury in HSCT and MDS patients.

Lymphoplasmacyte-rich meningioma: a convexity mass with regional enhancement in the adjacent brain parenchyma.

Lymphoplasmacyte-rich meningioma (LPM) is a rare, benign variant of meningioma, characterized by massive inflammatory cell infiltration and a variable proportion of meningothelial tumorous elements. Here we report the clinicopathological features of an LPM located at the right frontal convexity in a 37-year-old woman. The patient had suffered an initial generalized tonic-clonic seizure when she was 32 weeks pregnant. The lesion exhibited low intensity on T1-weighted MRI and high intensity on T2-weighted images, with surrounding parenchymal edema. The mass exhibited gadolinium enhancement with dural tail signs. Moreover, multiple foci of linear enhancement spreading through the sulci and into the nearby brain parenchyma were evident. At 1 month after parturition, en bloc removal of the mass, the attached dura mater and adjacent brain tissue was performed. Histologically, the mass located in the subdural space was composed of a mixture of B- and T-lymphocytes and plasma cells. Within the mass, multiple small lobules of meningothelial cells showing immunoreactivity for epithelial membrane antigen and vimentin were observed. The inflammatory cells had also infiltrated the subarachnoid and Virchow-Robin spaces, and the dura mater. The cerebral cortex showed ischemic changes, but no tumor cell invasion. On the basis of these histological features, the lesion appeared to be LPM with an inconspicuous meningothelial component and extensive inflammatory infiltration. This case appears to provide useful information on the pathogenesis of this variant.

Vertebral basilar system dolichoectasia with marked infiltration of IgG4-containing plasma cells: a manifestation of IgG4-related disease?

We report the histopathological features of vertebral basilar system dolichoectasia (VBD) in a 68-year-old man who died as a result of accompanying infarction of the medulla oblongata on day 6 of admission. During hospitalization, the patient was also found to have an elevated serum IgG level and tumors of the renal pelvis. A possible clinical diagnosis of VBD associated with IgG4-related disease was considered postmortem. Autopsy examination, limited to the intracranial tissues, revealed marked infiltration of IgG4-containing plasma cells in the adventitia and media of the vertebral and basilar arteries. Multiple fibrous nodules forming pseudotumors were also evident on the outer surface of the affected arteries. These histological features were very similar to those of arteriopathy, such as inflammatory aortic aneurysm, which has been described in patients with IgG4-related disease, suggesting that autoimmune mechanisms, known to be involved in the pathogenesis of visceral lesions in the disease, also played a role in the etiology of VBD in the present patient. In conclusion, we consider that the present case may represent VBD as a manifestation of IgG4-related disease.

Plasma cells and the chronic nonsuppurative destructive cholangitis of primary biliary cirrhosis.

UNLABELLED: There has been increased interest in the role of B cells in the pathogenesis of primary biliary cirrhosis (PBC). Although the vast majority of patients with this disease have anti-mitochondrial antibodies, there is no correlation of anti-mitochondrial antibody titer and/or presence with disease severity. Furthermore, in murine models of PBC, it has been suggested that depletion of B cells may exacerbate biliary pathology. To address this issue, we focused on a detailed phenotypic characterization of mononuclear cell infiltrates surrounding the intrahepatic bile ducts of patients with PBC, primary sclerosing cholangitis, autoimmune hepatitis, chronic hepatitis C, and graft-versus-host disease, including CD3, CD4, CD8, CD20, CD38, and immunoglobulin classes, as well as double immunohistochemical staining for CD38 and IgM. Interestingly, CD20 B lymphocytes, which are a precursor of plasma cells, were found in scattered locations or occasionally forming follicle-like aggregations but were not noted at the proximal location of chronic nonsuppurative destructive cholangitis. In contrast, there was a unique and distinct coronal arrangement of CD38 cells around the intrahepatic ducts in PBC but not controls; the majority of such cells were considered plasma cells based on their expression of intracellular immunoglobulins, including IgM and IgG, but not IgA. Patients with PBC who manifest this unique coronal arrangement were those with significantly higher titers of anti-mitochondrial antibodies. CONCLUSION: These data collectively suggest a role for plasma cells in the specific destruction of intrahepatic bile ducts in PBC and confirm the increasing interest in plasma cells and autoimmunity.

Biochemical, cytological and histopathological examination of sudden unexpected death in infancy.

To evaluate the pathophysiological mechanisms underlying sudden infant death syndrome (SIDS), four sudden unexpected death in infancy (SUDI) and four sudden deaths in children over 1 year of age were examined. In the SUDI cases, increased numbers of scavenger receptor A positive (SRA(+) ) cells (4/4), numerous platelet aggregates (3/4), and tumor necrosis factor (TNF)-α(+) cells (4/4) were observed in the peripheral blood (PB) smear preparations. Macrophage colony stimulating factor, interleukin (IL)-6, IL-8, TNF-α and IL-1ß all exceeded the normal levels. Minute foci of inflammatory lung injury (4/4), numerous platelet emboli in lungs and among cardiac myocytes (3/4) and appreciable contraction band necrosis (1/4) were observed. And neutrophils accumulated in the capillaries of injured organs and endothelial cells were extensively injured. From these findings, cytokine abnormality induced by SRA(+) cells in PB was considered to play an important role in the development of tissue injury, and platelet emboli or contraction band necrosis might have been the leading cause of death in our SUDI cases. Patients with characteristics thought to be similar to our SUDI cases were included in the SIDS group; cytokine abnormality was considered to be one of the underlying mechanisms in SIDS.

Scavenger receptor A index and coronary thrombus in patients with acute ST elevation myocardial infarction.

To examine the relationship between the scavenger receptor A (SRA) index (the number of SRA+ cells observed in 10 high power fields of peripheral blood (PB) smear samples; normal upper limit <30) and coronary thrombus, 389 thrombi obtained from 393 patients with acute ST elevation myocardial infarction were examined. Thrombi were classified into platelets (PT), mixed (MT), fibrin-rich (FT) and organizing thrombi (OT); 387, 269, 57 and 29 cases were detected, respectively. Patients were divided into group A (PT only, 89 cases), B (containing MT and PT but not FT, 243 cases), and C (containing FT, 57 cases). SRA+ cells had infiltrated into all FT cases and 147 of the 269 MT, but no PT. At hospitalization, the SRA index exceeded 30 in 276 patients. PT was observed in 274 cases, and MT and FT (residual mural thrombus; RMT) observed in 230. Infarct-related coronary artery was thought to be totally and rapidly occluded by PT that had formed as a result of severe stenosis due to extrusion of plaque content or growth of RMT. An abnormal increase of SRA+ cells is considered to be a useful finding to detecting the presence of PT and, probably, RMT.

Appearance of large scavenger receptor A-positive cells and increased small scavenger receptor A positive cells in peripheral blood is associated with mortality in systemic inflammatory response syndrome and multiple organ dysfunction syndrome.

We investigated the association of scavenger receptor A-positive (SRA(+) ) cells in peripheral blood (PB) with mortality in subjects with systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS). A total of 467 subjects with SIRS (62 of 467 satisfied the diagnostic criteria of MODS) were prospectively examined. The subjects were classified into three groups according to the SRA index (number of small SRA(+) cells in 10 high power field, normal upper limit < 30) and the appearance of large SRA(+) cells as follows: group A, large SRA(+) cells were not detected; group B, large SRA(+) cells were detected but SRA index did not exceed 30; group C, the two factors (appearance of large SRA(+) cells and SRA index > 30) coincided. The duration from the diagnosis of SIRS to death in groups A and B was significantly shorter than in group C. The mortality rate in group C was significantly higher than in groups A and B. Kaplan-Meier curves of group C showed significantly worse survival than groups A and B. These results indicate that the coincidence of two factors (appearance of large SRA(+) cells and SRA index > 30) may be useful to predict the outcome in patients with SIRS or MODS.

Hepatocellular carcinoma, with portal thrombus after viral eradication, disappeared by 5-fluorouracil and interferon.

Hepatocarcinogenesis after a sustained virological response (SVR) in type C chronic hepatitis and cirrhosis is an important issue in endemic areas; hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) therapy is especially very hard. We herein report a first case in which combination therapy with interferon-α and continuous intra-arterial infusion of 5-fluorouracil (designated as FAIT) provided a complete response in HCC with PVTT after SVR. Therefore, we think that FAIT is a good option to treat HCC with or without PVTT, even after SVR.

TTF-1 is useful for primary site determination in duodenal metastasis.

We report here on a case of duodenal metastasis from primary lung adenocarcinoma. A 69-year old man was diagnosed with primary lung adenocarcinoma. Four courses of combined chemotherapy with carboplatin and paclitaxel associated with irradiation of 60 Gy shrunk the lung tumor. However, soon after,the para-aortic lymph node became swollen. Esophagogastroduodenoscopy revealed three duodenal tumors. Differential diagnosis between malignant lymphoma and metastatic duodenal cancer was endoscopically difficult. The histology of biopsied specimens was poorly differentiated adenocarcinoma. Immunohistochemical analysis revealed a positive reaction for thyroid transcription factor-1 (TTF-1). Thus, we concluded that these were metastatic duodenal tumors from lung adenocarcinoma. Two courses of gemcitabine led to a complete remission in this duodenal metastasis and para-aortic lymph node swelling with only scarring remaining in computed tomography. He is now on the continuous generalized chemotherapy. In conclusion, duodenal metastasis from primary lung adenocarcinoma is rare and hard to diagnose. In such an instance, TTF-1 immunostaining is crucial to obtain the correct diagnosis.

[Case of visceral varicella-zoster virus infection after autologous peripheral blood stem cell transplantation in which severe abdominal pain preceded the skin rash].

We report a 54-year-old man who developed visceral varicella-zoster virus (VZV) infection after autologous peripheral blood stem cell transplantation (auto-PBSCT) without using immunosuppressive agents for multiple myeloma. He suffered from severe abdominal pain 2 months after auto-PBSCT, and morphine chloride was needed to control it. Since the characteristic skin rash of VZV infection appeared over his entire body on the seventh hospital day, aciclovir was immediately started with favorable results. It is extremely difficult to diagnose VZV infection when severe abdominal pain proceeds and the eruptions characteristic of VZV infections are absent. This may also result in devastating delays in effective antiviral treatment. The increase in fat density around the celiac trunk and the root of the superior mesenteric artery on computed tomography shown in this case may has contributed to the correct diagnosis of visceral VZV infection.

Histopathological and cytological examination of autopsy cases with multiple organ dysfunction syndromes.

To evaluate the role of small scavenger receptor A (SRA)-positive (SRA(+)) cells and large SRA(+) cells in the peripheral blood (PB) in the pathophysiological mechanisms underlying multiple organ dysfunction syndromes (MODS), 24 autopsy cases with MODS were examined. In addition to histopathological and immunohistochemical examination, cytokine levels of cardiac blood, the SRA index (number of small SRA(+) cells in 10 high power fields, upper limit <30), and appearance of large SRA(+) cells in PB were examined. The SRA index exceeded 30 in all cases. Large SRA(+) cells and tumor necrosis factor (TNF)-alpha(+) cells were detected in PB in all cases. Macrophage colony stimulating factor (M-CSF), interleukin (IL)-6 and IL-8 levels exceeded the normal level in all cases, and 18 and 15 cases had TNF-alpha and IL-1beta levels above the normal threshold, respectively. Lung injury and necrosis of cardiac myocyte were observed in all cases. Neutrophils and platelets accumulated in the capillaries of injured organs and endothelial cells were extensively injured. From these results, large SRA(+) cells differentiated from monocytes in PB were considered to play an important role in the development of MODS, and necrosis of cardiac myocytes together with lung injury might be the leading cause of death in MODS patients.

Intestinal anisakiasis can cause intussusception in adults: an extremely rare condition.

We report an extremely rare case of adult intussusception caused by anisakiasis. A 41-year-old man was admitted into our hospital for right lower abdominal colicky pain. Ultrasonography and computed tomography revealed the presence of intussusception. As pneumo-dynamic resolution by colonoscopy failed, surgery was performed. The anisakis body was found in the submucosal layer of the resection specimen. The patient was discharged 9 d after the operation. Anisakiasis may cause intussusception in any country where sushi or sashimi now exists as a popular food. If suspicious, detailed clinical interview as to food intake prior to symptom development is crucial.

[A case of intestinal tuberculosis associated with ileo-ileal fistula].

A 25-year-old woman was admitted with fever and right lower abdominal pain that had started 3 days after the administration of antituberculosis agents for pulmonary tuberculosis. She was given a diagnosis of intestinal tuberculosis with ileo-ileal fistula formation on computed tomography, colonoscopy and laboratory test findings. She was kept on anti-tuberculosis agents. Soon after, ileus and a micro abscess appeared near the fistula. Ileocecal resection with partial ileal resection resulted in a good postoperative clinical course. Tuberculosis is still a major infectious disease. Intestinal tuberculosis is very rarely associated with fistula formation, and when it occurs, is difficult to differentiate from Crohn disease. Our case strongly suggests that typical intestinal tuberculosis findings can help in differential diagnosis between intestinal tuberculosis and Crohn disease.

Thyroid Metastasis of Gastric Cancer: A Rare Occasion With Poor Prognosis.

A 68-year-old man was diagnosed as having advanced gastric cancer. Computed tomography showed a thyroid tumor with trachea deviation. This tumor exhibited mosaic echogenecity in ultrasonography. Signet-ring cell carcinoma was found by means of fine needle aspiration biopsy. This tumor gradually became swollen and the thyroid hormone levels in blood were increased without any clinical symptom. Shortly, he died from his illness in the 29th hospital day. Autopsy disclosed that the left lobe of the thyroid gland was highly invaded by malignant cells and that lymphogenic rather than angiogenic metastasis was highly probable. Thyroid metastasis of gastric cancer is extremely rare. The prognosis is very poor. Ultrasonography is a very useful modality especially when coupled with recently developed fine needle aspiration biopsy in differential diagnosis of thyroid tumors once malignancy is suspected. Therapeutic strategy largely depends on the nature of primary malignant tumor. If the tumor is slowly progressive such as renal cell carcinoma and breast cancer, extirpation of thyroid tumors may extend life expectancy. In conclusion, the metastatic thyroid tumor of gastric cancer is rare and shows poor prognosis. Fine needle aspiration biopsy under ultrasonography is strongly recommended as a useful diagnostic tool.

Limited resection for noninvasive bronchioloalveolar carcinoma diagnosed by intraoperative pathologic examination.

BACKGROUND: The establishment of limited resection procedures for non-small cell lung cancer is expected. Many groups have suggested noninvasive bronchioloalveolar carcinoma (BAC) to be a potential indication for limited resection. METHODS: We designed a prospective phase II study evaluating limited resection for noninvasive BAC diagnosed by intraoperative pathologic examination. From 1999 to 2007, limited resection was the procedure in 46 patients (16 men and 30 women; median age, 69 years; range, 49 to 83) who were diagnosed intraoperatively as having noninvasive BAC. The first end point was the predictive value of the intraoperative pathologic examination for noninvasive BAC diagnosis. The second end point was overall survival, disease-free survival, and cancer-specific survival, calculated using the Kaplan-Meier method. RESULTS: We performed wedge resections for 44 patients and segmentectomy for 2 patients. Permanent pathologic examination revealed 3 patients had primary lung adenocarcinomas other than noninvasive BAC. The predictive value of intraoperative pathologic examination for noninvasive BAC diagnosis was 94%. During a median 51-month follow-up, there were only 2 cancer unrelated deaths. The 5-year overall survival rate and the disease-free survival rate were 93%, and the 5-year cancer-specific survival rate was 100%. CONCLUSIONS: The results of our prospective phase II study indicate that limited resection, mainly by wedge resection, is a potentially curative surgical procedure and may be an acceptable alternative to lobectomy for patients with noninvasive BAC. Furthermore, an intraoperative pathologic diagnosis of noninvasive BAC is strongly predictive and allows for an intraoperative decision to perform a limited resection in these patients.