Establishment and characterization of a novel VEGF-producing HHV-8-unrelated PEL-like lymphoma cell line, OGU1.

Primary effusion lymphoma (PEL) is a rare B-cell lymphoma subtype that is characterized by lymphomatous effusion without the presence of masses, and it typically occurs in human immunodeficiency virus (HIV)-infected individuals. Lymphoma cells are universally positive for human herpesvirus 8 (HHV-8). Recently, a cavity-based effusion lymphoma that is similar to PEL without HHV-8 infection, called HHV-8-unrelated PEL-like lymphoma, has been reported in non-HIV-infected individuals. However, the pathophysiology of this lymphoma is largely undefined. We established a novel B-cell line OGU1 derived from a patient with HHV-8-unrelated PEL-like lymphoma. Notably, OGU1 cells produced vascular endothelial growth factor (VEGF) and expressed VEGF receptor 1, whose inhibitors retarded cell growth. Because VEGF acts as a vascular permeability and growth factor, it could play a role, at least in part, in the pathogenesis of this unique lymphoma. Thus, the OGU1 cell line is useful for the investigation of HHV-8-unrelated PEL-like lymphoma.

Peristomal pagetoid spread of urothelial carcinoma of the ureter.

Patients with ostomy including urinary stoma often develop peristomal complications, especially skin damage. The patient in this case was a 69-year old female with a history of urothelial carcinoma of the bladder and left ureter who underwent transurethral resection of a bladder tumor, nephroureterectomy and cystectomy combined with ureterocutaneostomy. Later, she had recurrence of urothelial carcinoma in the remaining ureter that spread to the peristomal epidermis, with a skin appearance resembling Paget's disease. We report this case based on its clinical significance since we believe it is the first description of this condition in the literature.

Recurrent solitary fibrous tumor of the pleura with malignant transformation and non-islet cell tumor-induced hypoglycemia due to paraneoplastic overexpression and secretion of high-molecular-weight insulin-like growth factor II.

A 41-year-old man was diagnosed with a solitary fibrous tumor (SFT) of the pleura in the posterior mediastinum. Despite two surgeries for excision, the SFT recurred and progressed with direct invasion of the chest wall and bone metastases. He was hospitalized because of cerebral infarction and presented with recurrent severe hypoglycemia fourteen years later. High-molecular-weight (HMW) insulin-like growth factor II (IGF-II) was identified in the serum and tumor using Western blotting and immunohistochemistry. These findings suggested that the cause of the recurrent severe hypoglycemia was SFT production of HMW IGF-II, a mediator of non-islet cell tumor-induced hypoglycemia (NICTH).

Non-secretory immunoglobulin E myeloma associated with immunoglobulin G monoclonal gammopathy of undetermined significance.

A 68-year old woman came to our hospital with a severe case of anemia. Serum immunoelectropheresis identified a monoclonal immunoglobulin (Ig) G and κ protein. The serum IgE level was within the nomal range and the amounts of remaining immunogloblins were low. On bone marrow aspirate, plasma cells made up 55.5% of nucleated cells and the plasma cells showed positive readings for IgE κ and IgG by immunohistochemistry. Serum immunofixation did not reveal the IgE monoclonal band. She was diagnosed as having non-secretory IgE myeloma with IgG monoclonal gammopathy of undetermined significance. The nature of this rare myeloma will be discussed.

Glucocorticoid- and androgen-secreting black adrenocortical adenomas: unique cause of corticotropin-independent Cushing syndrome.

OBJECTIVE: To describe the unique association of corticotropin-independent Cushing syndrome caused by cortisol- and androgen-secreting black adrenal cortical adenomas with myelolipomatous change. METHODS: We report the clinical, laboratory, radiologic, and pathologic findings from 2 patients who presented with androgen excess and typical signs and symptoms of Cushing syndrome. RESULTS: Endocrine investigations showed high serum cortisol concentrations that lacked diurnal rhythm, undetectable plasma corticotropin concentrations, and absence of serum cortisol suppression after overnight dexamethasone suppression tests. Serum levels of adrenal androgens were elevated. Computed tomography of the abdomen revealed unilateral adrenal masses (largest lesional diameters 4.0 and 3.1 cm). On the basis of the plurihormonal hypersecretion and the imaging characteristics, adrenocortical carcinoma was considered as a possible diagnosis. However, histopathologic analysis in both patients revealed black adrenal cortical adenomas with myelolipomatous change. After surgery, adrenal androgens normalized, and the signs and symptoms of Cushing syndrome and androgen excess resolved. There was no evidence of recurrent disease at last follow-up. CONCLUSIONS: A unique form of corticotropin-independent Cushing syndrome is described: cortisol- and androgen-secreting black adrenal cortical adenomas with myelolipomatous change. Although most patients with corticotropin-independent Cushing syndrome associated with androgen excess prove to have adrenocortical carcinoma, the clinician should be aware of the possibility of benign, black adrenal adenomas in this clinical setting.

Alteration of subcapsular adrenocortical zonation in humans with aging: the progenitor zone predominates over the previously well-developed zona glomerulosa after 40 years of age.

Few studies have examined functional adrenal zonation throughout human life. Adrenals from 61 surgical/autopsy patients from 1 day old to 92 years old who had no clinical endocrinological/mineralocorticoid abnormalities were assessed for immunohistochemically defined adrenal zonation. The zona glomerulosa (zG) was well developed in all 11 patients ranging in age from newborn to the 30s. After 40 years of age, however, the zG occupied less than one-quarter of the adrenal circumference, suggestive of zG involution. The other subcapsular areas were occupied by the progenitor zone (zP), which expressed neither cytochrome P450(aldo) nor P450(11ß) but 3ß-hydroxysteroid dehydrogenase and P450scc, although some autopsy cases had adrenals with zG zonation because of secondary aldosteronism, and others who had experienced severe stresses showed subcapsular zona fasciculata (zF). In conclusion, the adrenal cortex consists of homogeneous zG-topped columns from birth to adolescence. Subsequently, in the fifth decade of life, the cortex is reconstituted by integration of three types of cortical columns: scattered zG-topped columns and zonal zP-topped columns, the latter having the ability for bidirectional differentiation into either zG-topped columns or zF-topped columns, according to secondary aldosteronism or the presence of severe stresses. Such adrenocortical remodeling is ascribed to high-sodium/low-potassium diets.

A rare benign genitourinary tumor in a Japanese male: urinary retention owing to aggressive angiomyxoma of the prostate.

Close examination of a 67-year-old Japanese man, who complained of persistent nocturia, revealed that a semitransparent polypoid tumor had developed from the bladder neck to the prostatic urethra obstructing the internal urethral meatus, which resulted in excessive urinary retention and post-renal dysfunction. The tumor was resected by a transurethral procedure and a pathological examination of specimens revealed aggressive angiomyxoma (AAM) of the prostate. AAM usually develops in the intrapelvic and perineal organs of females. So far as we know, this is the second case of primary prostatic AAM reported in the English literature, and is the first case where the patient encountered urethral obstruction.

A case of primary renal angiosarcoma.

A 78-year old man was diagnosed with a left bleeding renal cyst from CT scan results. Serial CT scans revealed the left kidney mass to be increasing in size and a new lesion in the liver. Renal cell carcinoma with liver metastasis was diagnosed and a radical nephrectomy performed. The initial pathological diagnosis was a benign chronic hematoma. However, the liver mass increased in size and multiplied, while another mass emerged in the twelfth thoracic vertebra with spinal paralysis and was immediately removed. Pathological findings for that specimen showed malignancy of stromal cell origin but low atypia. The renal specimen was re-evaluated using whole cross-section analysis and immunohistochemistry, and diagnosed as a primary renal angiosarcoma. Recombinant interleukin-2 therapy was started immediately; however, the patient died of metastatic disease 13 months after the initial operation. Although contrast imaging depicted the primary lesion as a non-specific hematoma with little focal pooling, and low-grade cytological atypia was shown pathologically, the angiosarcoma was extremely aggressive.

A Case of Benign Schwannoma of the Transverse Colon with Granulation Tissue.

Schwannomas occurring in the gastrointestinal tract are rare, and among them, schwannomas of the large intestine are extremely rare. In this paper, we report a case of a macroscopically atypical schwannoma of the transverse colon. The case is a female aged 67. Stool occult blood test was positive, and colonoscopy revealed a protruded lesion resembling a type 1 carcinoma measuring 4 cm with a reddish and uneven surface on the transverse colon. The surface was smooth and lobulated in observation with indigo carmine spray, and granulation tissue was revealed by biopsies. CT of the abdomen showed an irregular mass, and clinical examinations could not rule out malignancy. Therefore, partial transverse colectomy with peripheral lymph node dissection was performed. Histologically, proliferation of spindle cells was observed originating from the muscularis propria, and most of the upper part of the lesion was replaced by granulation tissue. In immunohistochemical staining, S-100 protein and NSE were positive while KIT, CD34, desmin and smooth muscle actin were negative, and the tumor was therefore diagnosed to be a schwannoma. In addition, since the MIB-1 labeling index was low and virtually no mitosis was observed, it was diagnosed as benign tumor.

Penile malignant melanoma in a hemodialysis patient.

A patient who was receiving hemodialysis treatment developed melanotic macules on the surface of the penis in 2002 and showed a tumor-like mass in the same region in July 2006. The patient presented with a pedunculated tumor of 3 cm in diameter on the right side of his penis. The tumor was resected for biopsy and was diagnosed as malignant melanoma. The melanoma was in stage IIIB with pT4 N1 M0. The patient received interferon-beta for a total of three courses. A computed tomography scan in the 10th postoperative month did not find any additional metastatic foci or recurrence of the tumor. In the present case, side effects caused by interferon were not observed. Therefore, particularly in dialysis patients, immune therapy might be favored over anticancer drug treatment.

Unruptured pseudoaneurysm of the cystic artery with acute calculous cholecystitis incidentally detected by computed tomography.

Pseudoaneurysm of the cystic artery is rare; to our knowledge, fewer than 30 cases have been reported worldwide. We report the first case of an unruptured pseudoaneurysm of the cystic artery with concurrent acute calculous cholecystitis. We incidentally detected the aneurysm by contrast-enhanced computed tomography (CT) in the edematous, thickened wall of the gallbladder neck in a 71-year-old man, whereas in most of the reported cases the disease presented as hemobilia. Because of the high risk of aneurysm rupture in this location, we avoided such interventions as percutaneous cholecystostomy and laparoscopic cholecystectomy. The aneurysm was localized pathologically in the undisrupted gallbladder wall, and elective open cholecystectomy with ligation of the cystic artery was performed successfully. Our case highlights the usefulness of CT for both diagnosis and patient management. Open cholecystectomy with ligation of the cystic artery is demonstrated as a reasonable first line of treatment for this unusual condition.

Occult lung cancer incidentally found during surgery for esophageal and gastric cancer: a case report.

A 70-year-old male was admitted to our hospital because of advanced esophageal squamous cell carcinoma and early gastric adenocarcinoma. A esophagectomy and partial gastrectomy with three-field lymph node dissection (neck, mediastinum and abdomen) was performed. Both tumors had lymph node metastases. In addition, three mediastinal lymph nodes (two subcarinal lymph nodes and a middle thoracic paraesophageal lymph node) were involved with adenocarcinoma. To elucidate whether they were metastases from the gastric cancer, an immunohistochemical analysis was performed. The cancer cells in these lymph nodes were positive for cytokeratin (CK) 7 and negative for CK 20, thus suggesting metastasis from a nondigestive organ. Interestingly, they were positive for thyroid transcription factor 1 (TTF-1), indicating metastasis from a lung cancer. Since the preoperative computed tomographic scan showed no evidence of lung cancer, a diagnosis of metastases from an occult lung cancer was finally recorded. Ten months after surgery, the patient was alive without a recurrence or the appearance of a lung cancer.

Induction of an epithelial integrin alphavbeta6 in human cytomegalovirus-infected endothelial cells leads to activation of transforming growth factor-beta1 and increased collagen production.

Human cytomegalovirus (CMV) infection is a major cause of morbidity in immunosuppressed individuals, and congenital CMV infection is a leading cause of birth defects in newborns. Infection with pathogenic viral strains alters cell-cell and cell-matrix interactions, affecting extracellular matrix remodeling and endothelial cell migration. The multifunctional cytokine transforming growth factor (TGF)-beta1 regulates cell proliferation, differentiation, and extracellular matrix remodeling. Secreted as a latent protein complex, TGF-beta1 requires activation before binding to receptors that phosphorylate intracellular effectors. TGF-beta1 is activated by integrin alphavbeta6, which is strongly induced in the epithelium by injury and inflammation but has not previously been found in endothelial cells. Here, we report that CMV infection induces integrin alphavbeta6 expression in endothelial cells, leading to activation of TGF-beta1, signaling through its receptor ALK5, and phosphorylation of its intracellular effector Smad3. Infection of endothelial cells was also found to stimulate collagen synthesis through a mechanism dependent on both TGF-beta1 and integrin alphavbeta6. Immunohistochemical analysis showed integrin alphavbeta6 up-regulation in capillaries proximal to foci of CMV infection in lungs, salivary glands, uterine decidua, and injured chorionic villi of the placenta, demonstrating both its induction in endothelium and up-regulation in epithelium in vivo. Our results suggest that activation of TGF-beta1 by integrin alphavbeta6 contributes to pathological changes and may impair endothelial cell functions in tissues that are chronically infected with CMV.

Epirubicin and cyclophosphamide followed by docetaxel as primary systemic chemotherapy in locally advanced breast cancer.

BACKGROUND: The aim of this study was to evaluate the activity and toxicity of epirubicin and cyclophosphamide (EC) followed by docetaxel as primary systemic chemotherapy (PST) in locally advanced breast cancer. PATIENTS AND METHODS: In this phase II trial, 46 patients with locally advanced breast cancer (T > 3 cm or N > 1) received epirubicin (90 mg/m2) and cyclophosphamide (600 mg/m2) every 3 weeks for four cycles, followed by docetaxel (70 mg/m2) every 3 weeks for four cycles. Primary endpoints were pathological and objective response in the breast and axilla, and toxicities. RESULTS: The clinical response rate was 80.4% (95% confidence interval, 68.9-91.9%). Pathological response evaluation revealed 6 complete responses (CR: 13.0%). Patients with ER-negative tumors had a significantly higher rate of pathological CR than the others (33.3% vs. 3.2%; p = 0.0105). Febrile neutropenia occurred in 4 patients (8.7%). CONCLUSION: EC followed by docetaxel is an active and well-tolerated treatment as PST for locally advanced breast cancer.

[2-year complete remission after withdrawal of methotrexate in a rectal methotrexate-associated diffuse large B-cell lymphoma].

A 71-year-old man, who had been receiving methotrexate (MTX) and prednisolone for the treatment of rheumatoid arthritis, was admitted to our hospital in August of 2004 with rectal hemorrhage. Histological examination of an ulcerative lesion of the rectum revealed diffuse large B-cell lymphoma (DLBCL). Chemotherapy with the CHOP regimen with dose reduction following cessation of MTX was initiated. However, the patient experienced septic shock secondary to febrile neutropenia and was then followed up without chemotherapy. The DLBCL rectal lesion regressed spontaneously thereafter and had resolved completely without treatment 2 years after the initial presentation, suggesting that the withdrawal of MTX led to regression of the DLBCL. The DLBCL in our patient is compatible with MTX-associated lymphoproliferative disorders. Immunoglobulin gene rearrangement and Epstein-Barr virus (EBV) infection found in tumor cells indicated that the EBV was involved in the monoclonal proliferation of B-cells in this patient whose immune function was suppressed by MTX therapy.

Acquired factor V inhibitor responsive to corticosteroids in a patient with double cancers.

A 70-year-old woman suffering from HCV-related liver cirrhosis was admitted for abnormal bleeding. Laboratory findings included PT at 46.6 sec, APTT at >212 sec, factor V activity of <3%, and factor V inhibitor of 2 BU. Having experienced a persistent bleeding tendency for one month, the patient was started on prednisolone (0.8 mg/kg/day). Within a few days, the inhibitor became undetectable and clinical bleeding disappeared. Although clinical improvement was achieved, she died 6 months after the initial bleeding episode from the progression of a lung cancer. An autopsy revealed squamous cell carcinoma of the lung and hepatocellular carcinoma.

Collision carcinoma of the residual cervical esophagus 27 years after esophageal cancer surgery.

A case of collision carcinoma (squamous cell carcinoma and Barrett's adenocarcinoma) in the residual cervical esophagus of a 68-year-old woman at 27 years after subtotal esophagectomy for thoracic esophageal carcinoma is reported. The patient initially noticed cervical dysphagia in 2002, but did not seek treatment. In April 2004, the patient was referred to our department by a local physician with the diagnosis of carcinoma of the cervical esophagus. In September 2004, the patient underwent resection of the cervical esophagus and partial resection of the gastric tube combined with cervical lymph node dissection under a diagnosis of double cancer (i.e., metachronous cervical esophageal carcinoma and carcinoma of the gastric tube). Esophagogastric continuity was restored by transplantation of a free jejunal graft with vascular anastomosis. Pathological examination showed squamous cell carcinoma on the esophageal side of the esophagogastric anastomosis and columnar epithelium with a tongue-shaped extension across the anastomotic line that included Barrett's epithelium, as well as adenocarcinoma, on the gastric tube side. The squamous cell carcinoma and adenocarcinoma were contiguous, but there was a distinct border between them and no morphological transition. Immunohistochemical staining showed positivity for p53 in the squamous carcinoma cells, while it was negative in the adenocarcinoma cells. In contrast, HER2 (c-erb-2) was strongly positive in the adenocarcinoma cells, but negative in the squamous carcinoma. Based on these findings, it was concluded that two separate carcinomas had arisen at different sites and grown independently until they collided and merged to form a collision carcinoma.

Subdural hematoma associated with dural metastasis of gastric carcinoma: report of two cases.

We treated two cases of a subdural hematoma associated with dural metastasis of gastric cancer, from which both patients died. Case 1: A 60-year-old female patient was hospitalized with a diagnosis of type 4 gastric cancer of the antrum. The patient suddenly collapsed, and, subsequently, left hemiplegia and a depressed level of consciousness were noted. A head computed tomography (CT) scan revealed a subdural hematoma with midline shift. The patient was diagnosed with chronic subdural hematoma and underwent emergency burr hole irrigation. Case 2: A 73-year-old man was diagnosed with type 4 gastric cancer and a total gastrectomy plus splenectomy were performed together with dissection of the N1 and N2 lymph node groups (D2 dissection) in March 2006 (T3, N2, P0, H0, INFgamma, ly3, v0, por2). Postoperative adjuvant chemotherapy was performed using oral TS-1; following tests revealed no recurrence in the abdomen. In December 2006, gingival bleeding was noted with disseminated intravascular coagulation (DIC) and 10 days later, the patient was hospitalized with chief complaints of impaired consciousness and anorexia. CT scan revealed a right subdural hematoma with a midline shift. The patient was diagnosed with chronic subdural hematoma and underwent emergency burr hole irrigation and drainage. The dural biopsy of the two cases revealed adenocarcinoma noted in the dural blood vessel. Special staining revealed CEA-positive adenocarcinoma, and a diagnosis of the dural metastasis of gastric cancer was made. These patients' level of consciousness significantly improved postoperatively. However, DIC developed concurrently, and the patients died on the 13th and 14th postoperative day, respectively.