Author Correction: Aberrant methylated key genes of methyl group metabolism within the molecular etiology of urothelial carcinogenesis.

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Aberrant methylated key genes of methyl group metabolism within the molecular etiology of urothelial carcinogenesis.

Urothelial carcinoma (UC), the most common cancer of the urinary bladder causes severe morbidity and mortality, e.g. about 40.000 deaths in the EU annually, and incurs considerable costs for the health system due to the need for prolonged treatments and long-term monitoring. Extensive aberrant  DNA methylation is described to prevail in urothelial carcinoma and is thought to contribute to genetic instability, altered gene expression and tumor progression. However, it is unknown how this epigenetic alteration arises during carcinogenesis. Intact methyl group metabolism is required to ensure maintenance of cell-type specific methylomes and thereby genetic integrity and proper cellular function. Here, using two independent techniques for detecting DNA methylation, we observed DNA hypermethylation of the 5'-regulatory regions of the key methyl group metabolism genes ODC1, AHCY and MTHFR in early urothelial carcinoma. These hypermethylation events are associated with genome-wide DNA hypomethylation which is commonly associated with genetic instability. We therefore infer that hypermethylation of methyl group metabolism genes acts in a feed-forward cycle to promote additional DNA methylation changes and suggest a new hypothesis on the molecular etiology of urothelial carcinoma.

Bilateral Diffuse Pseudoangiomatous Stromal Hyperplasia (PASH) Causing Gigantomastia in a 33-Year-Old Pregnant Woman: Case Report.

Pseudoangiomatous stromal hyperplasia (PASH) is a benign proliferation of mammary stroma mostly described as an incidental microscopic finding. Clinically, it can manifest as a palpable, well-circumscribed breast mass or in rare cases as a diffuse bilateral process causing massive breast enlargement. The most postulated theory for aetiology of this condition is hormonal stimulation of mammary myofibroblasts, particularly by progesterone. A definite diagnosis of PASH is based on typical pathological findings like stromal hyperplasia and empty slit-like channels positive for myofibroblastic and negative for endothelial markers. The main clinical differential diagnosis is a fibroadedoma or phylloid tumour, and histologically a low-grade angiosarcoma. There are less than 200 cases of tumorous PASH and less than 20 of diffuse PASH reported so far. Here we present a case report of huge diffuse PASH, that is, to our knowledge, the first in a pregnant woman.

Cellularity, characteristics of hematopoietic parameters and prognosis in myelodysplastic syndromes.

BACKGROUND: Myelodysplastic syndromes (MDS) present with a normo- or hyperplastic bone marrow in most cases. We aimed at a characterization of patients with different types of cellularity. METHODS: We assessed marrow cellularity both by histology and cytology in 1270 patients and analyzed hematologic, cytogenetic, and prognostic parameters accordingly. RESULTS: The concordance of the assessment of cellularity differed dramatically between histology and cytology as only 36.5% were described as hypocellular by both methods (P < 0.0005) (hypocellular 16.4%, normocellular 23.3%, hypercellular 60.3%). There were no major differences with regard to hematopoietic insufficiency. The presence of fibrosis was associated to hypercellular bone marrow. Median survival differed from 38 months in hypocellular, 42 months in normocellular, and 25 months in hypercellular MDS (P < 0.0005). AML progression rates were 33% for hypercellular MDS after 2 yr, whereas hypo- and normocellular had a progression rate of 19% after 2 yr (P = 0.018). IPSS and IPSS-R were able to identify different risk groups within all three cellularity groups. CONCLUSION: Based on our data, hypocellular patients obviously do not present as a separate entity, as there were no striking differences with regard to cytogenetics and WHO types. Assessment of cellularity should be performed by histopathology.

Small intestine bleeding due to multifocal angiosarcoma.

We report a case of an 84-year-old male patient with primary small intestinal angiosarcoma. The patient initially presented with anemia and melena. Consecutive endoscopy revealed no signs of upper or lower active gastrointestinal bleeding. The patient had been diagnosed 3 years previously with an aortic dilation, which was treated with a stent. Computed tomography suggested an aorto-intestinal fistula as the cause of the intestinal bleeding, leading to operative stent explantation and aortic replacement. However, an aorto-intestinal fistula was not found, and the intestinal bleeding did not arrest postoperatively. The constant need for blood transfusions made an exploratory laparotomy imperative, which showed multiple bleeding sites, predominately in the jejunal wall. A distal loop jejunostomy was conducted to contain the small intestinal bleeding and a segmental resection for histological evaluation was performed. The histological analysis revealed a less-differentiated tumor with characteristic CD31, cytokeratin, and vimentin expression, which led to the diagnosis of small intestinal angiosarcoma. Consequently, the infiltrated part of the jejunum was successfully resected in a subsequent operation, and adjuvant chemotherapy with paclitaxel was planned. Angiosarcoma of the small intestine is an extremely rare malignant neoplasm that presents with bleeding and high mortality. Early diagnosis and treatment are essential to improve outcome. A small intestinal angiosarcoma is a challenging diagnosis to make because of its rarity, nonspecific symptoms of altered intestinal function, nonspecific abdominal pain, severe melena, and acute abdominal signs. Therefore, a quick clinical and histological diagnosis and decisive measures including surgery and adjuvant chemotherapy should be the aim.

Pancreatic incidentalomas: a growing clinical challenge exemplified by an intrapancreatic accessory spleen.

In part owing to an increasing use of high resolution imaging technologies a growing number of incidental pancreatic lesions are detected. A 40-year-old patient was admitted to our hospital to undergo resection for an unclear solid pancreatic tumor in the pancreatic tail. Preoperative imaging studies suspected an inactive neuroendocrine neoplasm. After distal pancreatectomy, the histopathological analysis revealed an intrapancreatic accessory spleen. Since reliable biomarkers are not established the clinical management of pancreatic incidentalomas is still challenging.

Mandibular aneurysmal bone cyst in a child misdiagnosed as acute osteomyelitis: a case report and a review of the literature.

The aneurysmal bone cyst is a very infrequent, benign bone lesion in children which rarely can be found at the craniofacial skeleton. Here, we describe a case presenting in the mandible as an acute swelling of the cheek, which was initially misdiagnosed as osteomyelitis resulting in a delay to definitive surgical treatment. The cause of misleading diagnosis is often owing to the rapid growth of the lesion, sometimes associated with painful soft tissue swelling indicating an infectious origin or a malignant tumor. Magnetic resonance imaging revealed the classic characteristics of aneurysmal bone cyst with severe destruction of the mandible. Therefore, curative tumor embolization and complete surgical excision was successfully performed. The aneurysmal bone cyst is a curable condition by radical excision, although relapse may occur when only incomplete excision is obtained. Therefore, aneurysmal bone cyst should be considered early when children present with unusual, rapid-growing neoformations of the extremities or the facial region.

[Rationale for bone marrow examination in patients with inflammatory rheumatic diseases]. / Die Rationale für Knochenmarkuntersuchungen bei Patienten mit entzündlich-rheumatischen Erkrankungen.

OBJECTIVE: Inflammatory rheumatic diseases and the applied immunosuppressive treatments can lead to bone marrow depressions and promote hematologic malignancies. Our objective was to explore indications for and results of bone marrow examinations in a large cohort. METHODS: Between 1990 and 2004 146 bone marrow examinations in 3638 patients were performed due to abnormal laboratory results. Medical history, results of bone marrow examination (morphology, histology) and cytogenetic data were investigated retrospectively. RESULTS: Patients' (67.8% female) mean age at bone marrow examination was 53.5 years (SD 15.5), median disease duration 2.9 years. Indications for bone marrow examination were changes in peripheral blood counts in 81.7%. In 52 patients (35.6%) clinically relevant, partially neoplastic bone marrow changes (5 non-Hodgkin lymphoma, 9 myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) and 3 myeloproliferative neoplasias) were evident. Medication history showed intake of hydroxy-/chloroquine (13.5%), methotrexate (17.3%), cyclosporin (7.7%), sulfasalazine (7.7%), mycophenolatmofetil, gold, leflunomide (each 1.9%), azathioprine (aza, 25.0%) or cyclophosphamide (cyc, 7.7%) prior to bone marrow examination. 7 out of 9 patients, who developed MDS/AML had been treated with either azathioprine alone or additionally with cyclophosphamide (n = 3). CONCLUSION: One third of our patients showed relevant bone marrow changes that might be associated to therapy. The risk seems to be increased especially in patients with inflammatory rheumatic diseases who had received azathioprine alone or in combination with cyclophosphamide. Health care providers should bear in mind the risk of hematologic malignancies and monitor patients closely in this respect. Bone marrow examination should be performed in case of changes in peripheral blood counts; especially clinically relevant anemia, granulocytes < 2,500/microl, thrombocytes < 100,000/microl and relevant changes over time should lead to bone marrow examinations.

Insulinomatosis: a multicentric insulinoma disease that frequently causes early recurrent hyperinsulinemic hypoglycemia.

BACKGROUND: Multicentric insulinoma disease was characterized with regard to its histopathology, multiple endocrine neoplasia type 1 (MEN1) status, precursor lesions, and the risk of hyperinsulinemic hypoglycemia recurrence. METHODS: Fourteen patients with multicentric insulinoma disease were compared with 267 patients with sporadic and familial insulinomas. The tumors were classified according to the World Health Organization (WHO) criteria. The MEN1 status was defined clinically and by germline mutation analysis. Detection of the MEN1 gene locus was performed using fluorescence in situ hybridization. The surgical interventions and the duration of disease-free survival were recorded. RESULTS: Fourteen patients (5%) without evidence of MEN1 showed 53 macrotumors and 285 microtumors expressing exclusively insulin. In addition, they had small proliferative insulin-expressing monohormonal endocrine cell clusters (IMECCs). No allelic loss of the MEN1 locus was detected in 64 tumors. All but one patient had benign disease. Recurrent hypoglycemia occurred in 6/14 patients (11 recurrences; mean time to relapse 8.4 y). Thirteen patients with MEN1 (4.6%) showed 41 insulinomas and 133 tumors expressing islet hormones other than insulin. IMECCs were not detected. Allelic loss of the MEN1 locus was found in 17/19 insulinomas. Recurrent hypoglycemia occurred in 4/13 patients (4 recurrences; mean time to relapse 14.5 y). Solitary insulinomas were found in 254/281 patients (90.4%). IMECCs were absent. There was no recurrent hypoglycemia in 84 patients with benign insulinomas. CONCLUSIONS: Insulinomatosis is characterized by the synchronous and metachronous occurrence of insulinomas, multiple insulinoma precursor lesions, and rare development of metastases, but common recurrent hypoglycemia. This disease differs from solitary sporadic and MEN1-associated insulinomas.

Mucinous cystadenoma of the appendix misdiagnosed as cystic hydatid disease of the liver: a case report.

INTRODUCTION: Primary neoplastic lesions presenting with a mucocele of the appendix are very rare and can be divided into benign variants of mucinous adenomas or cystadenomas, mucinous tumours of uncertain malignant potential or mucinous cystadenocarcinomas. Most of these tumourous mucoceles are asymptomatic and are found incidentally. The major complication of neoplastic mucinous appendiceal tumours is the development of a pseudomyxoma peritonei due to spreading of mucin-producing cells within the abdominal cavity. CASE PRESENTATION: A 44-year-old man presented with a history of non-specific symptoms of right upper abdominal pain. Abdominal ultrasound and computed tomography scan identified a cystic mass consistent with the morphological characteristics of an echinococcal hydatid cyst. After completing systemic albendazole therapy, an explorative laparotomy revealed a cystic tumour of the appendix. Ileocaecal resection was performed and pathology reports confirmed the diagnosis of a mucinous cystadenoma of the appendix. The postoperative course was uneventful. CONCLUSION: Here we present the case of a man with a mucinous cystadenoma of the appendix mimicking cystic hydatid disease. We discuss the importance of re-evaluation and differential diagnostic reflections in cases of appendiceal mucocele.

Additional use of DNA-image cytometry improves the assessment of resection margins.

BACKGROUND: Despite the histopathologic findings of tumor-free margins, patients with oral squamous cell carcinoma (SCC) often suffer from local tumor relapse. The purpose of this study was to determine the prognostic value of DNA-image cytometry in the assessment of resection margins. METHODS: DNA-image cytometry was performed in 40 SCC patients with histologically tumor-free resection margins. The follow-up period since the tumor resection was at least 3 years. RESULTS: Twenty patients showed a locoregional relapse of the SCC. Fourteen of these patients had aneuploid cells in DNA-image cytometry. Two patients who were relapse-free revealed aneuploid cells too. The sensitivity of the adjuvant use of DNA-image cytometry was 70% and the positive predictive value was 87.5%. CONCLUSIONS: The additional use of DNA-image cytometry is a reasonable tool for the assessment of the resection margins of SCCs. DNA-image cytometry could help to find the appropriate treatment option for the patients and thus might improve their prognosis.

Cystic renal dysplasia as a leading sign of inherited metabolic disease.

Glutaric acidemia type II and carnitine palmitoyltransferase type II deficiency are rare, but potentially treatable, inherited metabolic diseases. Hallmarks of the early onset form of both conditions are renal abnormalities and neonatal metabolic crisis. In this article, we report on two newborns with cystic renal dysplasia as a leading sign of these metabolic diseases. We focus on the clinical presentation and discuss the diagnostic tests and the available therapeutic options. We conclude that prenatal diagnosis of cystic renal dysplasia should alert the physician to the possibility of these metabolic diseases. This knowledge should prompt careful observation and, where necessary, early intervention during the postnatal period of catabolism.

Diffuse nesidioblastosis as a cause of hyperinsulinemic hypoglycemia in adults: a diagnostic and therapeutic challenge.

Hyperinsulinemic hypoglycemia is caused by uncontrolled insulin release either from neoplastic pancreatic beta-cells or from functionally defective beta-cells. The latter disorder, which is usually seen in newborns, has been called nesidioblastosis and is divided histopathologically into a focal and diffuse type. In adults, nesidioblastosis is rare, and therefore its histopathologic and clinical features are not well known. In our institution, 4 of 128 adult patients (>3%) suffering from hyperinsulinemic hypoglycemia were found to have diffuse nesidioblastosis. The remaining patients had an insulinoma resected successfully in all but one patient. The diagnosis of diffuse nesidioblastosis was established histopathologically after removing a segment of the distal pancreas. Resection of up to 90% of the pancreas relieved 2 of the 4 patients of their symptoms. We conclude that diffuse nesidioblastosis is rare in adults but may account for more than 3% of patients with hyperinsulinemic hypoglycemia. The histopathologic diagnosis relies predominantly on demonstration of beta-cell hypertrophy. The cause of the disease is not known but may be related to defects in the glucose recognition system of the beta-cell. Treatment consists of operative reduction of the beta-cell mass, but the extent of pancreatic resection required is hard to judge, and there is a thin line between successful treatment, persistence of the disease, and pancreatic endocrine insufficiency.

Adenomatoid odontogenic tumor of the mandible: review of the literature and report of a rare case.

Adenomatoid odontogenic tumor (AOT) is a rare odontogenic tumor which is often misdiagnosed as odontogenic cyst. To acquire additional information about AOT, all reports regarding AOT and cited in "pubmed" since 1990 onward were reviewed. AOT accounts for about 1% until 9% of all odontogenic tumors. It is predominantly found in young and female patients, located more often in the maxilla in most cases associated with an uneruppted permanent tooth. For radiological diagnose the intraoral periapical radiograph seems to be more useful than panoramic. However, AOT frequently resemble other odontogenic lesions such as dentigerous cysts or ameloblastoma. Immunohistochemically AOT is characterized by positive reactions with certain cytokeratins. Treatment is conservative and the prognosis is excellent. For illustration a rare case of an AOT in the mandible is presented.

Follicular lymphoid hyperplasia simulating intussusception in a 6-year-old boy: clinical, radiological and histopathological findings.

We report the case of a 6-year-old boy who initially presented with recurrent abdominal pain. Diagnostic imaging, including ultrasound and CT, showed findings typical of an ileocecal intussusception with abdominal lymphadenopathy. Sonographically, the morphological appearance of the intussusception did not change during a 4-week follow-up period. Surgery was performed on the tentative diagnosis of a tumour versus lymphoma. Upon laparatomy, intussusception was ruled out and a large, broad-based tumour of the caecum was palpable. The histopathology after ileocecal resection revealed follicular lymphoid hyperplasia. Where there is radiological suspicion of an intussusception in children with no or insignificant symptoms, follicular lymphoid hyperplasia should be included in the differential diagnosis.

Primary malignant tumors of the aorta: clinical presentation, treatment, and course of different entities.

OBJECTIVE: The objective of this study was to analyze possible correlations between the clinical presentation and the course of patients with different types of primary malignant aortic tumors. METHODS: A single academic center's experience was reviewed retrospectively. RESULTS: Four patients with primary malignant tumors of the aorta were treated in an 11-year period. Three different histologic entities were found: malignant fibrous histiocytoma, epitheloid angiosarcoma, and unclassified sarcoma. Two female patients presenting with clinical symptoms of vasculitis proved to have epitheloid aortic sarcoma. Both developed diffuse metastasis to bone and skin with initial lymphatic disease in the groin. The other patients developed local recurrence and pulmonary metastasis. Survival of the 4 patients was 11, 20, and 51 months, 1 patient with metastatic disease is still alive 6 months after surgery. CONCLUSION: Different types of malignant aortic tumors seem to have different clinical presentation and course.

Isolated peripheral neurilemoma attached to the tendon of the flexor digitorum longus muscle.

Neurilemomas are benign tumours arising from peripheral nerves with a Schwann cell sheath. They are normally painless and slowly growing, rarely causing motor disturbances. Neurilemomas are most common in the cranial nerves, in the trunk, the upper and lower extremities, but may appear anywhere. Especially rare are neurilemomas of the lateral peroneal nerve in the region of the fibular head and in the foot. We present the first detailed report of a neurilemoma localized between the Achilles tendon and the flexor digitorum longus muscle with separation of the tumour from the tibial nerve.