Detection and clinical relevance of hematogenous tumor cell dissemination in patients with ductal carcinoma in situ.

Hematogenous tumor cell dissemination is a crucial step in systemic disease progression and predicts reduced clinical outcome in breast cancer patients. Only invasive cancers are assumed to shed tumor cells into the bloodstream and infiltrate lymph nodes. However, recent studies revealed that disseminated tumor cells (DTCs) may be detected in bone marrow (BM) of patients with preinvasive lesions, i.e., ductal carcinoma in situ (DCIS). The purpose of this analysis was to examine the incidence and clinical value of DTC detection in a large series of patients with pure DCIS. 404 patients treated for DCIS at the University Hospital Tuebingen, Germany were included into this analysis. BM was analyzed by immunocytochemistry (pancytokeratin antibody A45-B/B3) using ACIS system (Chromavision) according to the ISHAGE evaluation criteria. Sentinel nodes were analyzed in 316 patients by step sectioning and hematoxylin-eosin staining. DTCs were detected in 63 of 404 patients (16 %). No correlation was observed between BM status and tumor size, grading, histology or Van Nuys prognostic index. In two cases, metastatic spread into lymph nodes was observed; isolated tumor cells were found in one patient. After a median follow-up of 45 months (range 3-131 months), 3 % of BM positive patients died compared to 1 % of BM negative patients (p = 0.254). Relapse of any kind was observed in 7 % of patients with DTCs vs. 5 % of patients without DTCs (p = 0.644). The differences in overall (p = 0.088) and disease-free survival (p = 0.982) calculated by log-rank test were not statistically significant. Tumor cell dissemination may be detected in patients diagnosed with DCIS. Whether these cells disseminate from real preinvasive mammary lesions or represent the earliest step of microinvasion, remains unclear. A longer follow-up may be necessary to accurately assess clinical value of these cells in DCIS patients.

A case of recurrent respiratory papillomatosis with malignant transformation, HPV11 DNAemia, high L1 antibody titre and a fatal papillary endocardial lesion.

BACKGROUND: Recurrent respiratory papillomatosis (RRP) is a rare disease, which is characterised by the growth of papillomavirus-induced papillomas within the respiratory tract. Malignant transformation occurs in less than 1% of the cases. CASE PRESENTATION: We report a case of human papillomavirus (HPV) type 11-associated juvenile-onset RRP (JORRP) initially diagnosed at the age of two years. Remarkably high copy numbers of HPV11 DNA and antibody titres targeting the capsid protein L1 were detected in the patient's serum. The patient developed squamous cell carcinomas in both lungs and extraordinarily an HPV11 DNA-positive papillary endocardial lesion in the left atrium of the heart, which caused thromboembolic events leading to the patient's death at 19 years old. CONCLUSION: We here report a severe case of JORRP hallmarked by HPV11 DNAemia and very high antibody titres directed against the major viral capsid protein L1. Furthermore, the extent of malignant transformation and the discovery of a very rare fatal endocardial lesion highlight the unpredictability of JORRP and the complexity of its clinical management.

Molecular detection of breast cancer metastasis in sentinel lymph nodes by reverse transcriptase polymerase chain reaction (RT-PCR): identifying, evaluating and establishing multi-marker panels.

The potential advantage of using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) methodology to detect metastasis in sentinel lymph nodes (SLNs) of breast cancer (BC) patients was evaluated in this prospective study. We measured the expression of relevant gene transcripts in SLNs using an innovative algorithm and compared the results of single-marker assays versus multi-marker assays with conventional histological detection methods. SLNs from women aged ≥ 18 years diagnosed with unilateral BC were examined by haematoxylin-eosin staining and immunohistochemistry and analysed for transcripts of several relevant genes using qRT-PCR (learning group). Four candidate panels of expressed transcript combinations with high sensitivity and specificity were selected for further investigation. The candidate panels were then validated using SLNs from a second group of BC patients (validation group). In the learning group, 74/314 SLN sections from 150 patients were positive for metastasis by histology. The transcripts analysed showed the following individual sensitivities/specificities: cytokeratin 19 (CK19) 94.6%/97.9%; mammaglobin 1 (MGB1) 82.4%/91.7%; mammaglobin 2 (MGB2) 82.4%/96.7%; carcinoembryonic antigen (CEA) 71.6%/97.5%; EPCAM (epithelial cell adhesion molecule) 91.9%/97.1%; and NY-BR-1 82.4%/93.8%. The optimal panel based on the predefined criteria comprised four markers: CK19, MGB1, EPCAM, and NY-BR-1, of which ≥ 2 had to be positive (95.9% sensitivity, 95.0% specificity, 85.5% positive predictive value (PPV), and 98.7% negative predictive value (NPV)). Overall concordance with histology was 95.2%. In the validation group, 84/315 SLN sections from 235 patients were histologically positive, and panel sensitivity, specificity and overall accuracy were 88.1, 95.2 and 93.3%, respectively, at the SLN section level. In conclusion, molecular staging using expression patterns of relevant transcripts in SLNs could serve as a useful complement to standard diagnostic work-up in BC patients. The proposed flexible multi-parametric approach does not improve the overall accuracy compared with the single-marker approach. However, it overcomes several limitations of the previously reported molecular assays for SLN diagnosis.

Expression of the embryonic stem cell marker SOX2 in early-stage breast carcinoma.

BACKGROUND: The SRY-related HMG-box family of transcription factors member SOX2 has been mainly studied in embryonic stem cells as well as early foregut and neural development. More recently, SOX2 was shown to participate in reprogramming of adult somatic cells to a pluripotent stem cell state and implicated in tumorigenesis in various organs. In breast cancer, SOX2 expression was reported as a feature of basal-like tumors. In this study, we assessed SOX2 expression in 95 primary tumors of postmenopausal breast cancer patients. METHODS: Samples from 95 patients diagnosed and treated at the University of Tuebingen Institute of Pathology and Women's Hospital were analyzed by immunohistochemistry for SOX2 expression in the primary tumor samples and in corresponding lymph node metastasis, where present. Furthermore, SOX2 amplification status was assessed by FISH in representative samples. In addition, eighteen fresh frozen samples were analyzed for SOX2, NANOG and OCT4 gene expression by real-time PCR. RESULTS: SOX2 expression was detected in 28% of invasive breast carcinoma as well as in 44% of ductal carcinoma in situ (DCIS) lesions. A score of SOX2 expression (score 0 to 3) was defined in order to distinguish SOX2 negative (score 0) from SOX2 positive samples (score 1-3) and among latter the subgroup of SOX2 high expressors (score 3 > 50% positive cells). Overall, the incidence of SOX2 expression (score 1-3) was higher than previously reported in a cohort of lymph node negative patients (28% versus 16.7%). SOX2 expression was detected across different breast cancer subtypes and did not correlate with tumor grading. However, high SOX2 expression (score 3) was associated with larger tumor size (p = 0.047) and positive lymph node status (0.018). Corresponding metastatic lymph nodes showed higher SOX2 expression and were significantly more often SOX2 positive than primary tumors (p = 0.0432). CONCLUSIONS: In this report, we show that the embryonic stem cell factor SOX2 is expressed in a variety of early stage postmenopausal breast carcinomas and metastatic lymph nodes. Our data suggest that SOX2 plays an early role in breast carcinogenesis and high expression may promote metastatic potential. Further studies are needed to explore whether SOX2 can predict metastatic potential at an early tumor stage.

Sudden death after pancreatic head resection: rupture of hepatic artery caused by clostridial infection.

BACKGROUND: Rupture of the hepatic artery caused by clostridial infection has not been reported before. METHODS: Case report and literature review. RESULTS: A 75 year-old man was admitted to the hospital for resection of a cystic tumor of the head of the pancreas. A pylorus-preserving radical pancreaticoduodenectomy was performed. On the fifth postoperative day, he developed fever (38.2 degrees C), and computed tomography scanning revealed free air in the subhepatic area near the pancreaticojejunal anastomosis. On the ninth postoperative day, the patient died suddenly. Autopsy revealed a ruptured hepatic artery secondary to clostridial infection. CONCLUSIONS: Close monitoring and early recourse to invasive diagnostic and therapeutic procedures may be advisable in the presence of suspect findings after pancreatic surgery to prevent this fatal complication.

Neuroelectric source imaging of steady-state movement-related cortical potentials in human upper extremity amputees with and without phantom limb pain.

Whereas several studies reported a close relationship between changes in the somatotopic organization of primary somatosensory cortex and phantom limb pain, the relationship between alterations in the motor cortex and amputation-related phenomena has not yet been explored in detail. This study used steady-state movement-related cortical potentials (MRCPs) combined with neuroelectric source imaging to assess the relationship of changes in motor cortex and amputation-related phenomena such as painful and non-painful phantom and residual limb sensations, telescoping, and prosthesis use. Eight upper limb amputees were investigated. A significant positive relationship between reorganization of the motor cortex (distance of the MRCP source location from the mirrored source for hand movement) and phantom limb pain was found. Non-painful phantom sensations as well as painful and non-painful residual limb sensations were unrelated to motor cortical reorganization. A higher amount of motor reorganization was associated with less daily prosthesis use, which also tended to be related to more severe phantom limb pain. These results extend previous findings of a positive relationship between somatosensory reorganization and phantom limb pain to the motor domain and suggest a potential positive effect of prosthesis use on phantom limb pain and cortical reorganization.

Event-related fMRI of the somatosensory system using electrical finger stimulation.

Cortical signal intensity changes due to brief (1 s) innocuous electrical stimuli applied to the second and fifth finger of the right hand were measured by means of fMRI at 1.5 T. The activation pattern in this event-related fMRI approach closely resembled that obtained in recent block-design studies. Activations were found in contralateral primary (SI) and bilaterally in secondary (SII) somato-sensory cortex as well as in posterior parietal cortex, insula, and supplementary motor area (SMA). In SI, the somatotopic organization of the hand area is demonstrated, more clearly to be seen in area 3b than in area 1 and 2. In conclusion, the feasibility to employ event-related somatosensory stimulation paradigms in fMRI studies is demonstrated.

Ruptured intracranial dermoid cysts.

BACKGROUND: Intracranial dermoid cysts are rare congenital neoplasms that are believed to arise from ectopic cell rests incorporated in the closing neural tube. The rupture of an intracranial dermoid cyst is a relatively rare event that typically occurs spontaneously. In the past it was believed that rupture is always fatal, a hypothesis that is not supported by more recently reported cases. The symptoms associated with rupture vary from no symptoms to sudden death. METHODS: The present paper analyzes published cases of ruptured intracranial dermoid cysts in terms of their age profile and their clinical presentation and describes an additional case. RESULTS: Analysis of published cases revealed headache (14 out of 44 patients; 31.8%) and seizures (13 out of 44 patients; 29.5%), to be the most common signs of rupture followed by, often temporary, sensory or motor hemisyndrome (7 out of 44 patients; 15.9%), and chemical meningitis (3 out of 44 patients; 6.9%). CONCLUSION: Headache occurred primarily in younger patients (mean age 23.5 +/- 9.3 years), whereas seizures primarily occurred in older patients (mean age 42.8 +/- 11.3 years). The patients with sensory or motor hemisyndrome associated with rupture of an intracranial dermoid cyst showed a more homogeneous age distribution (mean age 38.4 +/- 23.5 years).

Clinical and pathological characteristics, pathological reevaluation and recurrence patterns of cellular leiomyomas: a retrospective study in 76 patients.

OBJECTIVES: To analyze clinical and pathologic features as well as recurrence patterns of cellular leiomyomas (CL) in women who underwent surgical therapy for symptomatic disease. STUDY DESIGN: This retrospective study was conducted at the Department of Obstetrics and Gynecology, University Women's Clinic, Tuebingen, Germany. We identified all women who had CL on final diagnosis after surgery between January 1, 2000, and December 31, 2010. RESULTS: Our study sample comprised 76 women with a diagnosis of CL. A single uterine mass was present in 51.3% of the cases; in uteri with both CL and uterine leiomyomas (UL), the CL constituted the largest uterine mass in 20 of 21 (95.2%) cases. Additionally, in 98% of the uteri, CL were either the largest or the only uterine mass. Five women (6.6%; 5/76) had reported surgical procedures for symptomatic leiomyoma before the index surgery in our analysis. Three women underwent hysteroscopic resection of the leiomyomas and 2 women underwent abdominal myomectomy. Mean time to recurrence was 14.0 months (median 6.0; range, 4.0-52.0). Over the follow-up period, 6 women who underwent uterus-conserving surgery (12.0%; 6/50) with CL had leiomyoma recurrence. Five women underwent abdominal myomectomy and one underwent hysteroscopic resection of the CL. One patient had recurrence of a CL 43 months after abdominal myomectomy and underwent vaginal hysterectomy; the other five women had recurrences of UL. Mean time to recurrence was 28.6 months (median 12.5; range, 4.0-83.0). CONCLUSIONS: Recurrence rates of CL in our study group resemble recurrence rates of UL.

Condylar metastasis from prostatic carcinoma mimicking temporomandibular disorder: a case report.

BACKGROUND: Although metastatic carcinoma is the most common malignant tumor of the bone, less than 1% of all metastatic bone lesions are presented in the maxillofacial area. As the mandibular body is the most frequent localization, metastasis to the mandibular condyle is extremely rare. CASE REPORT: This report describes a rare case of prostate carcinoma metastatic to the mandibular condyle in a 75-year old man, who was referred because of persistent pain in the temporomandibular joint (TMJ) region and a limitation of opening, initially misdiagnosed and treated as temporomandibular disorder (TMD). Histopathological examination confirmed the suspected metastasis of prostate carcinoma and local radiation therapy was performed. DISCUSSION: TMD represent a diagnostic challenge and sometimes an interdisciplinary approach is required to prevent a delay of the correct treatment. Metastatic cancer should be included in the differential diagnosis of TMD, especially in patients with a malignant disease.

Asymptomatic melanoma of the superior cavo-atrial junction: The challenge of imaging.

METASTATIC LESIONS IN THE SUPERIOR VENA CAVA AND THE RIGHT ATRIUM ARE DIFFICULT TO DIAGNOSE: in computed tomography (CT), they are easily misinterpreted as artifacts, and the same region may be difficult to access using echocardiography. We present a case of asymptomatic metastasis of a malignant melanoma which was overlooked initially due to deficiencies in imaging. Using 18F-fluorodeoxyglucose positron emission tomography-CT, the metastasis was clearly identified and finally treated successfully. We discuss the diagnostic value of the various imaging modalities for intracardiac masses.

[A rare cause of thyreotoxicosis]. / Seltene Ursache einer Hyperthyreose.

BACKGROUND: Amiodarone-induced thyrotoxicosis (AIT) should be included in differential diagnoses of thyrotoxicosis in presence of a suggestive drug history. Adequate treatment requires knowledge of the underlying type of AIT. HISTORY AND ADMISSION FINDINGS: A 68-year-old male was admitted because of progressive dyspnea and tachyarrhythmia. Symptoms of thyrotoxicosis, including agitation, sleep disturbances, and palpitations, had developed 14 days earlier and the patient's condition had worsened despite initiation of antithyroid treatment. INVESTIGATIONS: Laboratory values showed manifest hyperthyroidism. Thyroid autoantibodies proved negative. C-reactive protein and erythrocyte sedimentation rate were slightly increased. Ultrasound revealed a moderately increased thyroid without nodules and with normal perfusion. DIAGNOSIS, TREATMENT AND COURSE: Suspecting AIT type 2, treatment with high-dosed glucocorticoids and antithyroid drugs was initiated. Under additional beta-blockade and heart insufficiency therapy the patient's condition significantly improved. After achievement of euthyreosis, thyroidectomy was performed. CONCLUSIONS: In patients with preexisting thyroid disorders, such as Grave's disease or functional autonomy in multinodular goiter, the high iodine content of amiodarone may cause iodine-induced thyrotoxicosis, also known as AIT type I. Treatment comprises high-dosed antithyroid drugs. In contrast, in patients suffering from AIT type II, toxic effects of amiodarone on a previously healthy thyroid result in destructive thyroiditis. Treatment consists of glucocorticoids in a dosage of 1 mg per kg body weight per day. Antithyroid treatment could be added in cases of equivocal diagnosis. In most cases, thyroidectomy is indicated. Whether amiodarone can be discontinued, should be discussed with the responsible cardiologist. Due to the long half-life time of amiodarone, treatment discontinuation will not result in an immediate improvement.