Sporadic adenoma or ulcerative colitis associated neoplasia? The endoscopist's information has an impact on diagnosis and patient management.

BACKGROUND: Diagnosing low grade intraepithelial neoplasia (LGIN) in patients with ulcerative colitis (UC) is difficult. Distinguishing between sporadic adenoma (SA) and UC associated LGIN is even more challenging but has clinical impact. We aimed to examine, if the morphological distinction between both entities is reliably possible, how it influences patient's outcome and the role of the endoscopist in this decision with respect to current endoscopy classification schemes. METHODS: Seven pathologists retrospectively reevaluated 425 cases of LGIN in UC patients, diagnosed between 2009 and 2017 with preceding expert consensus and follow up in two separate readings, based on published morphological differentiation criteria. In the first evaluation, the observers were blinded to any clinical data. In the second evaluation, they knew patients' age as well as endoscopic features. They also rated their subjective diagnostic certainty. RESULTS: Diagnostic correctness improved significantly in the second assessment as did the pathologists' confidence in their diagnoses (p < 0.001 - p = 0.019). Knowledge of clinical and endoscopical data led to a higher percentage of SA (71.8% vs. 85.6%). UC associated LGIN showed significant earlier LGIN relapse as well as more high grade intraepithelial neoplasia and carcinoma during follow up (p < 0.001, p < 0.001, p = 0.005). CONCLUSIONS: Distinction between SA and UC associated LGIN is important as it has an impact on patients' follow up and treatment. Morphological distinction remains difficult with moderate interobserver variability. Adequate clinical information significantly improves pathologists' diagnoses as well as their confidence in their diagnoses.

Correction to: Diagnostic impact of ascites cytology in 941 patients: malignancy rates and time of detection in ovarian cancer relative to other tumor types.

Unfortunately we did not explain the type of sample collection in "materials and methods".

Diagnostic impact of ascites cytology in 941 patients: malignancy rates and time of detection in ovarian cancer relative to other tumor types.

BACKGROUND: Cytological analysis of ascitic fluid is an important tool for diagnosis, staging, and prognostic assessment in patients with cancer, but more detailed information is needed regarding malignancy rates and the time sequence in which ascites develops for different sites of cancer origin. Especially, an increased early tumor diagnosis may improve the acceptance for cytological examinations for the tumor patients in oncological practice. METHODS: Ascites specimens from patients who were treated at Bayreuth Hospital from 2006 to 2015 were reevaluated retrospectively and correlated with clinical reports. RESULTS: 580 of all 941 ascitis specimens (61.6%) were from patients with malignancies with predominant appearance of gastrointestinal and gynecological tumors in 516/580 (89%) patients. Histologically, 549 (94.6%) were carcinomas, 23 (4%) hematological malignancies, 5 (0.9%) mesotheliomas and 3 (0.5%) were melanomas. Malignant ascitic fluid was noted in 298 of the 580 (51.4%) patients with cancer, thus the overall malignancy rate in the ascites specimens examined was 298/941 (31.7%). The most frequent malignancy rate for gynecological tumors we obtained in ovarian cancer with 85.7% and in the upper gastrointestinal tract with 77.8% for Barrett's carcinoma and 61,4% for gastric carcinoma. Regarding time of detection, malignant ascitic fluid was noted as a separate finding, prior or simultaneous to the histological diagnosis of cancer in 225/298 patients (75.5%). An outstanding earliest occurrence was found in ovarian carcinoma in 94.9% and in the gastrointestinal tract in pancreatic carcinoma in 66.7%. CONCLUSIONS: Tumor staging was the main important clinical question in our single center study of ascitic fluid, especially for patients with gastrointestinal and gynecological malignomas. The highest malignancy rate and earliest time of tumor detection caused the leading importance for ovarian tumors in malignant ascitic fluid. Moreover, the application of immunostains in our study allowed in 75.5% of all tumor patients a correct initial diagnosis, which is important for further clinical therapy.

Simultaneous endocrine expression and loss of melanoma markers in malignant melanoma metastases, a retrospective analysis.

Malignant melanoma metastases are chameleons of histopathology. In 4 primary malignant melanomas and 20 melanoma metastases expression of S-100, HMB-45 and melan-A as melanoma markers and CD56, synaptophysin and chromogranin-A as neuroendocrine markers was retrospectively analyzed. While all primary tumors expressed all 3 melanoma markers 7/20 of melanoma metastases had lost at least one melanoma marker, one had lost all three markers. Conversely about half of the samples stained for CD56, only 6/20 metastases were negative for all 3 neuroendocrine markers. None expressed chromogranin-A. Partial loss of melanoma markers and expression of neuroendocrine markers seems not to be infrequent. In patients with a history of malignant melanoma and suspected metastases, losing melanoma markers while expressing neuroendocrine markers is a potential diagnostic pitfall. Therefore all 3 melanoma markers should be performed as well as chromogranin-A staining. In doubt, metastases of the melanoma should be assumed.

Budding, tumor-infiltrating lymphocytes, gland formation: scoring leads to new prognostic groups in World Health Organization low-grade colorectal cancer with impact on survival.

Grading for colorectal carcinoma (CRC) is traditionally based on the percentage of gland formation. In recent years, high-grade CRC has become subject to more precise molecular grading strategies. Most, however, are low-grade cases according to the World Health Organization (WHO) with inhomogenous outcomes due to still insufficient characterization. On the other hand, budding and tumor-infiltrating lymphocytes have developed as interesting additive prognostic factors in CRC. Especially budding has been very well defined by the International Tumor Budding Consensus Conference recently. We analyzed a large collective of 576 WHO low-grade CRC cases, stages I to IV, diagnosed between 2005 and 2016 in terms of gland formation, budding, and tumor-infiltrating lymphocytes and developed a new, morphology-based risk score, taking into account each of the 3 parameters. For each parameter, 1 to 2 points were given, resulting in a sum score, dividing the CRC cases into a low-, an intermediate-, and a high-risk group. By our score, 179 (34.9%) of the cases were grouped as low risk, 241 (53.5) as intermediate risk, and 92 (35.5%) as high risk. The 3 groups differed significantly in pT, pN, and M as well as tumor stages, lymphatic vessel invasion, venous invasion, and overall survival (0.;P < .001 for low risk versus high risk, P = .038 for low versus intermediate risk, and P = .036 for intermediate versus high risk; log rank: median, 94.0 months [95% confidence interval {CI}, 74.9-113.1] for low risk; median, 63.0 months [95% CI, 44.0-82.0] for intermediate risk; and median, 40.0 months [95% CI, 23.4-56.7] for high risk) in Kaplan-Meier-analysis. Our proposed Bayreuth score enables separating the large group of WHO low-grade CRC cases into subgroups, which differ significantly in outcome.

Malignant ascites occurs most often in patients with high-grade serous papillary ovarian cancer at initial diagnosis: a retrospective analysis of 191 women treated at Bayreuth Hospital, 2006-2015.

BACKGROUND: Malignant ascites often develops in patients with ovarian cancer, but there is a lack of more detailed characterization of the different histological subtypes. METHODS: Ascites specimens from patients with ovarian cancer who were treated at Bayreuth Hospital from 2006 to 2015, with follow-up until December 2016, were reevaluated retrospectively. RESULTS: A total of 191 women (mean age 64 years, range 48-79) were included, of whom 180 (94.2%) had carcinoma, three (1.6%) had malignant mixed müllerian tumors (MMMTs), four (2.1%) had sex cord-stromal tumors (SCSTs), three (1.6%) had germ cell tumors (GCTs), and one (0.5%) had a sarcoma. The carcinoma group comprised 134 (70.1%) patients with high-grade serous papillary ovarian cancer, 17 (8.9%) with low-grade serous papillary ovarian cancer, 10 (5.3%) with mucinous carcinomas, nine (4.7%) with endometrioid carcinomas, six (3.1%) with clear cell carcinomas, and four (2.1%) with neuroendocrine tumors. The latter group consisted of two patients with mixed neuroendocrine-nonneuroendocrine tumors (MiNENs), one with only a small cell carcinoma (SCCO), and one with a mucinous carcinoid. The noncarcinomatous group of eight patients (4.2%) included three (1.6%) with Sertoli-Leydig cell tumor and mature cystic teratoma (MCT), one (0.5%) with a granulosa cell tumor, and one with a leiomyosarcoma. A statistically significant difference in the proportion of patients with malignant ascites was observed, at 17.7% (3/17) in those with low-grade serous papillary ovarian cancer and 91.8% (123/134) in those with high-grade serous papillary ovarian carcinomas. In both patients with MiNEN, the glandular tumor cell component was found in the ascites. Tumor cells were found in the ascitic fluid in 50% (5/10) of patients with mucinous ovarian carcinomas, 16.7% (1/6) of those with clear cell carcinomas, and 33.3% (1/3) of those with MMMTs. The two patients (2/3; 66.7%) with neoplastic squamous cell components in MCT and the only patient with a granulosa cell tumor in the SCST group (1/4; 25%) had malignant cell populations in the ascites, whereas patients with endometrioid cell carcinoma and leiomyosarcoma lacked tumor cells in the ascites. The malignant ascites was detected at the initial diagnosis in all 138 (100%) patients with ovarian neoplasms. CONCLUSIONS: High-grade serous papillary ovarian cancer was the main histological subtype most frequently found in ascites fluid in this series. The significant difference (P < 0.00001) in the malignancy rate in comparison with low-grade serous papillary carcinoma confirms the histological distinction between the two entities. Initial evidence of ovarian cancer in ascites fluid allows correct primary diagnosis in cytology specimens and is important for staging and prognosis.

What is the role of endoscopy and oesophageal biopsies in the management of GERD?

Gastroesophageal reflux disease (GERD) is a diagnosis applicable to "all individuals who are exposed to the risk of physical complications from gastroesophageal reflux, or who experience clinically significant impairment of health related well being (quality of life) due to reflux related symptoms, after adequate reassurance of the benign nature of their symptoms". It remains, predominantly, a symptom-based diagnosis, confirmed clinically by a response to acid suppression therapy although it is accompanied by demonstrable increases in acid exposure on esophageal pH-metry and by endoscopic and histological changes. Standard white light endoscopy permits diagnosis of erosive reflux disease (ERD) which, if present, should be graded for severity using the Los Angeles classification system. However, the role of endoscopy in clinical practice is, primarily, to evaluate patients with persistent symptoms, despite medical therapy, or to investigate alarm features and exclude complications such as Barrett' oesophagus which should be assessed using the Prague C & M criteria. Newer endoscopic techniques allow detection of 'minimal change' GERD lesions and Barrett's oesophagus-associated dysplastic or neoplastic lesions; however, none of the newer techniques has been validated for routine clinical practice. There is an increasing recognition that histology in GERD may provide useful diagnostic information, in part to exclude other lesions, such as eosinophilic oesophagitis, intestinal metaplasia and dysplasia or malignancy and, in part, to identify changes, such as basal cell hyperplasia, papillary elongation and, most recently, dilated intercellular spaces, that are consistent with GERD. However, more widespread incorporation of histology into the clinical management of GERD will require a standardized biopsy protocol and efforts to minimise interobserver differences in the identification of GERD-related histological changes.

Proteomic identification of aldo-keto reductase AKR1B10 induction after treatment of colorectal cancer cells with the proteasome inhibitor bortezomib.

Targeting the ubiquitin-proteasome pathway with the proteasome inhibitor bortezomib has emerged as a promising approach for the treatment of several malignancies. The cellular and molecular effects of this agent on colorectal cancer cells are poorly characterized. This study investigated the antiproliferative effect of bortezomib on colorectal cancer cell lines (Caco-2 and HRT-18). In order to define the proteins potentially involved in the mechanisms of action, proteome profiling was applied to detect the proteins altered by bortezomib. The in vitro efficacy of bortezomib as a single agent in colorectal cancer cell lines was confirmed. Proteome profiling with two-dimensional PAGE followed by mass spectrometry revealed the up-regulation of the major inducible isoform of heat shock protein 70 (hsp72) and lactate dehydrogenase B in both cell lines, as well as the induction of aldo-keto reductase family 1 member B10 (AKR1B10) in HRT-18 cells. Both AKR1B10 and hsp72 exert cell-protective functions. This study shows for the first time a bortezomib-induced up-regulation of AKR1B10. Small interfering RNA-mediated inhibition of this enzyme with known intracellular detoxification function sensitized HRT-18 cells to therapy with the proteasome inhibitor. To further characterize the relevance of AKR1B10 for colorectal tumors, immunohistochemical expression was shown in 23.2% of 125 tumor specimens. These findings indicate that AKR1B10 might be a target for combination therapy with bortezomib.

Chromosomal imbalances, 11q21 rearrangement and MECT1-MAML2 fusion transcript in mucoepidermoid carcinomas of the salivary gland.

The aim of this study was to determine genetic alterations in mucoepidermoid carcinomas of the salivary gland in association with clinical and histopathological parameters. Nineteen formalin-fixed, paraffin-embedded tumors were analysed by using comparative genomic hybridization (CGH), fluorescence in situ hybridization (FISH) on interphase nuclei and reverse transcriptase-polymerase chain reaction (RT-PCR) for detection of MECT1-MAML2 fusion transcript. The CGH analysis showed an overrepresentation of chromosome X and losses of entire chromosomes or regions on chromosome 1, 2, and 15 as the most frequent copy number changes. In 37% of the analysed tumors a MAML2-rearrangement by interphase FISH was detected, whereas 58% of the samples showed expression of MECT1-MAML2 fusion transcript. We conclude that the presence of MAML2-rearrangement as well as of MECT1-MAML2 fusion transcript may reflect a more favourable prognosis and may be a useful marker for clinical prediction of the biological behavior of these tumors as previously reported.

Identification of the rare EGFR mutation p.G796S as somatic and germline mutation in white patients with squamous cell carcinoma of the head and neck.

BACKGROUND: Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) are involved in tumorigenesis and response to targeted therapies in distinct cancer types. Squamous cell carcinomas of the head and neck (HNSCC) show an incidence of EGFR mutations varying from 7% in Asians to 0% to 4% in white patients. Mutational screening predominantly focuses on the analysis of hotspot regions of EGFR (exons 19 and 21). METHODS: In a follow-up study, we screened for mutations in exons 18 to 21 of the EGFR gene in 127 patients. RESULTS: In this cohort, a mutation frequency of 2.4% (3/127) was detected. In addition to the previously reported mutation p.K745R, the otherwise rare EGFR mutation p.G796S occurred in 2 patients with HNSCC (2/127). CONCLUSION: EGFR kinase mutations are rare in white patients with HNSCC. Extension of mutational screening to exon 20 may clarify the frequency and impact of the mutation p.G796S.

Cyclin D1 positive multiple myeloma: predominance of the short, 3'UTR-deficient transcript is associated with high cyclin D1 mRNA levels in cases with t(11;14) translocation, but does not correlate with proliferation rate or genomic deletions.

Multiple myeloma (MM) frequently shows overexpression of cyclin D1, either due to a t(11;14)(q13;q32) translocation, or in association with polysomy 11. The predominant expression of a cyclin D1 mRNA isoform lacking the 3'-untranslated region (Delta3'UTR) is associated with higher total cyclin D1 mRNA levels, increased proliferation and poor prognosis in mantle cell lymphoma, and can be caused by genetic alterations of the 3'UTR region. The role of this cyclin D1 isoform in MM is unknown. We therefore quantified levels of total and Delta3'UTR cyclin D1 mRNA by real-time RT-PCR in cytogenetically characterized cyclin D1+MM primary cases, and cyclin D1+cell lines. Both long and Delta3'UTR cyclin D1 transcripts were expressed in 35/41 MM cases, but none of the samples showed complete loss of the long transcript or genomic alterations of the 3'UTR. Predominance of the Delta3'UTR mRNA was associated with higher cyclin D1 levels in cases with t(11;14), but did not correlate with the proliferation rate, suggesting a different role of this isoform in MM.

Chlamydia psittaci in MALT lymphomas of ocular adnexals: the Austrian experience.

The presence of Chlamydia (C.) psittaci, C. pneumoniae and C. trachomatis DNAs in MALT lymphomas of ocular adnexals from 13 Austrian patients were studied. Gastrointestinal MALT lymphomas and gastritis specimens served as controls. Of 13 MALT lymphomas of the ocular adnexals, seven were positive for C. psittaci DNA. In contrast, one of 17 gastrointestinal specimens tested positive. All specimens were negative for C. trachomatis and C. pneumoniae DNAs. In conclusion, C. psittaci infection was observed in the majority of MALT lymphomas of ocular adnexals in Austrian patients.

IgVH mutational status and clonality analysis of Richter's transformation: diffuse large B-cell lymphoma and Hodgkin lymphoma in association with B-cell chronic lymphocytic leukemia (B-CLL) represent 2 different pathways of disease evolution.

Approximately 5% of B-cell chronic lymphocytic leukemia (B-CLL) patients develop a secondary aggressive lymphoma, usually of diffuse large B-cell type (DLBCL), termed Richter's transformation (RT). Rarely, classic Hodgkin lymphoma (HL) is observed. Published small series suggest that tumor cells in DLBCL and HL can be clonally identical to the B-CLL clone or arise as an independent, secondary lymphoma. We describe the morphology, immunophenotype, and clinical features of 34 classic RT patients with DLBCL, 6 cases of B-CLL with HL, and 8 cases with scattered CD30-positive Hodgkin and Reed-Sternberg (HRS)-like cells. The clonal relationship of the 2 components was analyzed using sequencing analysis of immunoglobulin heavy chain variable region (IgVH) genes. In classic RT, 18/23 B-CLL cases (78%) showed clonal progression to DLBCL with identical IgVH sequences in both lymphoma components, whereas in 5 cases (22%) the DLBCL was clonally unrelated. Among clonally related RT samples, 73% carried unmutated IgVH genes, whereas 4/5 unrelated cases were mutated. Immunophenotypically, most cases of DLBCL irrespective of clonal relatedness showed significant differences in phenotype compared with the B-CLL, with common loss of CD5 and CD23. Using immuno-laser capture microdissection, sequencing of the IgVH CDR3 region of isolated HRS cells showed that 2/2 cases with HL were clonally unrelated, whereas they were clonally identical in 1/2 cases of B-CLL with scattered HRS-like cells. HRS or HRS-like cells in all 3 unrelated cases showed evidence of Epstein-Barr virus infection. Of interest, 5/6 cases of B-CLL with HL, and 5/6 cases of B-CLL with HRS cells showed mutated IgVH genes.

Hemolytic uremic syndrome following Campath-1H induction.

Hemolytic uremic syndrome (HUS) is a rare complication following solid organ transplantation. We report on a patient who underwent renal transplantation using Campath-1H induction and tacrolimus maintenance therapy who developed HUS, which was managed by plasma exchange and switch to Rapamycin. However, graft function could not be restored.

Is higher income and educational status associated with poorer outcome in patients with Hodgkin's disease?

OBJECTIVES: The aim of the study was to determine the impact of socioeconomic status on relapse-free survival (RFS) in patients with Hodgkin's disease. METHODS: A number of factors were analyzed for their impact on relapse-free and overall survival in Hodgkin's disease using Cox regression. These factors included socioeconomic status (as defined by education and income), different treatment modalities and established clinical risk factors [e.g. age at diagnosis, stage of disease, involvement of three or more lymph nodes, presence or absence of a large mediastinal mass, E stages or elevation of erythrocyte sedimentation rate (ESR)]. The study used an initial sample of 126 patients recruited between 1969 and 1995 and a larger sample of 218 patients (recruited until 2002). Clinical data on disease and treatment characteristics were collected from medical records. RESULTS: In a univariate analysis, the following parameters had impact on RFS: treatment modality (combined treatment resulted in an improved RFS compared with patients treated with chemo- or radiotherapy alone), educational status and income. The 5- and 10-yr relapse-free survival rates were found to increase with decreasing educational level and decreasing average income per month. These results were significant in the initial and total samples and were also significant using multivariate analysis (hazard ratio for highest vs. lowest education group: 5.88; 95% confidence interval 1.87-18.52; for highest vs. lowest income group: 4.36; 95% confidence interval 1.35-14.05). CONCLUSION: Hodgkin's disease appears to be a striking exception from the usual positive correlation between high socioeconomic status and favorable treatment outcome in patients suffering from tumor. It is suggested that future studies on tumor genetics and biology and more detailed analysis of further socioeconomic parameters may be useful in clarifying this observation.

Burkitt's lymphoma of the stomach: a case report with molecular cytogenetic analysis.

In 1974, a 28-year-old man presented with a 12 cm sized ulcerated tumor involving the middle third of the stomach, which was originally diagnosed as "lymphosarcoma". Clinical recurrence of the lymphoma resulted in rapidly progressing disease and the patient died 4 months after initial diagnosis. Retrospective work-up of the 29-year-old tumor blocks revealed the typical histologic appearance and phenotype (CD20, CD10, BCL-6 positive) of Burkitt's lymphoma (BL) with a proliferation rate of 95%. By fluorescence in situ hybridization (FISH). the tumor cells were shown to harbor an IGH-MYC fusion indicating the presence of the hallmark Burkitt-translocation t(8;14)(q24;q32). Considering the typical clinical features of BL requiring appropriate treatment regimes the case presented here highlights the importance of modern histopathologic and molecular cytogenetic techniques for the proper classification of such rare lymphomas presenting at atypical sites.