[Drug-induced liver injury-significance of pathology]. / Drug-Induced Liver Injury ­ Stellenwert der Pathologie.

Many different medical agents, herbal products, and dietary supplements can induce drug-induced liver injury (DILI) as a clinically relevant complication. DILI, which is direct toxic or idiosyncratic, can have a broad spectrum of clinical appearances from elevation of liver enzymes to acute liver failure. DILI is categorized clinically according to the pattern of serum parameters or pathologically according to the pattern of histomorphology. Histopathological patterns can be described as hepatitic, granulomatous, cholestatic, ductopenic, fibrotic, steatotic, steatohepatitic, and vascular. Correlation to the corresponding drug can be carried out with the corresponding databases (US National Library of Medicine, Liver Tox; www.ncbi.nlm.nih.gov/books/NBK547852/ ). Liver biopsy, in contrast to a clinical/serological diagnostic, has the advantage of an exact resolution with evidence of pathophysiology, activity, regeneration, chronification, and prognosis. Co-occurrence of underlying liver disease can be excluded or confirmed. Histological patterns of DILI are described and illustrated. A diagnostic algorithm for the interpretation of liver biopsies is provided.

[Abdominal pain and unclear focal liver lesion in 46-year-old female patient]. / Rechtsseitiger Oberbauchschmerz und unklare Leberraumforderung bei einer 46-jährigen Patientin.

A 46-year-old woman presented with recurrent right upper quadrant pain. Abdominal ultrasound revealed an inhomogeneous liver lesion (4â€¯× 7 cm) with complex echotexture. Since further contrast-enhanced imaging tests were inconclusive and lesion integrity remained unclear, a left hemihepatectomy was performed. Histological examination revealed a hepatic epithelioid angiomyolipoma. Hepatic epithelioid angiomyolipoma is a rare, mostly benign, mesenchymal hepatic tumor, composed of smooth muscle cells, adipose tissue, and blood vessels of varying proportions, and its correct diagnosis remains a clinical challenge.

[Consequences of autopsies for the living : Causes of death in the clinical diagnosis "septic and toxic shock"]. / Konsequenzen von Autopsiebefunden für die Lebenden : Todesursachenfeststellungen bei der klinischen Diagnose "septisch-toxischer Schock".

BACKGROUND: There is reason to believe that the diagnosis of septic and toxic shock, as indicated on the death certificate, cannot be confirmed as the cause of death without autopsy and subsequent histological analysis. The external examination of the corpse can therefore not represent the sole basis for a reliable statement about the infection status of a corpse, e. g. as a prerequisite for embalming. MATERIAL AND METHODS: The validity of autopsy in determining septic and toxic shock as the cause of death is demonstrated in 7 exemplary cases. RESULTS: Decades of experience in a university pathology institute have shown that an external examination of the corpse alone is not suitable for certifying the cause of death if an infectious disease is suspected. Consequently, only autopsy with subsequent histological analysis provides reliable statements on the etiopathogenesis of the underlying process. Possible problems and discrepancies between clinical and pathological diagnoses are discussed on the basis of several cases with or without autoptic confirmation of the septic shock. The case of a missionary from Africa infected with Lassa virus serves to point out the seriousness of the threat an undiagnosed infection may represent to the attending staff. CONCLUSION: During the treatment of patients suspected to have an infectious cause of fever of unknown origin, compliance with the usual safety regulations, including adequate disinfecting measures, is essential. In cases with fatal outcome, not infrequently under the clinical picture of a septic and toxic shock, autopsy should be regularly performed to confirm the type of infection and the infectious cause of death. Rapid and open communication between the professional groups involved plays a crucial role in this process.

Prediction of outcome by lymph node ratio in patients with parotid gland cancer.

OBJECTIVE: Lymph node ratio (LNR) has been shown to be an independent predictor of recurrence risk and survival in different entities of carcinoma. METHODS: In this retrospective chart review, 128 patients with parotid gland cancer (PGC) subsequently treated by primary surgery were included. About 64% (n = 82) of these patients were additionally treated with adjuvant radiotherapy. Five-year overall survival rates were determined by subgroups based on LNR value. RESULTS: Lymph node ratio was found to be significantly associated with overall survival rate (P < 0.001). Using univariate analyses, pathological tumour-node-metastasis (TNM)-stage, UICC-stage grouping and extracapsular spread were found to be significant predictors of overall survival (P < 0.001). However, with a multivariate analyses, LNR remained the only independent predictor of overall survival (P = 0.043). CONCLUSIONS: After surgery for PGC, evaluation of the neck using LNR was found to reliably stratify the overall survival rate.

Histopathological assessment of tumour regression, nodal stage and status of resection margins determines prognosis in patients with oral squamous cell carcinoma treated with neoadjuvant radiochemotherapy.

OBJECTIVES: In advanced oral squamous cell carcinoma (OSCC), tumour regression after neoadjuvant radiochemotherapy seems to be an important prognostic factor. In this study, we intended to compare regression grading according to two previously described regression models and to analyse the association of tumour regression and other tumour characteristics with patients' characteristics and overall survival. METHODS: The retrospective study included 63 treatment-naive patients with primary OSCC of stages II-IV, who were treated with a concomitant neoadjuvant radiochemotherapy followed by radical surgery. Assessment of histopathological features was performed, there under regression grading according to two previously described regression models. RESULTS: Both tumour regression models provided comparable results in terms of distribution of different regression grades. In univariate analysis regression gradings (P = 0.003 and P = 0.007), ypT-stage, ypN-stage and status of resection margins (P < 0.001) were significantly associated with the 5-year overall survival (OS). None of the pretreatment clinicopathological parameters showed association with histopathological tumour regression. Multivariate analysis revealed the status of resection margins and of lymph node metastasis as statistically significant features for OS (P = 0.020 and P = 0.003, respectively). CONCLUSION: Tumour regression grading, nodal stage and status of resection margins predict prognosis in patients after neoadjuvant treatment. Currently, there are no pretreatment clinicopathological parameters, which predicting good tumour response to therapy. Thus, identifying non-responding patients, which might benefit from an intensified systemic therapy, requires surgical resection and consecutive histopathological assessment. Therefore, further investigation and validation of new, especially, molecular predictors of tumour response to radiochemotherapy remains an unmet, future clinical need.

The impact of laryngeal dysplasia on the development of laryngeal squamous cell carcinoma.

The aims of this study were to investigate the clinical course of patients with laryngeal dysplasia of various grades after surgical removal and analyze the percentage and time frame in which laryngeal dysplasia progresses to invasive carcinoma. The files of patients with surgical removal of laryngeal dysplasia and at least two microlaryngoscopies during a 10-year period were retrospectively reviewed. In total, 210 microlaryngoscopies of 70 adult patients were analyzed. Overall, of 295 biopsies taken 21 % showed no dysplastic alterations, 69 % showed dysplasia and 10 % showed invasive carcinoma, which had developed out of a laryngeal dysplasia. Dysplasia grades were equally distributed within the first three microlaryngoscopies (P = 0.31, P = 0.50, P = 0.55). The risk for developing laryngeal cancer out of laryngeal dysplasia showed no statistical correlation to the initial dysplasia grade (P = 0.26). On average, the malignant conversion took 127 weeks (mild dysplasia = 117 weeks; moderate dysplasia = 135 weeks; severe dysplasia = 82 weeks) (P = 0.27). Patients with laryngeal dysplasia are an inhomogeneous group and the grade of laryngeal dysplasia alone seems to be an insufficient prognostic factor for the development of laryngeal cancer.

MicroRNA profiling in locally advanced esophageal cancer indicates a high potential of miR-192 in prediction of multimodality therapy response.

To identify possible predictive markers, our study aimed to characterize microRNA (miRNA) profiles of responder and nonresponder in the multimodality therapy of locally advanced esophageal cancer. Initially, a microarray-based approach was performed including eight patients with esophageal cancer. Patients received neoadjuvant chemoradiation followed by surgical resection. Major histopathological response was defined if resected specimens contained less than 10% vital tumor cells (major/minor response: 4/4 patients). Intratumoral RNA was isolated from both, pretherapeutic tissue biopsies in addition to corresponding surgical specimens. The profile of 768 miRNAs was analyzed in 16 specimens (preneoadjuvant and postneoadjuvant therapy). Selected miRNAs were than analyzed on pretherapeutic and post-therapeutic biopsies of 80 patients with esophageal cancer, who underwent multimodality therapy (major/minor response: 30/50 patients). Comprehensive miRNA profiling identified miRNAs in pretherapeutic biopsies that were significantly different between major/minor responders. Based on the microarray results, miR-192, miR-194 and miR-622 were selected and the dysregulated miRNAs were studied on an extended series of esophageal cancer patients. The expression of miR-192, miR-194 and miR-622 was significantly reduced after neoadjuvant therapy confirming the array profiling data. Importantly, the pretherapeutic intratumoral expression of miR-192 and miR-194 was significantly associated with the histopathologic response of esophageal squamous cell carcinoma to multimodal therapeutic treatment. Therefore, in patients with locally advanced esophageal cancer undergoing neoadjuvant chemoradiation followed by esophagectomy, miR-192 and miR-194 in pretherapeutic biopsies are considered as indicators of major histopathologic regression.

Evaluation of histological regression grading systems in the neoadjuvant therapy of rectal cancer: do they have prognostic impact?

PURPOSE: Neoadjuvant treatment options have been developed to improve survival of patients with locally advanced rectal cancer. As only patients with a major histopatholocial response benefit from this preoperative therapy, several tumor regression grading systems have been developed. However, currently no accepted comprehensive grading system for clinical use is available. Therefore, we studied the impact of four histological regression grading systems in the neoadjuvant therapy of rectal cancer. METHODS: In this retrospective study, 85 patients with locally advanced rectal cancer were included. All patients received a neoadjuvant radiochemotherapy followed by surgical resection. The histological regression grading was evaluated using four classification systems: (1) grading system by the Japanese society of colorectal cancer, (2) grading system by Junker-Müller, (3) grading system by Dworak, (4) Cologne grading system. The four classification systems were analyzed for their prognostic impact. RESULTS: The following significant correlations were detected between the four classification systems and the ypTNM categories: (1) patients with a ypT3/4 category had significantly more often a worse histopathologic response in all four grading systems (p = 0.001); (2) a ypN0 category was significantly correlated with good histopathologic response only in the Cologne grading system; (3) in the Junker-Müller and Dworak grading systems, a ypM0 category was significantly correlated with a good histopathologic response (p = 0.046; p = 0.03). However, none of the used classification systems had a prognostic impact on survival. CONCLUSIONS: Currently, none of the analyzed histological regression grading systems is effective for clinical use.

Podoplanin expression in oral leukoplakia: prognostic value and clinicopathological implications.

OBJECTIVES: Current clinicopathological parameters cannot predict the risk of malignant transformation in oral leukoplakia sufficiently. Recent studies have shown that podoplanin is expressed in oral cancer and precancerous lesions. The aim of our study was to assess whether podoplanin expression in pretreatment biopsies could serve as a biomarker to predict the risk of malignant transformation in patients with oral leukoplakia. MATERIALS AND METHODS: In this retrospective study, podoplanin expression was analysed in 60 patients with previously untreated oral leukoplakia by immunohistochemistry. We investigated the associations between podoplanin expression and various clinicopathological variables including oral cancer-free survival (OCFS) and the SIN-classification. RESULTS: The chi-square-test revealed that high expression of podoplanin in pretreatment biopsies was associated with malignant transformation (P = 0.003) and increasing SIN-classification (P = 0.009). In univariate analysis, podoplanin expression in oral leukoplakia had a significant impact on OCFS (P = 0.009). The 5-year OCFS rate decreased from 100% for patients with no podoplanin expression to 41.7% for patients with the highest level of podoplanin expression. CONCLUSION: Although podoplanin expression and the SIN-classification served as factors to predict malignant transformation in patients with oral leukoplakia in univariate analysis, no significant impact was found for both factors in multivariate analysis.

Sequential control of hepatitis B virus in a mouse model of acute, self-resolving hepatitis B.

The determinants of an immune response to the human hepatitis B virus (HBV) are poorly understood. As studies in man and chimpanzees are limited, we aimed at developing a model of self-limiting hepatitis B in mice that helps to dissect the control of HBV by humoral and cellular immune responses. Adenoviral vectors containing 1.3-fold HBV genomes allowed an efficient and reproducible transfer of HBV genomes into mouse livers and initiated HBV replication in mice. HBV transcripts were detected in mouse livers for more than 3 months. HBsAg and HBeAg peaked around day 6 and slowly declined thereafter. A two-phase mild to moderate liver inflammation with elevated serum alanine transaminase activities was observed around day 7 and around day 70 when the vast majority of HBV-specific T cells were detected in the liver. HBV was initially controlled when specific and nonspecific T cells infiltrated the liver and intrahepatic interferon γ levels peaked around day 7, but replicated again from day 10 to day 24 and persisted at low levels thereafter despite the presence of HBV-specific T cells. Finally, HBV replication was terminated after a sufficient B-cell response had been mounted- indicated by anti-HBs seroconversion around day 35. HBV-specific T cells infiltrated the liver a second time around day 70 postinfection. This demonstrates that the established mouse model allows studying the onset and termination of HBV infection and will help to dissect the determinants of HBV control and clearance by the immune response.

Successful non-invasive treatment of stricturing fibrosing colonopathy in an adult patient.

OBJECTIVE: Fibrosing colonopathy (FC) is a rare entity associated with cystic fibrosis (CF). Until now, patients with stricturing FC have usually been treated surgically. In this instance, we aimed at avoiding surgery by applying a new conservative approach. - METHODS: Case report on an adult with CF who developed persistent abdominal pain due to a non-passable stricture in the right transverse colon. Histology confirmed fibrosing colonopathy. - RESULTS: Initially we treated the patient with prednisolone pulse therapy and additive antibiotic therapy. For maintenance therapy we administered budesonide. The patient underwent clinical, laboratory and endoscopic follow-up over a three-year period. The stricture healed and was easy to pass. A relapse in the cecum at the ileocecal valve again improved under steroid and antibiotic therapy. - CONCLUSIONS: We present a novel therapeutic approach for advanced stricturing FC in an adult patient which successfully avoided surgery (right hemicolectomy) over a three year follow up.

[Current aspects of liver allograft pathology]. / Aktuelle Aspekte zur Histopathologie im Rahmen der Lebertransplantation.

Liver allograft pathology continues to play an important role in the diagnosis and management of complications in the course of liver transplantation. This article summarizes important patterns of liver damage and also considers new aspects of transplant pathology from the literature. In the context of transplant rejection, late cellular rejection has aroused new interest. Histopathological changes in late rejection differ from acute cellular rejection and there seem to be similarities to de novo autoimmune hepatitis and idiopathic post-transplant hepatitis. Central perivenulitis is a typical change in late cellular rejection and should be differentiated from central toxic necrosis. Other important areas of transplant pathology include vascular and biliary changes resulting from surgical complications or as sequelae of immunosuppressive therapy. Furthermore, disease recurrence plays an important role and combined patterns of disease poses a challenge for the pathologist.

[Cytomegalovirus. Pathological-anatomical manifestations and detection methods]. / Zytomegalievirus. Pathologisch-anatomische Manifestation und Nachweisverfahren.

Human cytomegalovirus, a double-stranded DNA virus, is a member of the Herpesviridae family with high rates of transmission. Primary infection is often asymptomatic and leads to life-long latency. Reactivation may induce different organ manifestations, particularly in the setting of immunosuppression. Histopathologically, the virus can be detected by light microscopy. Different cell populations in different organs are transformed into"owl's eye" cells, which are pathognomonic. Immunohistochemistry and electron microscopy can be applied as complementary methods. Various PCR approaches in molecular pathology including nested PCR, capture probe ELISA-PCR and real time PCR confer HCMV tests high sensitivity and specificity. The present article discusses the methods of pathological diagnostic approaches and describes organ manifestations of HCMV.

Histological type of esophageal cancer might affect response to neo-adjuvant radiochemotherapy and subsequent prognosis.

BACKGROUND: This study investigates response and prognosis after neo-adjuvant chemoradiation (CTx/RTx) in patients with advanced esophageal carcinoma, according to histological type. PATIENTS AND METHODS: Patients with uT3 carcinoma of the esophagus treated with curative-intention esophagectomy from 1997 until 2006 were included in this retrospective analysis. Patients receiving preoperative CTx/RTx (5-fluorouracil, cisplatin, 36 Gy) were compared with those with primary surgery for pT3 tumors. Therapy response after CTx/RTx was evaluated using 'Cologne Regression Grade' (minor response: >or=10% vital residual tumor cells (VRTCs), major response: <10% VRTC or pathologic complete response). Prognosis was evaluated for adenocarcinoma (AC) and squamous cell carcinoma (SCC). RESULTS: Of 297 patients, 52% were SCC and 48% AC. In all, 192 patients underwent CTx/RTx, 100 (65%) SCC and 92 (64%) AC (nonsignificant). In SCC group 51% and in AC group 29% achieved major response (P < 0.01). Patients with major response had a 2-year survival rate (2y-SR) of 78% versus those with minor response or without CTx/RTx, with a 2y-SR of 45% (P = 0.001). Examining patients with major response exclusively, the prognosis of AC (2y-SR 85%) is better than that of SCC (2y-SR 54%) (P < 0.01). CONCLUSION: This retrospective study concludes that in esophageal tumors, response to and prognosis after neo-adjuvant CTx/RTx vary according to histology.

GNAS1 T393C polymorphism is associated with histopathological response to neoadjuvant radiochemotherapy in esophageal cancer.

Recent studies have shown an association between the GNAS1 T393C polymorphism and clinical outcome for various solid tumors. In this study, we genotyped 51 patients from an observational trial on cisplatin/5-FU-based neoadjuvant radiochemotherapy of locally advanced esophageal cancer (cT2-4, Nx, M0) and genotyping was correlated with histomorphological tumor regression. The C-allele frequency in esophageal cancer patients was 0.49. Pearson's chi(2)-test showed a significant (P<0.05) association between tumor regression grades and T393C genotypes. Overall, 63% of the patients in the T-allele group (TT+CT) were minor responders with more than 10% residual vital tumor cells in resection specimens, whereas T(-) genotypes (CC) showed a major histopathological response with less than 10% residual vital tumor cells in 80%. The results support the role of the T393C polymorphism as a predictive molecular marker for tumor response to cisplatin/5-FU-based radiochemotherapy in esophageal cancer.

Survivin expression in gastric cancer: Association with histomorphological response to neoadjuvant therapy and prognosis.

BACKGROUND AND OBJECTIVES: Neoadjuvant therapy is applied to improve the prognosis associated with advanced gastric cancer. Only patients with a major response seem to have a survival benefit. Predictive markers to allow individualisation of treatment could be helpful. We examined the association of survivin protein expression with histopathologic response to neoadjuvant chemotherapy and prognosis in patients with gastric cancer. METHODS: Forty patients with gastric cancer received neoadjuvant chemotherapy. Afterwards, 38 patients underwent total gastrectomy, while 2 patients received definitive chemotherapy because of tumour progression. Histomorphologic regression was defined as major response when resected specimens contained <10% tumour cells. Intratumoural survivin expression was determined by immunohistochemistry in pre- and post-therapeutic specimens and correlated with clinicopathologic parameters. RESULTS: The pre- and post-therapeutic intratumoural survivin protein expression was not associated with histomorphologic regression. Post-therapeutic survivin expression did not have prognostic impact. A significant association was detected between pre-therapeutic survivin levels and prognosis: patients with a higher survivin protein expression showed a significant survival benefit. In multivariate analysis pre-therapeutic survivin expression was characterised as an independent prognostic marker, besides pN-status and histopathologic regression. CONCLUSIONS: The pre-therapeutic survivin protein expression seems to be an independent prognostic marker in the multimodality treatment of advanced gastric cancer.

HIF-1alpha protein expression is associated with the environmental inflammatory reaction in Barrett's metaplasia.

The oxygen-regulated transcription factor subunit hypoxia inducible factor-1alpha (HIF-1alpha) is involved in angiogenesis, energy metabolism, cell survival, and inflammation. We examined the protein expression of HIF-1alpha within the progression of Barrett's sequence as well as the type and degree of the environmental inflammatory reaction. Squamous epithelium (SE), metaplastic, low- and high-grade dysplastic lesions, and tumor tissue of 57 resection specimens from patients with Barrett's adenocarcinoma were immunohistochemically analyzed. Active and chronic inflammatory reactions were classified according to the Updated Sydney System. HIF-1alpha protein expression increased significantly from SE to Barrett's metaplasia (BM) (P < 0.0001). From metaplasia through low- and high-grade dysplasia to cancer, no further increase could be detected. Active and chronic inflammation were also significantly different between SE and BM (P < 0.0001) but not during further progression in the sequence. HIF-1alpha protein expression did not correlate with histopathologic parameters or survival. HIF-1alpha protein expression pattern resembles the active and chronic environmental inflammatory reaction. All were significantly increased in metaplasia compared to SE without further change in tumor development. HIF-1alpha protein expression appears to be associated with inflammatory processes in the development of BM.

In vivo confocal laser endomicroscopy of the human liver: a novel method for assessing liver microarchitecture in real time.

BACKGROUND AND STUDY AIMS: Confocal endomicroscopy is a unique novel tool for in vivo histology in humans. Due to limitations imposed by the form of the equipment and by sterilization workflows, its use has been limited to the gastrointestinal tract so far. We have developed a rigid miniaturized probe for confocal endomicroscopy of the human liver during laparoscopy. PATIENTS AND METHODS: To assess the feasibility and potential clinical value of this new system (diameter 6.3 mm), 25 patients with liver disease were examined during routine minilaparoscopy under conscious sedation. RESULTS: Subsurface serial images (from surface to 250 microm) were generated in real time after fluorescein injection, permitting visualization of hepatocytes, bile ducts, sinusoids, and collagen fibers in vivo. Typical appearances of liver diseases were identified. Confocal diagnosis of moderate-to-severe steatosis and pericellular fibrosis correlated well with histopathologic analysis of subsequent biopsies (83.3 % and 84.6 %, respectively). In addition, intra-abdominal structures such as gallbladder, omentum, and stomach were analyzed by endomicroscopy. CONCLUSIONS: A miniaturized imaging system for confocal laparoscopy allowed in vivo microscopic analysis of healthy and diseased human liver for the first time during ongoing minilaparoscopy. Although such in vivo imaging does not yet compete with conventional histopathology, this novel confocal laparoscopy system may be of future relevance for immediate morphodynamic analysis in liver disease and the targeting of biopsies in vivo.

Serosal penetration is an important prognostic factor for gastrointestinal stromal tumors.

Predicting the malignant potential of gastrointestinal stromal tumors (GISTs) remains difficult. We assessed the value of serosal penetration, an established prognostic factor in solid tumors, to determine the clinical outcome in patients with GISTs. From 1996-2002, 25 consecutive patients with GIST underwent surgical resection at our Department. The histopathological presence of serosal penetration was assessed to predict clinical outcome. In addition, the established histopathological classification system by Franquemont (modified by using the Ki-67 proliferation index), was applied to each study patient. A Ki-67 index > or =5% (p<0.001) and a mitotic rate > or =5/50 high-power fields (p<0.047) significantly correlated with a shorter survival, whereas a tumor size >5 cm (p=0.07) tended towards a worse prognosis. The survival of patient groups defined by Franquemont (p=0.03) were of prognostic relevance. The presence of serosal penetration significantly correlated (p<0.01) with a shorter survival. Our data suggest that the presence of serosal penetration is a negative prognostic factor for GISTs. Serosal penetration may become a useful additional parameter for the classification of the malignant potential of GISTs. Since our data are merely hypothesis-generating, serosal penetration should be evaluated in large prospective databases.