[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.

The prognostic relevance of lymph node ratio in patients with oral squamous cell carcinoma treated with neoadjuvant therapy regimen and radical surgery.

BACKGROUND: This study aims at investigating the prognostic significance of lymph node ratio (LNR) in a cohort of patients with oral squamous cell carcinomas (OSCC), treated with neoadjuvant radiochemotherapy followed by radical surgery. METHODS: The study included 171 treatment-naive patients with biopsy-proven primary OSCC, being reviewed retrospectively. All patients received a concomitant neoadjuvant radiochemotherapy (RCT) followed by radical surgery of the primary tumor and neck dissection based on the pretreatment staging results. The Kaplan-Meier survival analysis method was used to estimate the events of interest for overall survival (OS). Prognostic factors were identified through univariate and multivariate analysis. RESULTS: The 5-year overall survival rate for all patients was 48 %. In univariate analysis, patient's age and data compiled from the histopathological examination as margin status, extracapsular spread, ypT, ypN, ypUICC, number of positive lymph nodes and lymph node ratio (LNR) had a statistically significant impact on overall survival. Multivariate analysis revealed an independent significant impact of patient age, ypT, margin status and LNR on OS. ypN showed no statistical significant impact on OS. CONCLUSION: Our results show that LNR is an important predictor for OS in patients with OSCC that were treated with neoadjuvant radiochemotherapy and radical surgery.

Neoadjuvant chemotherapy or chemoradiation for patients with advanced adenocarcinoma of the oesophagus? A propensity score-matched study.

BACKGROUND: Multimodal therapies are the standard of care for advanced adenocarcinomas of the oesophagus and gastro-oesophageal junction (AEG Types I and II). Only three randomised trials have compared preoperative chemotherapy with and without radiation. The results showed a small benefit for combined chemoradiation. In the meantime, newer therapy protocols are available. AIM: In a propensity-score matched study, we analysed patients with locally advanced AEG type I or II, treated with chemotherapy (FLOT-protocol) or chemoradiation (CROSS-protocol), followed by oesophagectomy, in a single high-volume centre. PATIENTS AND METHODS: Between 2011 and 2015, 137 patients with advanced (cT3NxcM0) adenocarcinoma received pre-operative therapy; 70% had chemoradiation (CROSS-protocol) and 30% had chemotherapy (FLOT-protocol). After propensity-score matching, 40 patients from the CROSS-group were selected for analysis. Postoperative histopathological response and prognosis were analysed. RESULTS: The two groups were comparable according to the matching criteria age, gender, tumour location, and year of surgery. R0-resection was achieved in 97% of patients in the CROSS-group and 85% of the FLOT-group (p = 0.049). Major response of the primary tumour was evident more often in the CROSS-group (17/40 pts. 43%) versus FLOT-group (11/40 pts. 27%) as well no lymph node metastasis (ypN0 = 68% versus ypN0 = 40%) (p = 0.014). Prognosis were not significantly different between the two groups. In multivariate analysis, only ypN-category was an independent prognostic factor. CONCLUSION: Compared to FLOT-chemotherapy, neoadjuvant chemoradiotherapy with the CROSS-protocol in locally advanced adenocarcinoma AEG types I and II resulted in better response by the primary tumour and less lymph node metastasis but without superior survival.

[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.

Bile duct carcinoma recurrence in the papillary region in a long-term survivor of hilar cholangiocarcinoma: a case report.

BACKGROUND: Because of its high rate of early recurrence and its poor prognosis, long-term survival after cholangiocarcinoma is rare; therefore, only limited information on patients surviving more than 5 years after surgical therapy is available. CASE PRESENTATION: We report the case of a 57-year-old white man who developed a distal bile duct carcinoma 9 years after curative surgical therapy of intrahepatic cholangiocarcinoma. He had undergone a right lobe hemihepatectomy 11 years ago. Nine years later, he was diagnosed with a distal bile duct carcinoma and a duodenopancreatectomy was performed. On histologic examination both carcinomas revealed a tubular and papillary growth pattern with cancer-free resection margins and for both carcinomas there were no signs of lymphatic infiltration or metastatic spreading. Targeted next-generation sequencing showed an identical activating mutation pattern in both carcinomas. CONCLUSIONS: Late recurrence of cholangiocarcinoma, even anatomically distant to the primary, in long-time survivors is possible and could be caused by a distinct tumor biology. A better understanding of the individual tumor biology could help hepatologists as well as hepatobiliary and pancreatic surgeons in their daily treatment of these patients.

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.

Influence of formalin fixation on tissue dimensions in palatal tonsils.

AIM: To investigate the change of tissue dimensions after formalin fixation, and to determine the optimal time of fixation. HYPOTHESIS: Formalin fixation may lead to shrinkage in tissue dimensions and may thus alter tumor stages. BACKGROUND: It is often observed in tumor surgery that the dimensions in vivo seem larger than after resection, and tissue appears to shrink further after formalin fixation. This might alter dimensions and assessment of spread of the tumor and thus lead to a lesser tumor classification and stage. In cases where the decision for adjuvant chemoradiation is based upon the stage, it may thus be of relevance for the patient to evaluate the pathologic and not the in vivo dimensions of the tumor. MATERIAL AND METHODS: In order to obtain comparable tissues, we investigated 100 palatal tonsils after cold steel dissection tonsillectomy for chronic tonsillitis. There were four time points investigated: directly after excision in the operating room and after four, 24 and 72 h of fixation in formaldehyde (4% Formaldehyde in phosphate buffer pH 7.4). The tissue was measured in the following dimensions: volume (ml), weight (g) and length, broadness and width (mm). RESULTS: The tissue size did not change significantly in dimensions except for an increase in length. The time of fixation did not influence the size. DISCUSSION: Formalin fixation does not significantly influence the tissue dimensions of palatal tonsils in comparison to direct ex vivo measurements. A minimal time of fixation of 20 h is required in order to stop all degenerative processes; however, longer fixation does not change the dimensions of the specimen. CONCLUSION: The null hypothesis has to be withdrawn that tissue dimensions are altered by formalin fixation. Thus, the histopathological measurements do not influence TNM staging.

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.

Thymoma--an important differential diagnosis of mediastinal tumours.

A 69-year-old man with slight dyspnoea underwent routine X-ray examination by his primary care physician. The X-ray and the CT showed a homogenous mass at the right side of the anterior mediastinum. The benignity and the origin of the tissue were still unknown. Therefore, we performed a CT-guided fine needle aspiration biopsy of the mediastinal mass. Histopathological examination finds out a spindle-cell or type A thymoma. Based on these findings we decide for a thoracoscopic resection of the thymoma. After the surgical intervention the patient was completely asymptomatic. In conclusion, because thymomas are prone to ectopic occurrence, they should be considered in the differential diagnosis of mediastinal tumors.

The prognostic impact of extracapsular lymph node involvement in rectal cancer patients: Implications for staging and adjuvant treatment strategies.

Limited data suggest that extracapsular lymph node involvement (LNI) has a negative prognostic impact in gastrointestinal malignancies. The aim of this study was to assess the prevalence and prognostic impact of LNI in patients with primary resected rectal cancer. Between 1997 and 2007, 243 rectal cancer patients underwent surgical therapy without neoadjuvant treatment at our Department. Of these, 12 (5%) patients received transanal endoscopic microsurgery and were not included for further analyses. In the remaining patients, a (low) anterior resection was performed in 79% and an abdominoperineal rectal amputation in 21%. The total number of analyzed lymph nodes and the number of metastatic lymph nodes with/without extracapsular LNI were determined and the prognostic impact of LNI was assessed. The median number of analyzed lymph nodes was 14. In total, 59% of patients were node-negative, 18% of patients were node-positive without extracapsular LNI and 23% of patients were node-positive with extracapsular LNI. A positive lymph node status with extracapsular LNI was significantly correlated with a poorer T-, N- and M-category, grading and more frequent lymphatic vessel infiltration compared with node-negative or node-positive without extracapsular LNI patients (p<0.001). The overall 5-year survival rate of node-negative patients was 75%, for node-positive without extracapsular LNI patients 69% and for node-positive with extracapsular LNI patients 36% (p<0.001). By multivariate analysis, the N-category with extracapsular LNI was characterized as an independent prognostic factor. Extracapsular lymph node involvement reveals an independent negative prognostic impact in patients with rectal cancer undergoing surgical therapy. Staging systems for rectal cancer should include the implementation of extracapsular lymph node involvement.

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.