Mismatch repair deficiency, chemotherapy and survival for resectable gastric cancer: an observational study from the German staR cohort and a meta-analysis.

PURPOSE: In a post hoc analysis of the MAGIC trial, patients with curatively resected gastric cancer (GC) and mismatch repair (MMR) deficiency (MMRd) had better median overall survival (OS) when treated with surgery alone but worse median OS when treated with additional chemotherapy. Further data are required to corroborate these findings. METHODS: Between April 2013 and December 2018, 458 patients with curatively resected GC, including cancers of the esophagogastric junction Siewert type II and III, were identified in the German centers of the staR consortium. Tumor sections were assessed for expression of MLH1, MSH2, MSH6 and PMS2 by immunohistochemistry. The association between MMR status and survival was assessed. Similar studies published up to January 2021 were then identified in a MEDLINE search for a meta-analysis. RESULTS: MMR-status and survival data were available for 223 patients (median age 66 years, 62.8% male), 23 patients were MMRd (10.3%). After matching for baseline clinical characteristics, median OS was not reached in any subgroup. Compared to perioperative chemotherapy, patients receiving surgery alone with MMRd and MMRp had a HR of 0.67 (95% CI 0.13-3.37, P = 0.63) and 1.44 (95% CI 0.66-3.13, P = 0.36), respectively. The meta-analysis included pooled data from 385 patients. Compared to perioperative chemotherapy, patients receiving surgery alone with MMRd had an improved OS with a HR of 0.36 (95% CI 0.14-0.91, P = 0.03), whereas those with MMRp had a HR of 1.18 (95% CI 0.89-1.58, P = 0.26). CONCLUSION: Our data support a positive prognostic effect for MMRd in GC patients treated with surgery only and a differentially negative prognostic effect in patients treated with perioperative chemotherapy. MMR status determined by preoperative biopsies may be used as a predictive biomarker to select patients for perioperative chemotherapy in curatively resectable GC.

[Pretherapeutic misclassification of esophageal cancer and adenocarcinoma of the esophagogastric junction : Possibilities and clinical consequences]. / Prätherapeutische Fehlklassifikationen bei Ösophaguskarzinomen und Adenokarzinomen des ösophagogastralen Übergangs : Möglichkeiten und klinische Konsequenzen.

During the course of a malignant disease, the tumor needs to be classified repeatedly in order to facilitate decision-making in treatment and to estimate patients prognosis; however, a wrong classification of tumors can occur in different stages of the disease course with tremendous consequences for the affected patients. This review discusses the possible misclassifications which can occur in patients with esophageal cancer or adenocarcinoma of the esophagogastric junction (EGJ), along with the consequences.

Proposal for an extended pTNM classification of thyroid carcinoma : Commentary on deficits of the 8th edition of the TNM classification.

In the 8th edition of the TNM classification of thyroid carcinomas, which was introduced in 2017, carcinomas with minimal extrathyroidal extension are no longer mentioned, which might cause problems. These tumors were explicitly categorized in previous TNM classifications (5-7th editions). Studies on the prognostic relevance of minimal extrathyroidal extension have shown conflicting results. Moreover, the vast majority of these studies retrospectively analyzed only subgroups of thyroid carcinomas (e.g. differentiated thyroid carcinoma, papillary thyroid carcinoma). The proposed subcategorization of the current TNM classification (8th edition) ensures the continuity of the parameter minimal extrathyroidal extension within the TNM categorization of thyroid carcinomas and also offers the possibility to prospectively analyze in a standardized manner the potential biological relevance of minimal extrathyroidal extension in relation to tumor categories (T/pT category).

Neoadjuvant rectal score as individual-level surrogate for disease-free survival in rectal cancer in the CAO/ARO/AIO-04 randomized phase III trial.

Background: Surrogate end points in rectal cancer after preoperative chemoradiation are lacking as their statistical validation poses major challenges, including confirmation based on large phase III trials. We examined the prognostic role and individual-level surrogacy of neoadjuvant rectal (NAR) score that incorporates weighted cT, ypT and ypN categories for disease-free survival (DFS) in 1191 patients with rectal carcinoma treated within the CAO/ARO/AIO-04 phase III trial. Patients and methods: Cox regression models adjusted for treatment arm, resection status, and NAR score were used in multivariable analysis. The four Prentice criteria (PC1-4) were used to assess individual-level surrogacy of NAR for DFS. Results: After a median follow-up of 50 months, the addition of oxaliplatin to fluorouracil-based chemoradiotherapy (CRT) significantly improved 3-year DFS [75.9% (95% confidence interval [CI] 72.30% to 79.50%) versus 71.3% (95% CI 67.60% to 74.90%); P = 0.034; PC 1) and resulted in a shift toward lower NAR groups (P = 0.034, PC 2) compared with fluorouracil-only CRT. The 3-year DFS was 91.7% (95% CI 88.2% to 95.2%), 81.8% (95% CI 78.4% to 85.1%), and 58.1% (95% CI 52.4% to 63.9%) for low, intermediate, and high NAR score, respectively (P < 0.001; PC 3). NAR score remained an independent prognostic factor for DFS [low versus high NAR: hazard ratio (HR) 4.670; 95% CI 3.106-7.020; P < 0.001; low versus intermediate NAR: HR 1.971; 95% CI 1.303-2.98; P = 0.001] in multivariable analysis. Notwithstanding the inherent methodological difficulty in interpretation of PC 4 to establish surrogacy, the treatment effect on DFS was captured by NAR, supporting satisfaction of individual-level PC 4. Conclusion: Our study validates the prognostic role and individual-level surrogacy of NAR score for DFS within a large randomized phase III trial. NAR score could help oncologists to speed up response-adapted therapeutic decision, and further large phase III trial data sets should aim to confirm trial-level surrogacy.

[Proposal for an extended pTNM classification of thyroid carcinoma : Commentary on deficits of the 8th edition of the TNM classification (German version)]. / Vorschlag zu einer erweiterten pTNM-Klassifikation der Schilddrüsenkarzinome : Kommentar zu Defiziten der 8. Auflage der TNM-Klassifikation.

In the 8th edition of the TNM classification of thyroid carcinomas, which was introduced in 2017, carcinomas with minimal extrathyroidal extension are no longer mentioned, which might cause problems. These tumors were explicitly categorized in previous TNM classifications (5-7th editions). Studies on the prognostic relevance of minimal extrathyroidal extension have shown conflicting results. Moreover, the vast majority of these studies retrospectively analyzed only subgroups of thyroid carcinomas (e.g. differentiated thyroid carcinoma, papillary thyroid carcinoma). The proposed subcategorization of the current TNM classification (8th edition) ensures the continuity of the parameter minimal extrathyroidal extension within the TNM categorization of thyroid carcinomas and also offers the possibility to prospectively analyze in a standardized manner the potential biological relevance of minimal extrathyroidal extension in relation to tumor categories (T/pT category).

[R1 resection of esophageal carcinoma]. / R1-Resektion beim Ösophaguskarzinom.

The microscopic identification of residual tumor tissue in the oral or aboral resection margins (R1 resection) of esophageal specimens following oncologic esophageal resection, increases the risk of tumor recurrence and disease-related morbidity. Esophageal resection with its associated risks is only meaningful, if an R0 situation can be safely achieved. The relevance of microscopic involvement of the circumferential resection margin (CRM) in esophageal carcinoma in its different definitions by the British and the American Societies of Pathology has up to now never been investigated in a prospective study. According to the German S3 guideline, radiochemotherapy should be performed in a postoperatively proven R1 situation, which cannot be converted by a curative extended re-resection into an R0 situation or in unfavorable conditions for an extended re-resection, independent of neoadjuvant therapy. In the case of an R1 situation in the region of the CRM, an extended re-resection is not simply possible on account of the anatomical conditions with corresponding limitations by the aorta and the spinal column, in contrast to extensions of the re-resection orally or aborally.

Distant metastases in colorectal carcinoma: A proposal for a new M1 subclassification.

INTRODUCTION: In 2010, the seventh Tumour-Node-Metastasis (TNM) cancer staging system of the International Union for Cancer Control (UICC) and the American Joint Committee of Cancer (AJCC) introduced a subdivision of M1 in the TNM classification of colorectal carcinomas. For the eighth TNM edition which will be released in the autumn of 2016 and will become effective in January 2017 new proposals are appreciated. The aim of our study was to define a new and better proposal for M1 subclassification. METHODS: In a total of 814 patients with stage IV colorectal carcinoma treated between 1995 and 2013 prognostic factors were analysed in univariate and multivariate analyses. RESULTS: Advanced age, treatment in the earlier period 1995-2003, involvement of multiple metastatic sites, and non-curative resection were found to be independent prognostic factors. In patients with only one metastatic site, survival was good in patients with liver or lung metastasis, moderate in patients with metastasis of the peritoneum or non-regional lymph nodes and poor in patients with other rarely metastatic involved organs. The new proposal defines M1a, Metastasis confined to one organ: liver or lung (2-year survival 51.6%); M1b, Metastasis confined to one organ: peritoneum or non-regional lymph nodes, or Metastasis confined to liver plus lung (2-year survival 39.4%); and M1c, Metastasis confined to one organ: all other sites, or Metastasis in more than one organ, except liver plus lung (2-year survival 21.6%). CONCLUSION: The new proposal can identify three prognostic groups in stage IV colorectal carcinomas with significant differences in survival.

[What Surgeons Need to Know About the Histopathological Processing of a Specimen]. / Was soll der Chirurg vom histopathologischen Präparate-Processing wissen?

A multitude of factors influence the state of tissue samples on their way from the biopsy site in the body to the pathologist's microscope. Some of these factors can be influenced by surgeons, while others are dealt with in pathology departments, but surgeons should know potential pitfalls and caveats and their influence on the pathohistological diagnosis. These factors influence diagnoses made on conventional stains, but even more so the results of immunohistochemical stains and molecular pathology examinations. Therefore, the work-up of tissue samples should be standardised. This is of utmost importance for biobank tissue samples, especially those for which a tissue treatment protocol is recommended.

[Molecular Pathological Aspects in Visceral Surgery]. / Molekularpathologische Aspekte in der Viszeralchirurgie.

New insights gained in the field of molecular medicine have led to fundamental progress in the diagnosis and treatment of tumour patients. Individualised treatment has been essentially facilitated by molecular diagnostics, which, by identifying and interpreting characteristic genetic alterations (biomarkers) in single cells and tissues, provide specific information to confirm the diagnosis and support the treatment of numerous diseases. Particularly with regard to the use of new targeted drugs, which often require the presence or absence of specific target structures or genetic alterations to induce response, the molecular pathological determination of predictive biomarkers plays an increasing role and helps clinicians to decide on optimal therapies for individual patients. The aim of this review is to highlight general aspects of molecular tumour pathology for relevant tumour entities and to present available targeted therapies.

[Neuroendocrine prostate cancer]. / Das neuroendokrine Prostatakarzinom.

BACKGROUND: Neuroendocrine carcinoma of the prostate (NEPC) is a rare, androgen-independent variant of prostate cancer with increasing incidence of over the past few years. It commonly progresses rapidly and is associated with a poor prognosis. Based on a different tumor biology compared to adenocarcinomas of the prostate, standard therapeutic approaches for prostate cancer are ineffective. To date, no specific treatment for NEPC exists. OBJECTIVES: The purpose of this work is to provide an overview of current histopathologic characteristics, histomorphologic classifications, and current as well as future treatment options for NEPC. MATERIALS AND METHODS: The literature was reviewed and clinical trials focusing on the above mentioned objectives are discussed. RESULTS: Current histomorphologic classifications aim to differentiate between NEPC including its variants and neuroendocrine transdifferentiated adenocarcinoma of the prostate. Regarding conventional chemotherapy, platinum-based schemes are still widely used. Antiangiogenetic drugs represent potential alternatives and are currently under clinical investigation. CONCLUSIONS: Histomorphological subtypes distinguish themselves in terms of aggressiveness, prognosis, and preferred therapeutic approaches. Treatment of NEPC differs fundamentally compared to adenocarcinoma of the prostate. There is only limited data available for the treatment of NEPC.

[New aspects for staging and grading of tumor metastases]. / Neue Aspekte von Staging und Grading von Tumormetastasen.

Modern therapeutic regimens have improved the prognosis of patients with metastatic tumours. This requires a subclassification of metastases with more categories than M0 versus M1/pM1. For some tumour entities UICC proposals exist for a subclassification of metastases: colorectal cancer, lung cancer, malignant bone tumours, malignant melanoma and Merkel cell carcinomas of skin, as well as uterine and prostate cancer. Metastases are graded according to the same principles as the corresponding primary tumours. Differences in the grade between primary tumour and metastases have been described without evident differences in prognosis. Recent reports showed a similar prognosis for colorectal carcinoma liver metastasis resected R0 or R1. In a certain percentage of R1 resections an inconsistent use of the R classification as to R1 may be responsible.

Impact of indication-shift of primary and adjuvant chemo radiation in advanced laryngeal and hypopharyngeal squamous cell carcinoma.

Based on level I evidence, postoperative platinum-based radiochemotherapy (PORCT) is the recommended standard of care in defined risk situations after resection of squamous cell carcinomas of the larynx and hypopharynx (LHSCC). The value of the addition of chemotherapy to adjuvant radiation in intermediate and high risk situations other than extracapsular spread or R1-/R2 resection is still debated. From 1993 to 2009, 555 patients (median follow-up: 24.4 months) with advanced LHSCC (UICC stages III-IVB) were treated in a curative intent. Patient data were continuously documented in the county of Leipzig cancer registry and were retrospectively analyzed as mono institutional survey. PORCT was introduced into the standard procedures in 2004, but also applied before in selected cases. Based on this paradigm shift, the patient population was divided into two comparative groups treated before and after 2004. 361 patients were treated before 2004. 43.8 % received primary surgery (OP) + postoperative radiotherapy (PORT) and 20.2 % OP + PORCT. 194 patients were treated after 2004: 21.1 % received OP + PORT and 35.6 % OP + PORCT. Regarding the PORCT groups, 20.6 % received cisplatin plus 5FU before 2004 which shifted to 59.4 % after 2004. The 3-year tumor-specific-survival rate of the whole cohort was improved from 47 to 60 % (p = 0.006). The subgroup treated with OP + PORT or PORCT improved from 56.1 to 68.5 % (p = 0.028). Localization proved to be a significant and independent factor. Only patients with advanced laryngeal cancer had significant improved survival (p < 0.01), while the improvement for hypopharyngeal cancer patients was not significant (p < 0.2). After 2004, there was a slight increase (+10.2 %) of primary radiochemotherapy (pRCT) due to stronger selection if R0 > 5 mm-resectability is unlikely. Standardised use of PORCT and pRCT considering clear indications showed to be significantly involved in improved survival in advanced LHSCC.

[New TNM classification of lung tumors]. / Neue TNM-Klassifikation der Lungentumoren.

The TNM classification of lung tumors has undergone many changes in the seventh edition published in 2010. These changes reflect current data and are based on the findings of the International Association for the Study of Lung Cancer (IASLC) from 81,495 patients and concern definitions of the T and M categories as well as stage grouping. They include a better description of regional lymph nodes of the lungs based on uniformly accepted definitions by the IASLC. The changes can lead to problems in the use of the definitions and will be discussed.

[New FIGO classification of ovarian, fallopian tube and primary peritoneal cancer]. / Neue FIGO-Klassifikation des Ovarial-, Tuben und primären Peritonealkarzinoms.

During recent years paramount changes have occurred in the pathogenesis of ovarian cancer and recent clinical studies identified new prognostic factors. Consequently, the FIGO has established a new staging system collectively covering carcinomas derived from the ovaries, the fallopian tubes and primary peritoneal cancers as well as malignant ovarian germ cell and sex-cord stromal tumors. The new staging system started on 01 January 2014. Major changes occurred in the FIGO IC/T1c stage with surgical spill (FIGO IC1/T1c1) versus capsule ruptured before surgery or tumor on ovarian or fallopian tube surface (FIGO IC2/T1c2) versus malignant cells in the ascites or peritoneal washings (FIGO IC3/T1c3). The regional lymph node metastases were subcategorised using a cut-off value of 10 mm as the largest dimension of the metastatic deposits. Distant metastases (excluding peritoneal metastases) were substaged as FIGO IVA/M1a in cases of cytologically or histologically proven pleural involvement and as FIGO IVB/M1b in cases of parenchymal metastases and metastases in extra-abdominal organs (including lymph nodes outside the peritoneal cavity and the inguinal lymph nodes).

[TNM classification of testicular tumors. Definitions and prerequisites for correct application]. / TNM-Klassifikation der Hodentumoren. Definitionen und Voraussetzungen einer richtigen Anwendung.

The TNM classification of testicular tumors has some special aspects. There is only one pT classification (with two exceptions) but there is an N as well as a pN classification. The category M1 can be subdivided in M1a and M1b, both of which can be used as cM and pM classifications. Serum tumor markers have been introduced as classification parameters in the TNM classification of testicular tumors which are used together with the anatomical spread in stage grouping but not in the definitions of the T, N and M categories.

[Proposals for standardization of autopsy reports]. / Vorschläge zur standardisierten Abfassung von Obduktionsberichten.

The decline in the number of autopsies not only in Germany has been attributed to several reasons. Complaints of clinicians about a non-uniform layout of autopsy reports may be one important reason. The lack of initiatives concerning standardization of autopsy reports contributes to a poor comparability of autopsy reports from different institutions and even within one institution. In order to promote harmonization of a protocol for autopsy results proposals for a standardization of autopsy protocols are given. These proposals are based on using modules for different parts of the autopsy protocols, thus giving different institutions the possibility to modify these modules.

[Case report about a 35 year old patient with cystic fibrosis and metastatic pancreatic cancer]. / Fallbericht eines 35 Jahre alt gewordenen Patienten mit Mukoviszidose und einem metastasierten Pankreaskarzinom.

Cystic fibrosis is the most common lethal genetic disease in Caucasian population. End-stage lung disease is the most frequent cause of death, however since therapeutic options have improved the life expectancy of patients with cystic fibrosis, increased incidences of gastrointestinal tumors including pancreatic carcinoma have been reported in several cohort studies from the USA and Europe. We report about a 35-year-old male patient who died from cystic fibrosis with a pancreatic carcinoma, which was histologically confirmed by autopsy. Additionally a low grade appendiceal mucinous neoplasm (LAMN) was diagnosed.