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The pathologist can contribute to recognizing hereditary causes of colorectal cancer via morphology. By identifying so-called index patients, it is possible to take preventive measures in affected families. The precise definition of the clinical presentation and the histopathological phenotype help to narrow the spectrum of expected genetic alterations. Novelties within Lynch syndrome include the recognition of EPCAM as a fifth gene locus, as well as the newly defined Lynch-like syndrome with evidence of somatic mismatch repair (MMR) mutations. With regard to polyposis-associated syndromes, the spectrum of polyps, whether serrated, hamartomatous or classic adenoma, is of crucial importance. The resulting differential diagnosis includes (attenuated) familial adenomatous polyposis ([a]FAP), MUTYH-associated polyposis (MAP), polymerase proofreading-associated polyposis (PPAP), phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS), Peutz-Jeghers syndrome and juvenile polyposis, each with a specific genetic background.

After introduction of the Bethesda microsatellite test panel demonstration of microsatellite instability (MSI) and/or loss of mismatch repair proteins (MMRD) was primarily used as a marker for cancer predisposition of Lynch syndrome (LS, previous: HNPCC). Nowadays MSI/MMRD has become an important biomarker to predict therapy response to checkpoint immunotherapies. MSI can be determined either by polymerase chain reaction (PCR)-based technologies with or without specification of fragment sizes or next generation sequencing (NGS) methods. Depending on the individual tumor entities, these test methods are used differently. Currently, MSI/MMRD is a tumor biomarker which covers a broad spectrum of indications in tumor pathology, especially in colorectal, endometrial and gastric cancer. In advanced carcinomas, MSI is an established predictor of therapy response to checkpoint-directed immunotherapies.

Hintergrund Antikorper gegen PD-1 oder PD-L1 konnen beim nichtkleinzelligen Bronchialkarzinom (NSCLC) starke und dauerhafte antitumorale Immunreaktionen hervorrufen. Die immunhistochemische Untersuchung von PD-L1 (PD-L1-Immunhistochemie [IHC]) wird als pradiktiver Biomarker getestet; in klinischen Studien wurden mehrere IHC-Assays und Auswertekriterien parallel eingesetzt.

The pathologist can contribute to recognizing hereditary causes of colorectal cancer via morphology. By identifying so-called index patients, it is possible to take preventive measures in affected families. The precise definition of the clinical presentation and the histopathological phenotype help to narrow the spectrum of expected genetic alterations. Novelties within Lynch syndrome include the recognition of EPCAM as a fifth gene locus, as well as the newly defined Lynch-like syndrome with evidence of somatic mismatch repair (MMR) mutations. With regard to polyposis-associated syndromes, the spectrum of polyps, whether serrated, hamartomatous or classic adenoma, is of crucial importance. The resulting differential diagnosis includes (attenuated) familial adenomatous polyposis ([a]FAP), MUTYH-associated polyposis (MAP), polymerase proofreading-associated polyposis (PPAP), phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS), Peutz-Jeghers syndrome and juvenile polyposis, each with a specific genetic background.

Valid HER2 testing is essential for the optimal care of patients with HER2-positive gastric cancer and the correct use of first-line treatment. Although all cases of breast cancer are routinely tested for the HER2 status, HER2 testing in gastric cancer has still not become part of the routine and is usually only done upon request by the therapist. An interdisciplinary group of German experts has taken on the challenges of HER2 testing in gastric cancer as an opportunity to address essential aspects and questions on the practical use of HER2 testing in this indication from the perspective of pathologists and therapists. The recommendations made in this article reflect the consensus of all participants and correspond to their opinions and long-term experience.

Mit Einfuhrung der Gesamtgenomsequenzierung konnte nachgewiesen werden, dass sich innerhalb eines Tumors eine erhebliche genetische Heterogenitat zeigt. Dieses Phanomen, welches das Vorkommen unterschiedlicher genetischer Zellklone in einem Tumor beschreibt, erschwert auch die HER2-Diagnostik. In diesem Ubersichtsartikel werden neue Erkenntnisse uber die Polysomie 17 und die genetische Tumorheterogenitat im Zusammenhang mit der HER2-Bestimmung des Mammakarzinoms dargestellt.

Although early stage malignant melanoma (MM) has a favorable prognosis five year survival rate is poor (

Non-neoplastic and non-hamartomatous colorectal polyps or tumor-like lesions comprise a very heterogeneous group of changes in the colorectal mucosa or the colon wall. Mucosal prolapse-associated lesions and inflammatory polyps, which are predominantly associated with chronic inflammatory bowel disease, are the most prominent examples for polypoid lesions difficult to distinguish from neoplastic lesions such as adenomas, hyperplastic/serrated polyps/adenomas and invasive carcinomas. The considerably less frequent tumor-like lesions like heterotopias, endometriosis, amyloid tumors and pseudolipomatous changes are histologically often well defined and should be considered in the differential diagnosis of colorectal lesions. The etiology, endoscopic and histological appearance of these entities and their most important differential diagnoses are discussed.

Etwa ein Drittel der kolorektalen Karzinome (KRK) treten familiar gehauft auf, wobei etwa 5% einen monogenetischen Erbgang aufweisen. Diagnostisch hilfreich ist die Unterscheidung zwischen Erkrankungen mit und ohne Polyposis sowie die Berucksichtigung von Tumorhistologie und Tumorspektrum des jeweiligen Patienten. Etwa 1% der KRK lassen sich auf die familiare adenomatose Polyposis coli (FAP) mit rasenartig vermehrten (>100) Adenomen zuruckfuhren. Weitere 2–3% betreffen das nicht mit Polyposis assoziierte HNPCC- bzw. Lynch-Syndrom, fur welches als einzigem Darmkrebssyndrom ein molekularer Gewebetest zur Verfugung steht. Immunhistochemisch erfolgt zunachst die Prufung auf einen Verlust der Expression eines Mismatch-Reparatur-Gens, woran sich bei unsicherem oder negativem Ergebnis der Test auf Mikrosatelliteninstabilitat (MSI) anschliest. Im Unterschied zu den vorgenannten Syndromen wird die MYH-assoziierte Polyposis (MAP) rezessiv vererbt und weist nur masig erhohte Polypenzahlen (im Mittel 15–30) auf. Sie ist differenzialdiagnostisch von attenuierten Formen der FAP mit

Die diagnostische Tumorpathologie sieht sich zunehmend mit einer neuen Herausforderung konfrontiert, die zunachst beim Mammakarzinom manifest geworden ist. Durch den Nachweis potenzieller Zielmolekule fur eine medikamentose Therapie, den sogenannten pradiktiven Markern, erlangt sie uber „Typing“ und „Grading“ hinaus eine gewachsene Informations- und Lenkungsfunktion fur die moderne Onkologie. Um dieser gerecht zu werden, wurden in Deutschland Ringversuche zur Uberprufung und Reproduzierbarkeit der am Tumorgewebe erfolgenden Bestimmungen der Steroidhormonrezeptoren und von Her-2 ins Leben gerufen, die seit 2002 jahrlich stattfanden und an denen jeweils bis zu 180 Institute teilnahmen. Mehr als 85% aller Teilnehmer erreichten gute Ergebnisse bei den in der taglichen Praxis vorherrschenden eindeutig positiven und negativen Fallen. Diskordante Bestimmungen waren eher bei den seltener vorkommenden niedrig-Steroidhormonrezeptor-exprimierenden Tumoren und den Her-2-Grenzfallen (2+) zu beobachten. Eine regelmasige Ringversuchteilnahme fuhrte gerade bei diesen problematischen Fallen zu deutlich verbesserten immunhistochemischen Farberesultaten. Die durch das Fach initiierte und sich selbst auferlegte Qualitatssicherung mit der erstmaligen Einrichtung von Ringversuchen wurde insbesondere durch die kooperierenden klinischen Facher als positive vertrauensbildende Masnahme begrust.

Die Diagnostik der Barrett-Schleimhaut und ihrer verschiedenen Grade der intraepithelialen Neoplasie (fruher: Dysplasie) gilt in mehreren Aspekten als schwierig. Auf einer Konsensus-Konferenz der Arbeitsgemeinschaft "Gastroenterologische Pathologie der Deutschen Gesellschaft fur Pathologie" wurde daher versucht eine Standardisierung der histopathologischen Diagnostik in folgenden Punkten zu erarbeiten: Diagnostik und Terminologie der Barrett-Mukosa, Abgrenzung der Barrett-Mukosa von der intestinalen Metaplasie der Kardia, diagnostische Kriterien der intraepithelialen Neoplasie, Anzahl der zu entnehmenden Biopsien sowie Wertigkeit zusatzlicher immunhistologischer und/oder molekularbiologischer Methoden. Abschliesend wurde eine Empfehlung zur Einholung einer "zweiten Meinung" bei intraepithelialer Neoplasie formuliert.

Beschrieben werden 3 Falle einer akuten segmentalen hamorrhagischen antibiotikaassoziierten Kolitis bei drei jungen Mannern im Alter von 30–33 Jahren, die wegen eines Infekts der oberen Luftwege, einer Tonsillitis oder im Rahmen einer HP-Eradikationstherapie oral mit Ampicillin oder Amoxicillin behandelt worden waren. Alle drei zeigten akut einsetzende krampfartige Bauchschmerzen und blutige Durchfalle, endoskopisch fand sich eine rechtsseitige segmentale hamorrhagische Kolitis, kein pathologischer Keimnachweis im Stuhl. Die histopathologische Untersuchung erbrachte den Befund eines Schleimhautodems mit fleckformigen oberflachlich betonten Einblutungen und eines schutteren mononuklearen Infiltrats der Lamina propria. Das Deckepithel war partiell desquamiert und wies intraepitheliale Ansammlungen von Erythrozyten auf. Bei allen Patienten kam es zu spontaner Restitution nach Absetzen der Medikation. Die diagnostischen Kriterien und deren Grenzen werden unter Berucksichtigung der vorliegenden Literatur diskutiert.

Neuroendocrine neoplasms of the digestive system are classified by current World Health Organization (WHO) guidelines as G1 and G2 neuroendocrine tumors (NET) as well as neuroendocrine carcinoma (NEC) based on proliferation and differentiation. The G1 NET tumors are highly differentiated, low proliferating and usually exhibit a favorable course of the disease without the development of metastases. In the case presented here, angioinvasion by a pT3 NET G1 was demonstrated after complete work-up of the mesenterial fat by acetone compression. The findings indicate an unfavorable course of disease requiring intensive surveillance.

The introduction of total genome sequencing led to the confirmation that tumors show substantial genetic heterogeneity. This phenomenon, which describes the presence of different genetic cell clones within a tumor also complicates the diagnostics of HER2. This article gives a review of new knowledge on polysomy 17 and genetic tumor heterogeneity in connection with HER2 determination of breast cancer.

Although early stage malignant melanoma (MM) has a favorable prognosis five year survival rate is poor (10%) in patients suffering from distant metastases. Due to molecular typing of MM recently high response rates were achieved in metastatic MM by using specific inhibitors directed against the mutated form of BRAF kinase, e.g. Vemurafinib and Dabrafinib. Therefore BRAF mutation analysis has become standard of care in advanced MM and pathologists are urged to provide a quality guaranteed molecular diagnostics. However, squamous neoplasias (e. g., keratoacanthomas) and recurrences of MM mostly within 6 months during targeted therapy point to the need of further translational research. Thus new drugs, such as MEK inhibitors, based on the MAP-kinase pathway downstream of BRAF have already effectively been used. Finally, the impact of molecular characteristics in different subtypes of MM (acral, mucosal, uveal) will be discussed with respect to their specific mutational spectrum (e.g. cKIT , NRAS , GNAQ).

Tumors of the anal canal are mostly epithelial in origin. The transition of gland-forming rectal mucosa via specialized urothelium-like cells at the dentate line to anal non-keratinized and finally perianal keratinized squamous epithelium implies a broad spectrum of tumor types, with most cancers exhibiting a mixture of different histological features. Moreover, secondary neoplasias extending into or metastasizing to the anal region need to be considered. Based on epithelial metaplasia at the transformation zone, poorly differentiated squamous anal carcinomas may show co-expression of both the squamous (CK5/6) and glandular type keratins (CK7). Since HPV infection of high-risk types (often 16 and 18) is etiologically associated with anal cancer, p16(INK4a) is highly sensitive and specific in the detection of high-grade anal squamous intraepithelial neoplasias (ASIN) and corresponding invasive squamous carcinomas. Diagnosis of secondary malignancies, including pagetoid extension into the anogenital region, requires the application of specific immunohistochemical marker panels.

Non-neoplastic and non-hamartomatous colorectal polyps or tumor-like lesions comprise a very heterogeneous group of changes in the colorectal mucosa or the colon wall. Mucosal prolapse-associated lesions and inflammatory polyps, which are predominantly associated with chronic inflammatory bowel disease, are the most prominent examples for polypoid lesions difficult to distinguish from neoplastic lesions such as adenomas, hyperplastic/serrated polyps/adenomas and invasive carcinomas. The considerably less frequent tumor-like lesions like heterotopias, endometriosis, amyloid tumors and pseudolipomatous changes are histologically often well defined and should be considered in the differential diagnosis of colorectal lesions. The etiology, endoscopic and histological appearance of these entities and their most important differential diagnoses are discussed.

One third of colorectal carcinomas (CRC) show familial clustering of which about 5% have a monogenetic trait. Distinction between disease with and without polyposis, tumor histology and tumor spectrum in a given patient are all of diagnostic relevance. Familial adenomatous polyposis (FAP) underlies approximately 1% of CRC characterized by rapidly forming (100) adenomas. In contrast to these about 2%-3% of CRC have a hereditary background without polyposis (HNPCC). This is the only hereditary tumour syndrome to date for which a tissue-based molecular screening test is available. Accordingly, expression analysis of mismatch repair genes (MSH2, MSH6 and MLH1, PMS2) is performed first. In the case of an equivocal result with no complete loss of expression testing of microsatellite instability (MSI) is added. In contrast to the other diseases MYH-associated polyposis (MAP) follows a recessive trait with polyp numbers usually between 15-30 adenomas and should be distinguished from attenuated forms of FAP with100 polyps in the differential diagnosis. In the case of suspected familial cancer syndrome genetic counseling is warranted in order to decide ultimately whether there is an indication for genetic testing (evidence of a germ-line mutation).

Based on data from a large multicenter phase III trial (ToGA study) trastuzumab has very recently been approved by the EMEA for metastatic gastric cancer and adenocarcinoma of the gastro-esophageal junction. Only patients with tumors which over express Her2 as defined by IHC2+ and a confirmatory FISH+ result, or IHC 3+, determined by an accurate and validated assay are eligible for trastuzumab therapy. However, testing of Her2 status by immunohistochemistry (IHC) differs from breast cancer in core aspects: 1. IHC2+/3+ is scored even though membranous staining is incomplete if membrane staining is clearly detectable even at low magnification (2.5x/5x, 3+) or medium magnification (10x/20x, 2+). 2. Additionally, membrane staining at the appropriate intensity found in at least 10% of tumor cells is restricted to resection specimens. Evaluation of Her2 in situ hybridization (ISH) is similar to breast cancer with ratio values ofor =2.0 indicating Her2 gene amplification. Taking these modifications into account and defining the HER2 positive subgroup as IHC 3+ and IHC2+/FISH+, approximately 16% of gastric cancers are considered Her2 positive, affecting mainly tumor regions with intestinal (gland forming) type carcinoma. In contrast to breast cancer, up to one-third of gastric cancers show a heterogeneous Her2 status both at IHC and ISH levels which favors bright field ISH over FISH.

Determining ErbB2/Her-2/neu status has become an essential part of breast cancer diagnosis and a prerequisite before considering a patient's eligibility for treatment with trastuzumab. Currently the most common techniques to assess ErbB2 status in routine practice are the identification of receptor overexpression by means of immunohistochemistry (IHC) and the analysis of gene amplification by means of dual color fluorescence in situ hybridisation (FISH). According to recent recommendations ("ASCO/CAP Guidelines" and German S3 guidelines for breast cancer) the choice of primary test procedure--IHC or ISH - is left to the individual institution. Both techniques are of equal predictive value provided that strict quality precautions have been taken: internal test validation by comparing IHC and (F)ISH, carrying out controls, and annual participation in round-robin tests. Equivocal IHC (score 2+) has to be checked by ISH for amplification. Borderline ISH (ratio 1.8-2.2 or gene copy number 4.0-6.0) should be retested by counting additional cells or performing IHC. In approximately 5% of cases these criteria give conflicting results and the gene copy number alone generates over 90% of the equivocal ISH cases, mostly due to chromosome 17 polysomy. These cases need to be tested by IHC since over-expression is very exceptional and only these tumors have the potential to be trastuzumab responders.

Today, more than 80% of men diagnosed with prostate cancer (PCA) by PSA screening do not die from the sequelae of their disease. About 70% present with early, organ-confined cancer and almost half of them are small (5 cm(3)) without evidence of progression over years (insignificant PCA). It is assumed that screening brings the diagnosis of PCA forward by about 9 years and that in almost one third of these cases immediate radical prostatectomy or radiotherapy would result in overtreatment. Thus, the treatment strategy of "active surveillance" with selective but delayed intervention for patients with organ-confined PCA could be an attractive alternative to the known curative therapy options. However, a prerequisite of such a therapeutic approach would be a precise identification of patients at high risk for cancer progression. Careful work-up of prostate core needle biopsies including improved pre-embedding preparation and detailed interpretation are of the utmost importance. A Gleason scoreor =6 and tumor in only one or two cores are considered predictive of organ-confined cancer. Pathologists should concentrate on correct Gleason scoring in core needle biopsies and identification of lesions that exclude a patient from active surveillance.

In the age of personalized medicine, and in addition to typing and grading, breast cancer pathologists are now also involved in determining biomarkers such as steroid hormone receptors and Her-2, which are of the utmost importance in adjuvant therapy. In order to assure quality of these biomarker assays, external proficiency testing has been implemented in Germany. Since 2002 trials have been conducted annually, with up to 180 participating laboratories. More than 85% of all participants achieved good results in clearly negative and positive cases seen in daily practice. If at all, discordant results were observed in the rarer low steroid-hormone receptor expressing tumors and Her-2 borderline cases (2+). Regular participation in interlaboratory testing leads to significantly improved immunohistochemical results, particularly in these problematic cases. Tissue microarrays (TMA) with 20-24 different breast cancer samples including cell lines meant that a huge number of pathologists were challenged with identical samples, providing the prerequisite for comparability. Participation is recommended for pathology departments involved in the service for breast units. The organizational frame work of the trials is described here. The confidence of cooperating disciplines in breast cancer biomarkers assessed by pathologists will be fostered by external proficiency testing as presented here.

Although twin studies indicate that inherited genetic factors contribute to about 35% of colorectal cancers (CRC), the exact genetic background has currently been elucidated in only 5-10% of cases. These comprise several hereditary cancer predisposition syndromes that present with a high number of syn- or metachronous neoplasms within an affected person and/or family. Many of these tumors exhibit typical histopathological changes. In general, one should discriminate between cancer syndromes associated with adenomatous and non-adenomatous (i.e., hamartomatous) polyps, the latter being quite rare. The patient's age often serves as a substantial hint to hereditary cancer. The next step of diagnostic work-up includes analysis of microsatellite instability (MSI) together with immunohistochemical detection of a loss of expression in one of the most frequently affected mismatch repair genes (MSH2, MSH6; MLH1, PMS2). Finally, the molecular demonstration of a gene mutation in the blood or germline is the most expensive and tedious procedure. This requires a signed informed consent from the patient after appropriate genetic counseling.

The simultaneous occurrence of different hepatic tumors is rare. We present for the first time a concomitant manifestation of an angiomyolipoma, a focal nodular hyperplasia, a bile duct adenoma, and a cavernous hemangioma in a 63-year-old female patient. The largest of the tumors, preoperatively suspected to be hepatocellular carcinoma, was an angiomyolipoma with monotypic epithelioid histology and positive immunoreactivity for HMB-45, actin, desmin, and pancytokeratin. The significance of immunohistochemistry for the differential diagnosis of hepatic neoplasms is emphasized. Finally, a review of the literature with special regard to etiology and pathogenesis of neoplastic liver disease is given, leading to the assumption that the association of four different benign intrahepatic tumors is rather more fortuitous than pathogenetically related, despite the putative similar pathogenesis of focal nodular hyperplasia and hemangioma.

Three cases of acute segmental hemorrhagic antibiotic-associated colitis are described occurring in three male adults between 30 and 33 years of age after treatment with oral ampicillin or amoxicillin because of upper respiratory tract infection, tonsillitis, or HLO eradication therapy, respectively. All presented with cramping abdominal pain and bloody diarrhoea of acute onset, however, microbial analysis of fecal samples was negative. Endoscopy showed right-sided segmental hemorrhagic colitis. Histopathological examination demonstrated edema, patchy superficial hemorrhage and a scattered predominantly mononuclear infiltrate of the lamina propria. The surface epithelium was partly desquamated and displayed foci of grouped intraepithelial red blood cells. All patients spontaneously recovered after discontinuation of antimicrobial therapy. The value and limitations of diagnostic features are discussed with respect of the literature.

We present a case of pigmented adrenal paraganglioma in a 39-year-old female patient with associated neurofibromatosis type 1 (NF1). Histology showed features typical for phaeochromocytomas except for varying amounts of brown pigment within the cytoplasm of tumour cells, which proved to be melanin by histochemical and ultrastructural analysis. The occurrence of melanin is believed to reflect the origin of this neoplasm from multipotent cells of the neural crest. Pigmented phaeochromocytoma has to be taken in consideration in the differential diagnosis of pigmented neoplasms, especially in the adrenal gland, where it has to be discriminated from pigmented cortical adenoma (so-called black adenoma) and primary malignant melanoma.

Restrictive dermopathy is a rare, fatal, autosomal recessive, congenital skin disease. Rigidity of translucent thin skin, which is thus highly vulnerable and tears, spontaneously causes intra-uterine fetal akinesia or hypokinesia deformation sequence (FADS), characteristic dysmorphic facies with fixed open mouth in O position, and generalized joint contractures (arthrogryposis). Polyhydramnios and pulmonary hypoplasia are distinctive manifestations, leading to respiratory insufficiency and premature delivery at about 31 weeks of gestation. We report on a case of a prematurely born infant who presented with the typical morphological features and describe the light- and electron-microscopical findings as described in the literature.

During the last few years, the molecular basis of several cancer predisposition syndromes has been discovered which offers new tools for cancer prevention and early detection. This will be demonstrated in one of the most frequent hereditary cancer syndromes, namely the hereditary nonpolyposis colorectal cancer (HNPCC) which accounts for about 5% to 8% of CRC. Thereby, families with exclusively CRC (Lynch type I syndrome) and those with extracolonic cancers especially of endometrium, stomach, small bowel and upper urinary tract (Lynch type II syndrome) can be discriminated. At the molecular level, HNPCC is caused by germline mutations in one of the mismatch repair genes (hMSH2, hMLH1, hMSH6, hPMS2). Thus, nucleotide mispairings occurring particularly within simple repetitive genomic sequences (microsatellites) during replication are no longer be repaired properly and can be demonstrated by PCR as so-called microsatellite instability (MSI). Since more than 90% of HNPCC associated and only about 15% of sporadic CRC show MSI, this test is a useful tool for HNPCC screening. In case of a negative result HNPCC is highly unlikely. In positive cases (withor = 2 out of 5 unstable defined microsatellite markers) the definite molecular diagnosis can only be obtained by sequencing the mismatch repair genes from the patient's blood or normal DNA. As immunohistochemistry reveals loss of hMSH2 or hMLH1 expression in most MSI positive CRC, these data provide useful information for the sequencing strategy. Molecular tumor screening by MSI test and immunohistochemistry is recommended in patients i.) with a positive family history (acc. to the Amsterdam criteria), ii.) suffering from multiple HNPCC related carcinomas, iii.) with HNPCC related cancer before 45 ys of age, and iv.) with right-sided CRC exhibiting medullary, signet-ring or mucinous differentiation. Finally, these tests as well as genetic counseling and treatment of the patient need to be done by an interdisciplinary approach. Thereby, the pathologist can substantially contribute to identify HNPCC related carcinomas either by clinical or morphological criteria and to initiate the molecular screening test.