[Show abstract][Hide abstract] ABSTRACT: We report a case of basaloid pancreatic carcinoma
with clinical, pathological, and genomic data. The 73-year-old
male patient had jaundice, acholic stool, diarrhea, weight loss,
and a large, painless gall bladder. His GGTwas highly elevated.
The pancreatic head contained a tumor, which was
resected by partial pancreatoduodenectomy with pancreatogastric
anastomosis, cholecystectomy, and lymphadenectomy.
On gross examination, a 3.8-cm white firm nodule was found,
which microscopically was composed of basaloid cell nests
with a less than usual desmoplastic stromal background and
focally PANIN. Immunohistochemical profile displayed
strong CK5/6, CK19, p63, EGFR, vimentin, and evident
CK14 expression and absence of expression of CK7,
chromogranin, synaptophysin, and BRCA1. A high Ki-67
index and p53 expression were noted. Sequencing of the most
frequent 46 oncogenes with ionTorrent (AmpliSeq PCR)
method identified PIK3CA, KRAS, and TP53 genes as drivers
and variants of the FGFR3, PDGFRA, KIT, KDR, EGFR,
RET, and ATM genes. The tumor we report displays histopathological
appearances similar to the previously described
case and a genomic landscape fitting to the general population
of pancreatic carcinomas.We hypothesize that this tumor may
belong to the group of DNA damage repair-deficient pancreatic
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 11/2014; · 2.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: From the aspect of the contemporary pathologic diagnostics of lung cancer, it is a key issue of
the tissue obtained since small biopsies and cytology still play a major role. In the non-small cell lung cancer
era, cytology considered equal to biopsy. However, in recent years it is unable to provide quality diagnosis
and must be replaced by biopsy. Various molecular techniques can handle various different tissue samples
which must be considered during molecular pathology diagnosis. Besides, tumor cell-normal cell ratio in the
obtained tissue as well as the absolute tumor cell number have great significance whose information must
be provided in the primary lung cancer diagnosis. Last but not least, for continuous sustainable molecular
diagnostics of lung cancer rational algorythms, affordable technology and appropriate reimbursement are
Translational Lung Cancer Research. 10/2014; 3(5):301.
[Show abstract][Hide abstract] ABSTRACT: The appearance of lung metastases is associated with poor outcome and the management of patients with secondary pulmonary tumours remains a clinical challenge. We examined the vascularisation process of lung metastasis in six different preclinical models and found that the tumours incorporated the pre-existing alveolar capillaries (i.e. vessel co-option). During the initial phase of vessel co-option, the incorporated capillaries were still sheathed by pneumocytes, but these incorporated vessels subsequently underwent different fates dependent on the model. In five of the models examined (B16, HT1080, HT25, C26 and MAT B-III), the tumour cells gradually stripped the pneumocytes from the vessels. These dissected pneumocytes underwent fragmentation, but the incorporated microvessels survived. In the sixth model (C38), the tumour cells failed to invade the alveolar walls. Instead, they induced the development of vascularised desmoplastic tissue columns. Finally, we examined the process of arterialisation in lung metastases and found that they became arterialized when their diameter grew to exceed 5 mm. In conclusion, our data show that lung metastases can vascularise by co-opting the pulmonary microvasculature. This is likely to have important clinical implications, especially with respect to anti-angiogenic therapies.
The Journal of Pathology 10/2014; · 7.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The clinical expectations how pathologists should submit lung cancer diagnosis have changed
dramatically. Until mid 90-ties a clear separation between small cell lung carcinoma (SCLC) and nonsmall
cell lung carcinoma (NSCLC) was mostly sufficient. With the invention of antiangiogenic treatment a
differentiation between squamous and non-squamous NSCLC was requested. When epidermal growth factor
receptor (EGFR) mutation was detected in patients with pulmonary adenocarcinomas and subsequent specific
treatment with tyrosine kinase inhibitors (TKIs) was invented, sub-classification of NSCLC and molecular
analysis of the tumor tissue for mutations was asked for. Pathologists no longer submit just a diagnosis, but
instead are involved in a multidisciplinary team for lung cancer patient management. After EGFR several
other driver genes such as echinoderm microtubule associated protein like 4-AL-Kinase 1 (EML4-ALK1),
c-ros oncogene 1 , receptor tyrosine kinase (ROS1), discoidin domain receptor tyrosine kinase 2 (DDR2),
fibroblast growth factor receptor 1 (FGFR1) were discovered, and more to come. Due to new developments in
bronchology (EUS, EBUS) the amount of tissue submitted for diagnosis and molecular analysis is decreasing,
however, the genes to be analyzed are increasing. Many of these driver gene aberrations are inversions or
translocations and thus require FISH analysis. Each of these analyses requires a certain amount of tumor cells
or one to two tissue sections from an already limited amount of tissues or cells. In this respect new genetic test
systems have been introduced such as next generation sequencing, which enables not only to detect multiple
mutations in different genes, but also amplifications and fusion genes. As soon as these methods have been
validated for routine molecular analysis this will enable the analysis of multiple genetic changes simultaneously.
In this review we will focus on genetic aberrations in NSCLC, resistance to new target therapies, and also to
methodological requirements for a meaningful evaluation of lung cancer tissue and cells.
Lung Cancer: Targets and Therapy 10/2014; 3(5):291.
[Show abstract][Hide abstract] ABSTRACT: Prostate cancer is one of the leading cancer types in males in the developed world. Radiotherapy is a major method in the curative treatment of prostate cancer however, up to 30% of the patients experience local relapse. Arachidonic acid metabolites have been shown to have important role in cancer. 12-lipoxygenase (12-LOX) has been proven to significantly influence prostate cancer progression, by apoptosis regulation and by promoting cancer cell survival. In this study we examined whether 12-LOX inhibition may increase radiation sensitivity of prostate cancer cells in vitro and in vivo. Prostate cancer cell lines were treated with 12-LOX inhibitors, different doses of radiation and the combination of 12-LOX inhibitors and radiation. We measured the effect of these treatments through clonogenic survival and apoptosis in vitro and tumor growth in vivo in a tumor xenograft model. 12-LOX inhibition and radiation both increased apoptosis and decreased clonogenic survival of prostate cancer cell lines in vitro. Combined treatment resulted in a supra-additive effect in vitro. In vivo both 12-LOX inhibition and radiotherapy caused delay in growth of the xenograft tumors but the combined treatment resulted in the strongest growth inhibition. The presented data prove that 12-LOX and its metabolite 12(S)-HETE have a major role in prostate cancer cell progression and radiosensitivity. We have shown by different methods in vitro and in vivo that inhibition of 12-LOX activity significantly sensitizes prostate cancer cells to radiation. Therefore we can state that 12-LOX inhibitors are promising compounds to be developed to become a new class of clinical radiation sensitizers in prostate cancer.
[Show abstract][Hide abstract] ABSTRACT: We have already demonstrated in a small cohort of 17 non-small cell lung cancer patients that ERCC1 (excision repair cross-complementation group 1) protein expression decreased after platinum-based treatment, however, certain clinicopathological parameters, such as histologic subtypes, ERCC1 expression scores, chemotherapeutic combinations, response rate, gender and smoking history were not analyzed. The aim of our present study was to extend the studied cohort and analyze those parameters. ERCC1 protein expression was examined in 46 patients treated with neoadjuvant chemotherapy. 46 bronchoscopic biopsy samples (27 squamous cell carcinomas /SCC/ and 19 adenocarcinomas /ADC/) together with their corresponding surgical biopsies were studied. ERCC1 immunohistochemistry was performed on formalin-fixed, paraffin-embedded tissues. Staining scores were calculated by multiplying the percentage of positive tumor cells (0-100) by the staining intensity (0-3). 24/27 bronchoscopic SCC tissues expressed ERCC1. Thirteen of these cases became negative after neoadjuvant therapy and the expression differences between pre- and postchemotherapy samples were highly significant (p < 0.001). 11/19 bronchoscopic ADC tissues expressed ERCC1. Six of these cases became negative after neoadjuvant therapy and the expression differences were significant (p < 0.010). There was no newly expressed ERCC1 postoperatively. Comparison of staining score changes revealed more pronounced decrease in SCC (p = 0.032). We observed no correlation between initial ERCC1 level or ERCC1 decrease and overall survival, but we demonstrated correlations between decrease in ERCC1 expression and histologic subtypes of tumors and gender. We could confirm our previous data in a larger cohort that platinum-based chemotherapy affects the ERCC1 expression probably referring to an induction of tumor cell selection.
[Show abstract][Hide abstract] ABSTRACT: Ectopic lymphoid structures have been described in several tumor types including metastatic lesions, but not primary tumors, of patients with melanoma. Here we present evidence of B-cell follicles in primary cutaneous melanomas, being present in 39 of 147 cases (27 %). B-cell clusters were associated with T lymphocytes, most of which belonging to CD45RO(+) memory T cells. A network of CD21(+) follicular dendritic cells was demonstrated in 8 of 22 cases studied (36 %). MECA-79(+) HEV-like venules were observed in the neighborhood of the follicles in the majority of cases, however, their presence was not confined to tumors hosting ectopic lymphoid structures. The appearance of B-cell aggregates did not show association with the outcome of the disease, although a trend for their higher prevalence was observed in thicker tumors. Our results show that neogenesis of lymphoid structures does occur in primary melanomas, albeit with lower frequency compared to that reported in metastases.
Pathology & Oncology Research 04/2014; · 1.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Platinum-based chemotherapy is the most common treatment in advanced-stage lung adenocarcinoma. Because the clinical significance of KRAS mutational status in this setting has not yet been clearly determined, a mutation subtype-specific analysis was performed in the so far largest cohort of Caucasian patients with KRAS mutant advanced-stage lung adenocarcinoma treated with platinum-based chemotherapy.
505 Caucasian stage III-IV lung adenocarcinoma patients with known amino acid substitution-specific KRAS mutational status and treated with platinum-based chemotherapy were included. The correlations of subtype-specific KRAS mutations with smoking status, progression-free and overall survival (PFS and OS, respectively) and therapeutic response were analysed.
Among 338 KRAS wild-type, 147 codon 12 mutant and 20 codon 13 mutant patients, there were no mutation-related significant differences in PFS or OS (P values were 0.534 and 0.917, respectively). Eastern Cooperative Oncology Group (ECOG) status and clinical stage were significant independent prognostic factors. KRAS mutation showed a significant correlation with smoking status (P=0.018). Importantly, however, G12V KRAS mutant patients were significantly more frequent among never-smokers than all other codon 12 KRAS mutant (G12x) subtypes (P=0.016). Furthermore, this subgroup tended to have a higher response rate (66% versus 47%; P=0.077). A modestly longer median PFS was also found in the G12V mutant cohort (233days; versus 175days in the G12x group; P=0.145).
While KRAS mutation status per se is neither prognostic nor predictive in stage III-IV lung adenocarcinoma, subtype-specific analysis may indeed identify clinically relevant subgroups of patients that may ultimately influence treatment decisions.
European journal of cancer (Oxford, England: 1990) 04/2014; · 4.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: There are conflicting data on the potential prognostic and predictive role of mutant KRAS in nonsmall cell lung cancer (NSCLC).
KRAS is the most frequently mutated oncogene in lung adenocarcinoma patients of non-Asian ethnicity. Novel data also revealed that allelic variants of mutant KRAS are different concerning their biochemistry, which may influence their prognostic and predictive role in NSCLC. Though mutant KRAS is not the target of molecular therapy yet, a molecular diagnostic algorithm involving KRAS determination can define a subgroup of tumors where no further diagnostic test is necessary due to the exclusivity of this driver oncogene mutation. Recent data indicated that the prognostic role of mutant KRAS in lung adenocarcinomas in Asian patients is evident, while more research is neccessary in non-Asian populations. Studies also suggest the potential predictive role of mutant KRAS in the context of chemosensitivity of NSCLC which may depend on the individual drug types. Recent data on the negative predictive role of KRAS mutation on the efficacy of EGFR tyrosine kinase inhibitor (TKI) therapies confirm previous findings.
Studies on the prognostic and predictive role of mutant KRAS in lung adenocarcinoma must be extended to the analysis of the potential role for allelic variants.
Current opinion in oncology 01/2014; · 3.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Platinum-based chemotherapy is the most common treatment in advanced-stage lung adenocarcinoma. Because the clinical significance of KRAS mutational status in this setting has not yet been clearly determined, a mutation subtype-specific analysis was performed in the so far largest cohort of Caucasian patients with KRAS mutant advanced-stage lung adenocarcinoma treated with platinum-based chemotherapy.
505 Caucasian stage III–IV lung adenocarcinoma patients with known amino acid substitution-specific KRAS mutational status and treated with platinum-based chemotherapy were included. The correlations of subtype-specific KRAS mutations with smoking status, progression-free and overall survival (PFS and OS, respectively) and therapeutic response were analysed.
Among 338 KRAS wild-type, 147 codon 12 mutant and 20 codon 13 mutant patients, there were no mutation-related significant differences in PFS or OS (P values were 0.534 and 0.917, respectively). Eastern Cooperative Oncology Group (ECOG) status and clinical stage were significant independent prognostic factors. KRAS mutation showed a significant correlation with smoking status (P = 0.018). Importantly, however, G12V KRAS mutant patients were significantly more frequent among never-smokers than all other codon 12 KRAS mutant (G12x) subtypes (P = 0.016). Furthermore, this subgroup tended to have a higher response rate (66% versus 47%; P = 0.077). A modestly longer median PFS was also found in the G12V mutant cohort (233 days; versus 175 days in the G12x group; P = 0.145).
While KRAS mutation status per se is neither prognostic nor predictive in stage III–IV lung adenocarcinoma, subtype-specific analysis may indeed identify clinically relevant subgroups of patients that may ultimately influence treatment decisions.
[Show abstract][Hide abstract] ABSTRACT: Tumor angiogenesis and receptor tyrosine kinases (RTK) are major novel targets in anticancer molecular therapy. Accordingly, we characterized the vascular network and the expression pattern of angiogenic RTK in the most frequent pediatric brain tumors. In a retrospective collection of 44 cases (14 astrocytoma, 16 ependymoma and 14 medulloblastoma), immunohistochemistry for VEGFR1, VEGFR2, PDGFRα, PDGFRβ, and c-Kit as well as microvessel labeling with CD34 and SMA were conducted on surgical specimens. We found a significantly higher vascular density in ependymoma. Glomeruloid formations were abundant in medulloblastoma but rare or almost absent in astrocytoma and ependymoma, respectively. C-Kit and VEGFR2 labeled blood vessels were more abundant in ependymoma than in the other two types of tumors. In contrast, medulloblastoma contained higher number of PDGFRα expressing vessels. In tumor cells, we found no VEGFR2 but VEGFR1 expression in all three tumor types. PDGFRα was strongly expressed on the tumor cells in all three malignancies, while PDGFRβ tumor cell expression was present in the majority of medulloblastoma cases. Interestingly, small populations of c-Kit expressing cancer cells were found in a number of medulloblastoma and ependymoma cases. Our study suggests that different angiogenic mechanisms are present in ependymoma and medulloblastoma. Furthermore ependymoma patients may benefit from anti-angiogenic therapies based on the high vascularization as well as the endothelial expression of c-kit and VEGFR2. The expression pattern of the receptors on tumor cells also suggests the targeting of specific angiogenic tyrosine kinase receptors may have direct antitumor activity. Further preclinical and biomarker driven clinical investigations are needed to establish the application of tyrosine kinase inhibitors in the treatment of pediatric brain tumors.
Pathology & Oncology Research 11/2013; · 1.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Established clinicopathologic characteristics of non-small cell lung cancer patients define a subgroup responding better to EGFR-TK inhibitors: adenocarcinoma histology, ethnicity, sex, smoking status, presence of activating EGFR mutation, and/or K-RAS wild type. However, EGFR mutation does not automatically lead to increased activity of the protein influenced by several factors. As adenocarcinoma can be further divided into histologic subclasses, we have compared adenocarcinomas without lepidic growth pattern (NLAC) to those characterized by pure or predominant lepidic growth (LAC) for EGFR protein expression and autophosphorylation activity (Y1173), as determined by immunohistochemistry. This pretarget therapy cohort comprised a total of 110 surgically operated patients of stage I non-small cell lung cancer: 49 NLAC and 61 LAC variants. The LAC group had a significantly better prognosis and the incidence of phospho-EGFR-positive tumors was significantly higher compared with NLAC. Patient sex did not influence EGFR activity, but the incidence of pEGFR-positive tumors was significantly lower among smoker patients. There was no statistically significant difference in EGFR or KRAS mutation frequencies between the 2 groups. In NLAC, pEGFR-positive tumors occurred exclusively among EGFR-mutant/K-RAS wild-type tumors. On the contrary, in LAC tumors, pEGFR-positive tumors were similarly frequent in the EGFR or K-RAS mutant groups indicating an interesting feedback activation of EGFR signaling in K-RAS mutant tumors. Our data also indicate that EGFR mutation leads to EGFR autophosphorylation only in a small fraction of adenocarcinoma patients, which might have clinical significance.
Diagnostic molecular pathology: the American journal of surgical pathology, part B 11/2013; · 2.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The mortality of patients with solid tumors is mostly due to metastasis that relies on the interplay between migration and proliferation. The "go or grow" hypothesis postulates that migration and proliferation spatiotemporally excludes each other. We evaluated this hypothesis on thirty-five cell lines (12 mesothelioma, 13 melanoma and 10 lung cancer) on both the individual cell and population levels. Following three-day-long videomicroscopy, migration, proliferation and cytokinesis-length were quantified. We found a significantly higher migration in mesothelioma cells compared to melanoma and lung cancer while tumor types did not differ in mean proliferation or duration of cytokinesis. Strikingly, we found in melanoma and lung cancer a significant positive correlation between mean proliferation and migration. Furthermore, non-dividing melanoma and lung cancer cells displayed slower migration. In contrast, in mesothelioma there were no such correlations. Interestingly, negative correlation was found between cytokinesis-length and migration in melanoma. FAK activation was higher in melanoma cells with high motility. We demonstrate that the cancer cells studied do not defer proliferation for migration. Of note, tumor cells from various organ systems may differently regulate migration and proliferation. Furthermore, our data is in line with the observation of pathologists that highly proliferative tumors are often highly invasive.
Experimental Cell Research 08/2013; · 3.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: No: 320 Date of submission: 03.18.2013 Section: Clinical science -pancreatic cancer
Collected series of resected intraductal papillary mucinous tumours (IPMTs) of the pancreas and correlation between the mucin expression profile and the malignant potential Background: IPMTs have attracted attention as a new pathological entity. Behind the different appearance of the different subtypes, there is different behaviour. Aim: The aim of our study was to present the different mucin expression and its correlation with the malignant potential. Patients & methods: The resected specimens were examined twice by different pathologists and when either different or uncertain diagnoses resulted, was the sample excluded. 41 patients were proved to have IPMT between the period of 2002-2012. Samples were immunhistochemically labelled for MUC1, MUC2 and MUC5AC. The patients were grouped according to type of the tumour, i.e. main duct-(MD), branch duct-(BD) or mixed-type (MX) IPMTs. We also created subgroups based on the mucin expression profile, like intestinal (I – MUC1-, MUC2+, MUC5AC±), pancreatobiliary (PB – MUC1+, MUC2-, MUC5AC±) and gastric-type (G – MUC1-, MUC2-, MUC5AC+). Results: 13 MD-, 10 BD-and 18 MX-type IPMTs were found. In total only 17,1% were found to be benign. The malignancy rate in the MD, BD and MX groups was 61,5%, 60%, 72,2%, respectively. Based on the mucin expression profile 17 I-, 11 G-and 13 PB-type IPMTs were found. All patients in the PB-group while 64,7% and 27,3% of the I-and G-groups were malignant, respectively. Conclusion: The lack of MUC1 expression may be related to a less invasive characteristics of IPMTs, while the MUC5AC expression alone can be related to benign potential. In contrast, MUC2+ and MUC5AC+ or MUC1+ and MUC5AC+ expression can increase the rate of success of diagnosing invasive IPMTs.
[Show abstract][Hide abstract] ABSTRACT: Pathological classification of malignant melanoma did not change in the past decade, it was just completed with UV-induced skin alterations. A new feature, however, is the establishment of molecular classification of melanoma indicating that beside the most frequent genetic alterations (BRAF, NRAS, CKIT mutations) there is a wide variety of rare molecular subclasses. Unfortunately, none of these genetic alterations can be used to discriminate benign lesions from malignant ones. The frequently used "melanoma" markers are mostly melanosomal markers, therefore they are not helpful for this diagnostic purpose either. More recently, novel FISH kits have been developed analyzing characteristic copy number alterations specific for malignant melanoma. Though melanosomal markers are helpful in differencial diagnostics, the presence of normal melanocytes in various tissues (lymph nodes, intestine or brain) requires application of molecular techniques when melanoma metastasis is in question.
[Show abstract][Hide abstract] ABSTRACT: Malignant melanoma biologically can be divided into non-metastatic and metastatic forms which cannot be predicted precisely using classical clinicopathological parameters, therefore studies on novel genetic or protein markers are abundant in the literature. These studies did not result in clinically useful markers because mostly ignored the results of studies on the genetic basis of metastatic potential of malignant melanoma. Accordingly, the list of promising novel markers is short (BCL2, CDK2, MART-1, OPN). Similar to other solid malignancies, introduction of targeted therapy into clinical practice of melanoma turned the attention toward the genetic basis of resistance to chemo- and targeted therapies. These novel data could lead to the development of molecular diagnostics which can help in designing more effective therapeutic strategies of malignant melanoma.
[Show abstract][Hide abstract] ABSTRACT: Metastasis of human cancer is an organ-selective process that is determined by anatomical and biological factors as well as by specific microenvironmental properties. Dissemination of visceral malignancies to the skin is rather rare and usually occurs in a later stage of the disease. Using statistical approaches, both positive (renal and lung cancers) and negative (pancreatic and liver cancers) organ preferences can be identified in a variety of cancers. While certain cancer types are characterized by random distribution for skin metastasis (liver cancer), a number of cancers demonstrate a colonization preference to the region of origin: lung cancer to the supradiaphragmatic (mostly chest) and colorectal cancers to the infradiaphragmatic (abdominal) skin regions. In certain cases, however, skin metastasis develops more frequently at specific distant locations, as evidenced by the dissemination of renal cancer at the head and neck region. These findings are clinically relevant and useful especially in patients where skin metastasis is the first indication of a malignancy. Nevertheless, it is a strong argument for the predominant role of microenvironmental factors in cancer dissemination. On the other hand, skin metastases of visceral cancers provide a unique model to analyze the pathomechanisms determining organ selectivity, including the organ-specific vascularization, the dermatome-specific innervation, or immunological and developmental factors.
CANCER AND METASTASIS REVIEW 05/2013; · 9.35 Impact Factor