[Show abstract][Hide abstract] ABSTRACT: Figure 1. Pulmonary tissue, (hematoxylin and eosin stain, original magnification ×10) from the explanted lungs from the patient in our study with Gaucher disease and severe pulmonary hypertension. There are vascular changes with intimal thickening and medial hypertrophy of small centrilobular pulmonary arteries consistent with pulmonary hypertension. The insert (hematoxylin and eosin stain, original magnification ×40) shows a cluster of Gaucher cells in the pulmonary alveolar interstitium.
[Show abstract][Hide abstract] ABSTRACT: Introduction:
Pulmonary neuroendocrine tumors (pNETs) are difficult to classify. We performed a population-based analysis to investigate the pNETs nomenclature application in daily pathology practice METHODS: Conclusions from pathology reports (2003-2012) describing carcinoids, (large cell) neuroendocrine carcinomas ((LC)NEC) and carcinomas with neuroendocrine features/differentiation were retrieved from PALGA (the Dutch Pathology Registry) by queries on location and diagnosis and screened for terminology. Cases with non-pulmonary/unknown origin and small cell lung cancer (SCLC) were excluded. Diagnoses were clustered into subgroups and retrieved terminology was compared to WHO 2015 diagnoses. By means of an online questionnaire, interpretation of the retrieved non-WHO nomenclature from pathology reports was evaluated (physicians (N=35) / pathologists (N=19).
3216 unique pathology conclusions with 55 different pNET diagnoses (N=3052) and 20 uncertain diagnoses (N=164) were analyzed. Non-WHO nomenclature was used in 15% (N=488) of diagnoses. Diagnoses could be clustered into carcinoids (N=1086), NEC (N=1316), carcinomas with neuroendocrine features/differentiation (N=624) and unspecified pNETs (N=26). Non-WHO nomenclature within these clusters was found for 7% of carcinoids, 20% of NECs, 13% of carcinomas with neuroendocrine features/differentiation and 100% of unspecified pNETs and was observed more often in conclusions of biopsy/cytology specimens (62/12%) compared to resection specimens (26%). Questionnaire analysis revealed that 4/19 non-WHO nomenclature diagnoses were uniformly interpreted (>50% agreement) by physicians and 10/19 diagnoses by pathologists.
In 15% of pNETs other than SCLC, a non-WHO nomenclature diagnosis was provided, more frequently on smaller specimens. The interpretation was different between physicians and pathologists. Application of uniform nomenclature among all clinicians is advocated.
Preview · Article · Jan 2016 · Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer
[Show abstract][Hide abstract] ABSTRACT: This is the second part of a two-part review on soft tissue tumours which may be encountered in the mediastinum. This review is based on the 2013 WHO classification of soft tissue tumours and the 2015 WHO classification of tumours of the lung, pleura, thymus and heart and provides an updated overview of mesenchymal tumours that have been reported in the mediastinum.
Preview · Article · Sep 2015 · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin
[Show abstract][Hide abstract] ABSTRACT: The mediastinum is an anatomically defined space in which organs and major blood vessels reside with surrounding soft tissue elements. The thymus is an important organ in the mediastinum, and many of the masses encountered in the mediastinum are related to this organ. Most neoplasms diagnosed in the mediastinum are epithelial tumours (thymomas and thymic carcinomas), lymphomas or germ cell tumours. In contrast, soft tissue tumours of the mediastinum are rare. In 1963, Pachter and Lattes systematically reviewed soft tissue pathology of the mediastinum, covering the hitherto described [2, 226, 227] In this review, based on the 2013 WHO classification of soft tissue tumours and the 2015 WHO classification of tumours of the lung, pleura, thymus and heart, we provide an updated overview of mesenchymal tumours that may be encountered in the mediastinum.
Preview · Article · Sep 2015 · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin
[Show abstract][Hide abstract] ABSTRACT: Aggressive fibromatosis (AF) is a locally infiltrating soft-tissue tumor. In a population-based study in the Netherlands, we evaluated time trends for the incidence and treatment of AF.
In PALGA: Dutch Pathology Registry, all patients diagnosed between 1993 and 2013 as having extra-abdominal or abdominal wall aggressive fibromatosis were identified and available pathology data of the patients were evaluated. Epidemiological and treatment-related factors were analyzed with χ (2)and regression analysis.
During the study period, 1134 patients were identified. The incidence increased from 2.10 to 5.36 per million people per year. Median age at the time of diagnosis increased annually by B 0.285 (P = 0.001). Female gender prevailed and increased over time [annual odds ratio (OR) 1.022; P = 0.058]. All anatomic localizations, but in particular truncal tumors, became more frequent. During the study period diagnostic histological biopsies were performed more often (annual OR 1.096; P < 0.001). The proportion of patients who underwent surgical treatment decreased (annual OR 0.928; P < 0.001). When resection was preceded by biopsy, 49.8 % of the patients had R0-resection versus 30.7 % in patients without biopsy (P < 0.001).
In this population-based study, an increasing incidence of extra-abdominal and abdominal-wall aggressive fibromatosis was observed. The workup of patients improved and a trend towards a nonsurgical treatment policy was observed.
Full-text · Article · Jun 2015 · Annals of Surgical Oncology
[Show abstract][Hide abstract] ABSTRACT: Previous studies have shown that Imatinib mesylate (Gleevec), a selective tyrosine kinase inhibitor of c-KIT and platelet-derived growth factor receptors (PDGFR), is highly effective in c-KIT/CD117-positive gastrointestinal stromal tumors (GIST), especially in those having activating mutations in c-kit exon 11. In addition, gain-of-function mutations in the juxtamembrane domain (exon 12) and the kinase activation loop (exon 18) of PDGFRα were found in GISTs. Importantly, the presence and type of these mutually exclusive c-KIT or PDGFRα mutations were found to be associated with the response to imatinib. Here, we examined the prevalence of c-kit exon 11 and PDGFRα exons 12 and 18 mutations in other tumor types known to express these tyrosine kinase receptors in order to explore which other cancer types may potentially benefit from imatinib treatment. We determined the mutational status of these commonly mutated exons by direct sequencing in 11 different tumor types (in total: 215 unrelated cases), including GIST, chordoma, and various distinct tumors of lung, brain and its coverings, and skin cancer. Of the 579 exons examined (211 c-kit exon 11, 192 PDGFRα exon 12, 142 PDGFRα exon18, 17 PDGFRα exon 12 and 17 PDGFRβ exon 18), only 12 (all GIST) harbored mutations (10 c-kit exon 11 and 2 PDGFRα exon18). From these data we conclude that activating c-KIT and PDGFR mutations are sporadic in human cancers known to overexpress these tyrosine kinase receptor genes and suggest that, except in GIST, this overexpression is not correlated with activating mutations. The latter may imply that these wild-type c-KIT and PDGFR tumor types will probably not benefit from imatinib treatment.
Full-text · Article · Oct 2014 · Cancer biology & therapy
[Show abstract][Hide abstract] ABSTRACT: Background
Aggressive fibromatosis (AF) comprises tumors with a varying biological behavior. Genetic tumor characteristics may be predictive of recurrence; hence, the prognostic value of three specific mutations on the CTNNB1 gene was evaluated in relation to known clinicopathologic risk factors in patients with primary, sporadic AF.
In a multi-institutional retrospective cohort study of patients with primary extra-abdominal and abdominal wall AF who underwent surgical treatment, the original pathology specimens were reviewed for the presence of a T41A, S45F, and 45P mutations on the CTNNB1 gene. For these mutations, the risk of recurrence was analyzed by the Kaplan–Meier method with log-rank test. Univariable and multivariable Cox regression was performed to calculate hazard ratios.
A total of 101 patients were analyzed. During a median follow-up of 41 months, 17 recurrences were detected; the cumulative 5-year recurrence rate was 22.8 %. A specific CTNNB1 mutation was found in 76 patients, with the majority of patients having a T41A mutation (n = 49). CTNNB1 mutations were associated with the risk of recurrence: the presence of a S45F mutation was associated with a 5-year cumulative risk of recurrence of 63.8 % (P
No preview · Article · Oct 2014 · Annals of Surgical Oncology
[Show abstract][Hide abstract] ABSTRACT: The aim of our study was to evaluate the quality of histo- and cytomorphological features of PAXgene-fixed specimens and their suitability for histomorphological classification in comparison to standard formalin fixation. Fifteen colon cancer tissues were collected, divided into two mirrored samples and either formalin fixed (FFPE) or PAXgene fixed (PFPE) before paraffin embedding. HE- and PAS-stained sections were scanned and evaluated in a blinded, randomised ring trial by 20 pathologists from Europe and the USA using virtual microscopy. The pathologists evaluated histological grading, histological subtype, presence of adenoma, presence of lymphovascular invasion, quality of histomorphology and quality of nuclear features. Statistical analysis revealed that the reproducibility with regard to grading between both fixation methods was rather satisfactory (weighted kappa statistic (k
w) = 0.73 (95 % confidence interval (CI), 0.41–0.94)), with a higher agreement between the reference evaluation and the PFPE samples (k
w = 0.86 (95 % CI, 0.67–1.00)). Independent from preservation method, inter-observer reproducibility was not completely satisfactory (k
w = 0.60). Histomorphological quality parameters were scored equal or better for PFPE than for FFPE samples. For example, overall quality and nuclear features, especially the detection of mitosis, were judged significantly better for PFPE cases. By contrast, significant retraction artefacts were observed more frequently in PFPE samples. In conclusion, our findings suggest that the PAXgene Tissue System leads to excellent preservation of histomorphology and nuclear features of colon cancer tissue and allows routine morphological diagnosis.
Full-text · Article · Aug 2014 · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin
[Show abstract][Hide abstract] ABSTRACT: Pulmonary carcinoids are neuroendocrine tumors histopathologically subclassified into typical (TC; no necrosis, <2 mitoses per 2 mm) and atypical (AC; necrosis or 2 to 10 mitoses per 2 mm). The reproducibility of lung carcinoid classification, however, has not been extensively studied and may be hampered by the presence of pyknotic apoptosis mimicking mitotic figures. Furthermore, prediction of prognosis based on histopathology varies, especially for ACs. We examined the presence of interobserver variation between 5 experienced pulmonary pathologists who reviewed 123 originally diagnosed pulmonary carcinoid cases. The tumors were subsequently redistributed over 3 groups: unanimously classified cases, consensus cases (4/5 pathologists rendered identical diagnosis), and disagreement cases (divergent diagnosis by ≥2 assessors). κ-values were calculated, and results were correlated with clinical follow-up and molecular data. When focusing on the 114/123 cases unanimously classified as pulmonary carcinoids, the interobserver agreement was only fair (κ=0.32). Of these 114 cases, 55% were unanimously classified, 25% reached consensus classification, and for 19% there was no consensus. ACs were significantly more often in the latter category (P=0.00038). The designation of TCs and ACs by ≥3 assessors was not associated with prognosis (P=0.11). However, when disagreement cases were allocated on the basis of Ki-67 proliferative index (<5%; ≥5%) or nuclear orthopedia homeobox immunostaining (+; -), correlation with prognosis improved significantly (P=0.00040 and 0.0024, respectively). In conclusion, there is a considerable interobserver variation in the histopathologic classification of lung carcinoids, in particular concerning ACs. Additional immunomarkers such as Ki-67 or orthopedia homeobox may improve classification and prediction of prognosis.
Full-text · Article · Jul 2014 · American Journal of Surgical Pathology
[Show abstract][Hide abstract] ABSTRACT: In lung cancer, clinically relevant prognostic information is provided by staging. Staging forms the basis for the treatment options and this is briefly summarized in the introduction. Epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase are biomarkers used for prediction of chemotherapy and prediction of targeted treatment. Other driver biomarkers in lung cancer (point mutations and rearrangements in specific genes including Her2, BRAF, NUT, MET, ROS1, DDR2, FGFR1, KRAS, and PTEN) might potentially provide additional information for clinical decision making. Owing to the low prevalence of mutations in predictive markers, patient numbers in studies are usually small, with the exception of EGFR. These mutations increase our understanding of the biology of lung cancer. Mutation analysis as a basis for treatment choice can have an impressive clinical impact with dramatic responses. However, as yet the impact of these approaches to overall survival is less striking.
No preview · Article · Jan 2014 · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin
[Show abstract][Hide abstract] ABSTRACT: The incidence of cutaneous squamous cell carcinoma (SCC) is increasing worldwide. Despite a growing body of literature on prognostic factors, it remains unclear how tumor differentiation grade influences patient survival. The aim of this study was to investigate a possible correlation between cutaneous SCC differentiation, local recurrence, metastasis, and patient survival.
All consecutive patients treated for cutaneous SCC between 2001 and 2008 were retrospectively analyzed. Univariate survival analysis was used to assess the association of different tumor characteristics with survival.
One hundred thirty-one patients with 155 SCCs were included (median follow-up, 81 months; range, 27-125 months). Although no significant correlation between tumor differentiation grade and local recurrence could be found, it was an independent prognostic factor for metastatic disease and overall survival (OS). Metastasis-free survival at 5 years was significantly higher in well-differentiated tumors (70%) compared to moderately (51%) and poorly differentiated SCCs (26%; P = 0.012); identical percentages were found for OS (P = 0.005). Furthermore, patients with incomplete excision of the first tumor showed an increased relative risk of dying of SCC of 4.0 (95% confidence interval, 2.4-6.6; P < 0.001) compared to excision with clear margins.
Studies that investigated the relationship between SCC differentiation grade and patient survival are scarce and inconsistent. The present study indicates tumor differentiation grade is an independent prognostic factor for OS. This finding suggests poor differentiation of cutaneous SCC alone is sufficient to upstage the primary tumor in the TNM classification system.
No preview · Article · Jan 2014 · Annals of plastic surgery
[Show abstract][Hide abstract] ABSTRACT: Thirty-year-old observations report frequent asymptomatic Clostridium difficile carriage among cystic fibrosis (CF) patients. In this case-control study, we found more carriers among CF patients than controls (47% versus 11%), but most strains carried by CF patients were non-toxigenic (77% versus 17%). Among CF patients, carriers were younger, with more severe pulmonary disease than non-carriers. Strains belonged to multiple PCR-ribotypes, suggesting that these CF patients did not acquire strains from each other.
No preview · Article · Nov 2013 · Clinical Microbiology and Infection
[Show abstract][Hide abstract] ABSTRACT: Pulmonary neuroendocrine (NE) proliferations are a diverse group of disorders which share distinct cytological, architectural and biosynthetic features. Tumours composed of NE cells are dispersed among different tumour categories in the WHO classification of tumours and as such do not conform to a singular group with regards to treatment and prognosis. This is reflected by the highly variable behaviour of NE proliferations, ranging from asymptomatic, for instance in diffuse idiopathic pulmonary NE cell hyperplasia and tumourlets, to highly malignant cancers such as small cell lung cancer and large cell NE carcinoma. In this review NE proliferations are described as distinct entities ranging from low grade lesions to high grade cancers. The differential diagnoses are considered with each of the entries. Finally, mention is made of tumours which may show some NE features.
No preview · Article · May 2013 · Journal of clinical pathology
[Show abstract][Hide abstract] ABSTRACT: Purpose
Lung ischemia-reperfusion injury (LIRI) is a risk factor for development of primary graft dysfunction after lung transplantation. Treatment with surfactant ameliorates LIRI, but the optimal timing and surfactant dose are unknown. We compared the efficacy of surfactant treatment before ischemia with treatment at and 24 hours after reperfusion.
Methods and Materials
Male Sprague-Dawley rats (n=98) were randomized to receive intratracheally administered porcine surfactant in high (200 mg/kg) or low dose (50 mg/kg) either 1 hour before ischemia, at the start of reperfusion, or 24 hours after reperfusion. Sham-operated and untreated LIRI animals served as controls. LIRI was induced by clamping the bronchus, pulmonary artery and veins of the left lung for 150 minutes. After 72 hours, arterial oxygenation, pulmonary compliance, inflammatory cells in broncho-alveolar-lavage fluid and histological pulmonary injury were assessed.
LIRI caused hypoxemia, impaired lung compliance, diffuse alveolar damage, inflammation consisting of granulocytes, macrophage and lymphocytes, and upregulation of MHCII+ on antigen presenting cells. Pretreatment with 200 mg/kg surfactant improved survival and lung function, averted fibroproliferation, and reduced diffuse alveolar damage and infiltration of T-cells in the ischemic lung. Surfactant treatment after reperfusion resulted in a mortality rate comparable to untreated LIRI and had no effect on pulmonary function, independent of the dose. Low dose surfactant reduced inflammation independent of the time of application, but the effect on lung function was less pronounced.
Pretreatment with high dose surfactant is superior to low dose treatment. Surfactant pretreatment is superior to treatment directly-, or 24 hours after reperfusion.
No preview · Article · Apr 2013 · The Journal of Heart and Lung Transplantation
[Show abstract][Hide abstract] ABSTRACT: Autologous T cells genetically modified to express a chimeric antibody receptor (CAR) against carboxy-anhydrase-IX (CAIX) were administered to 12 patients with CAIX-expressing metastatic renal cell carcinoma (RCC). Patients were treated in three cohorts with a maximum of 10 infusions of a total of 0.2 to 2.1 × 10(9) CAR T cells. CTC grade 2-4 liver enzyme disturbances occurred at the lowest CAR T cell doses, necessitating cessation of treatment in four out of eight patients in cohorts 1 and 2. Examination of liver biopsies revealed CAIX expression on bile duct epithelium with infiltration of T cells, including CAR T cells. Subsequently four patients were pre-treated with CAIX monoclonal antibody (mAb) G250 to prevent CAR-specific toxicity and showed no liver toxicities and indications for enhanced peripheral T cell persistence. No clinical responses were recorded. This report shows that CAIX-targeting CAR T cells exerted antigen-specific effects in vivo and induced liver toxicity at the lowest dose of 0.2 × 10(9) T cells applied, illustrating the potency of receptor-modified T cells. We provide in-patient proof that the observed "on-target" toxicity is antigen-directed and can be prevented by blocking antigenic sites in off-tumor organs and allowing higher T cell doses.Molecular Therapy (2013); doi:10.1038/mt.2013.17.
Full-text · Article · Feb 2013 · Molecular Therapy
[Show abstract][Hide abstract] ABSTRACT: Specific texts on infectious diseases and those in textbooks on pulmonary pathology commonly approach the subject of infection in the lung from an etiological microbiological perspective, listing infectious agents by taxonomy followed by associated pathology. However, in practice one is faced with a specimen in which a reaction pattern is seen (usually of inflammatory nature) which may be indicative of a specific type of infection. In these circumstances an approach leading from reaction pattern to specific microbiological diagnosis is required. This approach will form the basis of this review. General aspects are covered without exhaustive discussion of specific microbiology. For more detailed discussion of specific entities the reader is referred to the excellent textbooks on pulmonary pathology and those on pathology of infectious diseases. The reaction patterns described here are combinations of gross pathology and cellular reactions. The breakdown of these patterns is somewhat arbitrary and artificial. In many cases the pattern will not be absolutely typical and many overlapping features will be present in individual cases.
No preview · Article · Feb 2013 · Diagnostic Histopathology
[Show abstract][Hide abstract] ABSTRACT: Epithelial to mesenchymal transition (EMT) is typically defined by the acquisition of a spindle cell morphology in combination with loss of E-cadherin and upregulation of mesenchymal markers. However, by studying E-cadherin inactivation in 38 human breast cancer cell lines, we noted that not all cell lines that had undergone EMT had concomitantly lost E-cadherin expression. We further investigated this discrepancy functionally and in clinical breast cancer specimens. Interestingly, reconstitution of wild-type E-cadherin cDNA in a E-cadherin negative cell line that had undergone EMT (MDA-MB-231) did not revert the spindle morphology back to an epithelial morphology. Neither were changes observed in the expression of several markers known to be involved in the EMT process. Similarly, upregulation of E-cadherin via global DNA demethylation in eleven cell lines that had undergone EMT did not induce a change in cell morphology, nor did it alter the expression of EMT markers in these cells. Next, we extracted genes differentially expressed between cell lines that had undergone EMT versus cell lines that had not undergone EMT. Caveolin-1 was identified to be an excellent marker for EMT, irrespective of E-cadherin status (specificity and sensitivity of 100 %). Consistent with our observations in the breast cancer cell lines, expression of Caveolin-1 identified a subset of basal breast cancers, particularly of metaplastic pathology, and only 50 % of these lacked E-cadherin expression. The discrepancy between E-cadherin loss and EMT was thus reproduced in clinical samples. Together, these results indicate that in human breast cancer loss of E-cadherin is not causal for EMT and even not a necessity.
Full-text · Article · Jan 2013 · Breast Cancer Research and Treatment