Pulmonary interstitial glycogenosis - A systematic analysis of new cases.

BACKGROUND: Pulmonary interstitial glycogenosis (PIG) is a rare paediatric interstitial lung disease of unknown cause. The diagnosis can only be made by lung biopsy. Less than 100 cases have been reported. Clinical features, treatment and outcomes have rarely been assessed systematically in decent cohorts of patients. METHODS: In this retrospective multicentre study, the clinical presentation, radiologic findings, pattern of lung biopsy, extrapulmonary comorbidities, treatment and outcome of eleven children with PIG were collected systematically. RESULTS: 10/11 children presented with respiratory distress immediatly after birth and 8/11 needed invasive ventilation. In 8/11 children extrapulmonary comorbidities were present, congenital heart defects being the most common. 7/11 children received systemic glucocorticoids and of these four showed a clear favorable response. During a median follow-up of 3.0 years (range 0.42-12.0) one child died, while 10 patients improved. Chest CT-scans showed ground-glass opacities (7/10), consolidations (6/10), linear opacities (5/10) and mosaic attenuation (4/10) without uniform pattern. Besides interstitial thickening related to undifferentiated glycogen positive mesenchymal cells all tissue samples showed growth abnormalities with reduced alveolarization. CONCLUSIONS: PIG is associated with alveolar growth abnormalities and has to be considered in all newborns with unexplained respiratory distress. Apparent treatment benefit of glucocorticosteroids needs to be evaluated systematically.

Airway-centered interstitial fibrosis - an under-recognized subtype of diffuse parenchymal lung diseases.

Airway centered interstitial fibrosis (ACIF) has been recently suggesed as a rare histological pattern of interstitial lung disease of variable etiology and outcome. It is characterized by fibrosis of the respiratory bronchioles and the peribronchiolar interstitium. We describe the clinical features of 13 patients (7 female, mean age 55 years) with histologically proven ACIF in 12 cases and long-term follow up. In ten patients, exogenous agents could be detected (mould n=5, wood n=2, leather exposure n=1, occupational exposure n=2). Two patients had rheumatoid arthritis and 1 patient suffered from recurrent aspiration. In three patients no associated exposure could be detected. Eight patients were never-smokers, while five were ex- smokers. At time of diagnosis patients presented with a moderate restrictive ventilation impairment and sever reduction in diffusion capacity (VC 61%, TLC 66%, DLCOc-SB 38% pred.). All patients were started on immunosuppressive therapy with steroids which were combined with azathioprine in seven and with mycophenolate mofetil in one patient. Median time of follow up was 52 months (2-127 months). Patients with ACIF due to exogenous agents or associated with RA were stable with immunosuppressive therapy. One patient with idiopathic ACIF showed a progressive deterioration within 29 months despite immunosuppression and died while on a waiting-list for lung transplantation. In our experience ACIF is a rare finding, which is relatively frequently observed in the context of hypersensitivity pneumonitis, aspiration and rheumatoid arthritis, while idiopathic ACIF was a minority. In the majority of patients, ACIF showed a favorable long-term outcome with immunosuppressive therapy. (Sarcoidosis Vasc Diffuse Lung Dis 2018; 35: 218-229).

[Predictive PD-L1 immunohistochemistry for non-small cell lung cancer : Current state of the art and experiences of the first German harmonization study]. / Prädiktive PD-L1-Immunhistochemie beim nichtkleinzelligen Bronchialkarzinom : Aktueller Stand und Erfahrungen der ersten deutschen Harmonisierungsstudie.

BACKGROUND: Antibodies against PD-1 and PD-L1 can cause strong and durable anti-tumor immune responses in non-small cell lung cancer (NSCLC). Immunohistochemistry for PD-L1 (PD-L1 IHC) was tested as a predictive biomarker. Several IHC assays and interpretation criteria were developed in parallel. AIM: The clinical significance of PD-L1 IHC in NSCLC and the optimum method for staining and interpretation of the results are the subject of ongoing studies. The diagnostic application of immunotherapy in NSCLC necessitates harmonization of PD-L1 IHC to obtain evidence for guidelines; therefore, a consensus opinion on a well-founded diagnostic mode of testing should be defined based on published studies and the results of the first German PD-L1 IHC harmonization study. METHODS: 1. Summary of the current data situation. 2. Evaluation of the first German PD-L1 IHC harmonization study (centralized, staining with PD-L1 IHC analogous to studies, 15 cases of NSCLC, 4 IHC study assays [28­8, 22C3, SP142 and SP263] and scoring by 9 pathologists). RESULTS: The use of PD-L1 IHC in NSCLC is suitable for identification of patients with an increased probability of a clinical benefit from immunotherapy. The various proportional cut-offs used to interpret the staining results can be summarized in a total score, which can be reproducibly assessed. The staining patterns of the four assays investigated were, however, not congruent in all situations. DISCUSSION: In principle, the use of PD-L1 IHC for assessment of the expression in tumor cells is a reliably determinable biomarker. Evaluation algorithms should be based on published clinical trials. For NSCLC approvals with obligatory PD-L1 IHC are to be expected but it remains to be seen to what extent PD-L1 IHC will be implemented in the clinical routine.

[Diffuse pulmonary meningotheliomatosis]. / Diffuse pulmonale Meningotheliomatose.

In two patients with bilateral micronodular pulmonary changes a diffuse pulmonary meningotheliomatosis was found. A 73-year-old woman presented with bilateral disseminated miliary pulmonary nodules as a radiological incidental finding. The surgical lung biopsy showed multiple tiny nodular proliferations meningothelial-like cells, corresponding "minute pulmonary meningothelial-like nodules", MPMN. A 60-year-old lady with similar radiological findings showed also proliferations of meningothelial-like cells in a transbronchial cryo-biopsy. These lesions are well known to pathologists as curious isolated incidental findings on histological examination of lung specimens. The here described diffuse form of these changes is very rare; its knowledge is important for the differential diagnosis with neoplastic proliferations and other diffuse parenchymal diseases of the lung. This rare diagnosis is made on histological grounds and is also possible in transbronchial biopsies when careful correlation with clinical and radiological data, knowledge of the entity and adequate specimens are provided.

High resolution compression elastography and color doppler sonography in characterization of breast fibroadenoma.

PURPOSE: To evaluate the use of color Doppler sonography and free hand sonoelastography in the assessment of breast fibroadenomas according to their size and shape. MATERIALS AND METHODS: From December 2012 to March 2013 women with 16 solid breast masses, classified as BI-RADS category 3 or 4 were examined with B-mode ultrasound, sonoelastography and color Doppler sonography. Lesions were subdivided according to their shape in round, ovoid or macrolobulated and according to their size (<2.0 cm or ≥2.0 cm). Two readers assessed sonoelastographic findings at 12.5 MHz using the tsukuba elasticity score and results of Doppler sonography using a score of 0, 1 or 2, depending on the degree of perfusion. RESULTS: Among the 16 examined lesions 3 showed a round shape, 9 were ovoid and in 4 cases a macrolobulated appearance could be seen. No significant differences concerning Tsukuba-score depending on various shapes of fibroadenomas in B-mode sonography could be shown (p = 0.91) and also comparison of Tsukuba-scores and size of masses revealed no significant differences (p = 1.0). Sizes of fibroadenomas ≥2 cm were significantly associated with an increased vascularization of the lesions (p = 0.04) and a macrolobulated appearance in B-mode sonography (p = 0.04). CONCLUSION: The combination of color Doppler sonography and sonoelastography in addition to B-mode sonography leads to an increased accuracy in distinguishing benign from malignant breast masses and to an improvement in characterization of fibroadenomas independent of their shape or size.

Resection of pulmonary metastases from colon and rectal cancer: factors to predict survival differ regarding to the origin of the primary tumor.

BACKGROUND: The purpose of the present study was to determine differences in prognostic factors for survival of patients with pulmonary metastases resected in curative intent from colon or rectum cancer. METHODS: Between 1980 and 2006, prognostic factors after resection of pulmonary metastases in 171 patients with primary rectum or colon tumor were evaluated. Survival of patients after surgical metastasectomy was compared with that of patients receiving standard chemotherapy by matched-pair analysis. RESULTS: Median survival after pulmonary resection was 35.2 months (confidence interval 27.3-43.2). One-, 3-, and 5-year survival for patients following R0 resection was 88.8, 52.1, and 32.9 % respectively. Complete metastasectomy (R0), UICC stage of the primary tumor, pleural infiltration, and hilar or mediastinal lymph node metastases are independent prognostic factors for survival. Matched-pair analysis confirmed that pulmonary metastasectomy significantly improved survival. Although no difference in survival for patients with pulmonary metastases from lower rectal compared to upper rectal or colon cancer was observed, factors to predict survival are different for patients with lower and middle rectal cancer (R0, mediastinal and/or hilar lymph nodes, gender, UICC stage) compared with patients with upper rectal or colon cancer (R0, number of metastases). CONCLUSIONS: Our results indicate that distinct prognostic factors exist for patients with pulmonary metastases from lower rectal compared with upper rectal or colon cancer. This supports the notion that colorectal cancer should not be considered as a single-tumor entity. Metastasectomy, especially after complete resection resulted in a dramatic improvement of survival compared with patients treated with chemotherapy alone.

[Epithelial-myoepithelial carcinoma of the trachea. Case report and review of the literature]. / Epithelial-myoepitheliales Karzinom der Trachea. Fallbericht und Literaturübersicht.

The tracheobronchial glands are considered to be counterparts of the minor salivary glands in the respiratory tract and can develop similar tumors (tumors of salivary gland type). Within this group of neoplasia epithelial-myoepithelial carcinoma of the respiratory tract is very rare and the diagnosis is often difficult. The first case of this tumor entity in the trachea is reported and a review of the literature on these tumors is presented. The exact histological classification as well as the localization and the endoscopic findings of these lesions are crucial for therapeutic decision-making.

[Gastrointestinal mixed adenoneuroendocrine carcinomas. An attempt at classification of mixed cancers]. / Gastrointestinale gemischte adenoneuroendokrine Karzinome. Versuch einer Ordnung des Gemischten.

Mixed adenoneuroendocrine carcinomas (MANECs) are a challenge for the diagnostics and the concept of a histogenetic tumor typing. They are classified into three malignant subgroups: high grade malignant MANECs combine an adenoma or adenocarcinoma with a small cell or large cell neuroendocrine carcinoma, intermediate grade malignant MANECs consist of a neuroendocrine tumor (NET grade 1 or 2), often a globlet cell carcinoid and a poorly differentiated adenocarcinoma or diffuse carcinoma of signet ring cell type. The prototype of a low grade malignant MANEC is the globlet cell carcinoid. Molecular analysis indicates a common clonal origin of the different components in MANECs. The prognosis is determined by the most aggressive tumor component. The pathogenesis of MANECs is apparently a sequence of increasing malignant transformation which leads either from an adenoma/adenocarcinoma to a small or large cell neuroendocrine carcinoma or from a neuroendocrine tumor (NET), often a globlet cell carcinoid to a poorly differentiated adenocarcinoma or a diffuse carcinoma of signet ring cell type.

[Prognostic marker profiles for risk of distant metastases in colorectal cancer]. / Markerprofile für das Fernmetastasierungsrisiko des Dickdarmkarzinoms.

In colorectal cancer (CRC) prognostic markers correlating with distant metastasis are of high clinical value. In recent years it could be demonstrated that sporadic CRC with microsatellite instability (MSI) exhibits a very low risk for distant spread. Within this group the medullary subtype represents a morphological prototype. In the new WHO classification other morphological variants, such as mucinous, signet ring cell, serrated, cribriform comedo type and solid-undifferentiated forms are graded according to their microsatellite status. The clinical value of BRAF mutations is also dependent on the microsatellite status. Recent data have shown an ambivalent prognostic impact of BRAF mutations. A BRAF mutation in combination with MSI is associated with a good prognosis, whereas a BRAF mutation in the background of microsatellite stability (MSS) indicates a very poor outcome. Based on the concept of migrating stem cells, combined high scores of CD133 and nuclear ß-catenin expression can be additionally used as markers for a high risk of distant metastasis. Hence, an immunohistochemical algorithm can be defined by the combination of three markers (hMLH1, CD133 and ß-catenin) which allows CRC with either a very high or a very low risk of distant spread to be identified.

[Mucinous neoplasms of the vermiform appendix, Pseudomyxoma peritonei, and the new WHO classification]. / Muzinöse Neoplasien der Appendix vermiformis, Pseudomyxoma peritonei und die neue WHO-Klassifikation.

Mucinous neoplasms of the appendix are rare tumors, some of them characterized by an enigmatic discrepancy between a benign morphologic appearance and an aggressive biologic potential, associated with a poor prognosis and high mortality. The clinical picture of pseudomyxoma peritonei is, with few exceptions, caused by mucinous appendiceal neoplasms and differs in many aspects from usual peritoneal carcinomatosis. The controversy regarding terminology, diagnostic criteria, classification and therapy of these tumors has lasted for decades. The revised edition of the World Health Organization Classification of Tumors of the Digestive System proposes a uniform reporting system for mucinous appendiceal neoplasms and the peritoneal disease associated with it, thereby creating a comparable basis for pathological diagnosis, clinical therapy and further scientific studies.

[Development of molecular-pathologic entities of colorectal cancer]. / Entwicklung molekularpathologischer Entitäten beim Dickdarmkarzinom.

Molecular-pathologic tumor entities are characterized by a unique combination of morphological, genetic, molecular and clinical features. Increased molecular subtyping and development of diagnostics towards molecular-pathologic entities can be expected for frequent solid cancer types in the future. Initial steps towards this development are discussed for the subtypes of serrated adenocarcinoma, medullary carcinoma and micropapillary carcinoma of colorectal cancer. Based on current knowledge, medullary carcinoma of the colon is definitely a molecular-pathologic entity. A high-risk-subtype and a low-risk-subtype - but not the whole group - of colorectal serrated adenocarcinomas also fulfill the criteria of a molecular-pathologic entity. In contrast, micropapillary carcinoma shows a distinct infiltrative pattern, which can occur as part of colorectal cancer, but which is not a molecular-pathologic entity in its own right.

Variable beta-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment.

Invasion and dissemination of well-differentiated carcinomas are often associated with loss of epithelial differentiation and gain of mesenchyme-like capabilities of the tumor cells at the invasive front. However, when comparing central areas of primary colorectal carcinomas and corresponding metastases, we again found the same differentiated epithelial growth patterns. These characteristic phenotypic changes were associated with distinct expression patterns of beta-catenin, the main oncogenic protein in colorectal carcinomas, and E-cadherin. Nuclear beta-catenin was found in dedifferentiated mesenchyme-like tumor cells at the invasive front, but strikingly, as in central areas of the primary tumors, was localized to the membrane and cytoplasm in polarized epithelial tumor cells in the metastases. This expression pattern was accompanied by changes in E-cadherin expression and proliferative activity. On the basis of these data, we postulate that an important driving force for progression of well-differentiated colorectal carcinomas is the specific environment, initiating two transient phenotypic transition processes by modulating intracellular beta-catenin distribution in tumor cells.

[beta-Catenin induces invasive growth by activating matrix metalloproteinases in colorectal carcinoma]. / beta-Catenin induziert invasives Wachstum durch die Aktivierung von Matrixmetalloproteinasen in kolorektalen Karzinomen.

beta-catenin was shown to be a major oncoprotein in colon cancer development. Its oncogenic function as a transcriptional activator is upregulated by mutations in the APC tumor suppressor gene, leading to a constitutive activation of the proliferation-associated genes c-myc and cyclin D. The aim of this study was to demonstrate a role of APC-mutations and dysregulated beta-catenin also for the progression of colorectal cancer, by identifying new target genes of beta-catenin associated with tumor invasion and metastasis. Potential invasion genes regulated by beta-catenin and its DNA binding partner TCF4 were identified by a computer search for the consensus DNA binding sequence in relevant promoter regions. Specific DNA binding was confirmed by gel shift assays. Functional importance of beta-catenin for the activation of identified genes was determined by luciferase reporter assays. The significance was demonstrated by coexpression of nuclear beta-catenin and the identified target genes by immunohistochemistry. Among other invasion genes, we identified the matrix metallo proteinases MMP-7 and MMP-1 activated by beta-catenin in the tumor cells. MMP-7 is an important factor for invasion and metastasis and overexpressed in 75% of colon carcinomas. The significance for human colon cancer development was demonstrated by a correlated overexpression of beta-catenin and the MMPs, beginning in large, severely dysplastic adenomas. Our results explain the high percentage of MMP-7 overexpression in colorectal tumors and the resulting activation of invasive growth. Moreover by identifying dysregulated beta-catenin as a transcriptional activator of MMPs and other invasion factors, we demonstrated an important role of mutated APC not only for early steps but also for the progression of colorectal carcinogenesis.