Publications by authors named "Ramona Erber"

33 Publications

DICER1-Mutated Botryoid Fibroepithelial Polyp of the Parotid Duct: Report of the First Case.

Head Neck Pathol 2021 Jul 19. Epub 2021 Jul 19.

Institute of Pathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), University Hospital Erlangen (UKER), Krankenhausstrasse 8-10, 91054, Erlangen, Germany.

DICER1, a member of the ribonuclease III family, is involved in the biogenesis of microRNAs and, hence, it influences gene expression regulation. DICER1 germline (associated with the inherited DICER1 syndrome) or somatic mutations have been linked to tumorigenesis in histogenetically diverse benign and malignant neoplasms in different organs including pleuropulmonary blastoma, cystic nephroma, embryonal rhabdomyosarcoma, nasal chondromesenchymal hamartoma, poorly differentiated thyroid carcinoma, thyroblastoma, intracranial sarcoma and gonadal Sertoli-Leydig cell tumors in addition to others. Moreover, rare botryoid (giant) fibroepithelial polyps may harbor this mutation. Herein, we describe the first reported case of a DICER1-mutated botryoid fibroepithelial polyp occurring within the parotid duct of a 65-year-old female who has no other features or family history of the DICER1 syndrome. Based on its distinctive morphology, we tested this lesion specifically for DICER1 mutations and confirmed the presence of a pathogenic DICER1 variant with a low allele frequency, consistent with a somatic mutation.
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http://dx.doi.org/10.1007/s12105-021-01364-yDOI Listing
July 2021

Mammographic density and prognosis in primary breast cancer patients.

Breast 2021 Jun 17;59:51-57. Epub 2021 Jun 17.

Department of Gynecology and Obstetrics, Erlangen University Hospital, Comprehensive Cancer Center, European Metropolitan Area Erlangen-Nuremberg (CCC ER-EMN), Friedrich Alexander University of Erlangen-Nuremberg, Erlangen, Germany.

Purpose: Mammographic density (MD) is one of the strongest risk factors for breast cancer (BC). However, the influence of MD on the BC prognosis is unclear. The objective of this study was therefore to investigate whether percentage MD (PMD) is associated with a difference in disease-free or overall survival in primary BC patients.

Methods: A total of 2525 patients with primary, metastasis-free BC were followed up retrospectively for this analysis. For all patients, PMD was evaluated by two readers using a semi-automated method. The association between PMD and prognosis was evaluated using Cox regression models with disease-free survival (DFS) and overall survival (OS) as the outcome, and the following adjustments: age at diagnosis, year of diagnosis, body mass index, tumor stage, grading, lymph node status, hormone receptor and HER2 status.

Results: After median observation periods of 9.5 and 10.0 years, no influence of PMD on DFS (p = 0.46, likelihood ratio test (LRT)) or OS (p = 0.22, LRT), respectively, was found. In the initial unadjusted analysis higher PMD was associated with longer DFS and OS. The effect of PMD on DFS and OS disappeared after adjustment for age and was caused by the underlying age effect.

Conclusions: Although MD is one of the strongest independent risk factors for BC, in our collective PMD is not associated with disease-free and overall survival in patients with BC.
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http://dx.doi.org/10.1016/j.breast.2021.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237359PMC
June 2021

Understanding PD-L1 Testing in Breast Cancer: A Practical Approach.

Breast Care (Basel) 2020 Oct 6;15(5):481-490. Epub 2020 Oct 6.

Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.

Background: Immune checkpoint inhibitors (ICI) have changed therapy strategies for cancer patients tremendously. Some approved ICI acquire testing of PD-L1 expression on tumor and/or immune cells. However, since PD-L1 testing is a comprehensive issue with various assays, antibody clones, scoring methods, and cut-offs, we aimed to summarize the recommendations and technical and histopathological issues of diagnostic PD-L1 assessment with an emphasis on invasive breast cancer (IBC).

Summary: Besides other (pre)analytical considerations, selecting the most adequate PD-L1 immunohistochemical assay/antibody clone is important. In-house assay validation, prediagnostic training, and internal and external quality assurance should be implemented. The current most relevant PD-L1 assays and scores will be explained in this review. Moreover, recommendations for PD-L1 testing in IBC are outlined.

Key Messages: Atezolizumab plus nab-paclitaxel therapy is approved for adult patients with locally advanced or metastatic triple negative breast cancer (mTNBC), if the tumor-associated immune cells express PD-L1. - This PD-L1 immune cell positivity is defined as an immune cell (IC) score, which refers to the area occupied by PD-L1 positive immune cells (lymphocytes, dendritic cells, macrophages, and granulocytes) as a percentage of the whole tumor area. The cut-off is an IC score ≥1%. In the approval study for atezolizumab in mTNBC, IC score was assessed using the Ventana PD-L1 SP142 assay. Other assays or laboratory developed tests may be used depending on country-specific drug approvals. However, harmonization studies have to show whether other PD-L1 tests are reliable and of clinical value to predict the response of breast cancer patients to ICI.
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http://dx.doi.org/10.1159/000510812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650134PMC
October 2020

Tumour-Infiltrating Inflammatory Cells in Early Breast Cancer: An Underrated Prognostic and Predictive Factor?

Int J Mol Sci 2020 Nov 3;21(21). Epub 2020 Nov 3.

Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany.

The role of tumour-infiltrating inflammatory cells (TIICs) in the disease progression of hormone-receptor-positive breast cancer (HR+ BC) is largely unclear since it is generally regarded as the least immunogenic BC subtype. This study investigated the prognostic significance of CD1a+ dendritic cells, CD20+ B cells, CD45RO+ memory T cells and CD4+ T-helper cells in HR+ BC. One hundred and forty-six patients were treated for early stage, distant-metastases-free HR+ BC in an accelerated partial breast irradiation (APBI) phase II trial. Immunohistochemistry was used to double-stain two adjoining sets of tissue microarrays from pre-RT (radiotherapy) tumour resection samples for CD1a/CD20 and CD45RO/CD4. Cell densities of CD1a+, CD20+, CD45RO+ and CD4+ TIICs in the stromal and intraepithelial compartment were registered semiautomatically. High densities of CD20+ and CD4+ TIICs were strongly associated with reduced disease-free survival (DFS), while high stromal CD45RO+ TIIC densities were indicators of subsequent successful treatment. An immunoscore based on CD20+ and CD45RO+ TIIC densities identified three different risk groups ( < 0.001). Thus, contrary to current assumptions, intratumoural immune cell composition might be an important prognostic indicator and a possible contributing factor in the outcome of HR+ BC and should be the subject of further research. Specifically, B-cell infiltration entailed an increased relapse rate and could play an important role in disease progression.
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http://dx.doi.org/10.3390/ijms21218238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663093PMC
November 2020

PIWI-Like 1 and PIWI-Like 2 Expression in Breast Cancer.

Cancers (Basel) 2020 Sep 24;12(10). Epub 2020 Sep 24.

Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg (FAU), 91054 Erlangen, Germany.

PIWI-like 1 and PIWI-like 2 play a role in stem cell self-renewal, and enhanced expression has been reported for several tumor entities. However, few studies have investigated PIWI-like 1 and PIWI-like 2 expressions in breast cancer subtypes regarding prognosis. Therefore, we examined protein expression in a large consecutive cohort of breast cancer patients and correlated it to breast cancer subtypes and survival outcome. PIWI-like 1 and PIWI-like 2 expressions were evaluated using immunohistochemistry in a cohort of 894 breast cancer patients, of whom 363 were eligible for further analysis. Percentage and intensity of stained tumor cells were analyzed and an immunoreactive score (IRS) was calculated. The interaction of PIWI-like 1 and PIWI-like 2 showed a prognostic effect on survival. For the combination of high PIWI-like 1 and low PIWI-like 2 expressions, adjusted hazard ratios (HRs) were significantly higher with regard to overall survival (OS) (HR 2.92; 95% confidence interval (CI) 1.24, 6.90), disease-free survival (DFS) (HR 3.27; 95% CI 1.48, 7.20), and distant disease-free survival (DDFS) (HR 7.64; 95% CI 2.35, 24.82). Both proteins were significantly associated with molecular-like and PAM50 subgroups. Combining high PIWI-like 1 and low PIWI-like 2 expressions predicted poorer prognosis and both markers were associated with aggressive molecular subtypes.
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http://dx.doi.org/10.3390/cancers12102742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598687PMC
September 2020

Histology of Luminal Breast Cancer.

Breast Care (Basel) 2020 Aug 15;15(4):327-336. Epub 2020 Jul 15.

Institute of Pathology, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nürnberg (FAU), Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.

Background: Invasive breast cancer (IBC) can be categorized into prognostic and predictive molecular subtypes (including luminal breast cancer) using gene expression profiling. Luminal IBC comprises a variety of histological subtypes with varying clinical and pathological features.

Summary: IBC of no special subtype is the most common histological subtype in general and likewise within luminal IBC. Classical invasive lobular breast cancer, typically clustering into luminal subgroup, is characterized by discohesive growth and loss of E-cadherin expression. Infrequent, morphologically distinct luminal IBC subtypes are tubular, invasive cribriform, mucinous, and invasive micropapillary carcinomas. Breast carcinoma with apocrine differentiation, with characteristic expression of androgen receptor (AR), often clusters into the luminal AR category. Rarely, neuroendocrine neoplasms of the breast can be seen. IBC of the male breast usually matches with the luminal subtype.

Key Messages: Independently from histological subtypes, invasive breast cancer (IBC) can be divided into molecular subtypes based on mRNA gene expression levels. Using this molecular subtyping, risk scores based on gene expression profiling (established for hormone receptor-positive, HER2-negative IBC), grading, and Ki-67 index, prognosis of patients with luminal breast cancer and response to chemotherapy can be predicted. In routine diagnostics, the expression of estrogen receptor (ER) and progesterone receptor (PR), HER2 status, and the proliferation rate (Ki-67) are used to determine a surrogate (molecular-like) subtype. Within luminal(-like) IBC, no special subtype and invasive lobular breast carcinoma are the most common histological subtypes. Other rare histological subtypes (e.g., tubular carcinoma) should be recognized due to their distinct clinical and pathological features.
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http://dx.doi.org/10.1159/000509025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490665PMC
August 2020

HLA-G and HLA-F protein isoform expression in breast cancer patients receiving neoadjuvant treatment.

Sci Rep 2020 09 25;10(1):15750. Epub 2020 Sep 25.

Department of Gynaecology and Obstetrics, Erlangen University Hospital, Comprehensive Cancer Center Erlangen-EMN, Friedrich Alexander University of Erlangen-Nuremberg (FAU), Universitätsstrasse 21-23, 91054, Erlangen, Germany.

The immunosuppressive human leukocyte antigens HLA-G and HLA-F are expressed on trophoblast and malignant cells. Four membrane-bound and three soluble HLA-G protein isoforms have been described, which have different immunosuppressive potentials. HLA-F has three transcript variants, resulting in three different protein isoforms. The aim of this study was to evaluate the prognostic and predictive value of HLA-G and HLA-F protein isoform expression patterns in patients with breast cancer. Core biopsies were taken at diagnosis in patients with HER2+ (n = 28), luminal B-like (n = 49) and triple-negative (n = 38) breast cancers who received neoadjuvant chemotherapy. Expression levels of HLA-F and -G were correlated with the pathological complete response (pCR). Protein expression was determined by Western blot analysis, using two antibodies for each HLA, specific for different isoforms. The protein expression of HLA isoforms did not significantly differ between breast cancer subtypes. However, some initial indications were found for an association between the soluble HLA-G6 protein isoform and pCR in HER2+ breast cancer. The study provides preliminary evidence for the evaluation of HLA-G isoform expression, in particular HLA-G6, as a possible new marker for pCR in HER2+ breast cancer.
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http://dx.doi.org/10.1038/s41598-020-72837-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519664PMC
September 2020

Adenomatoid Tumor of the Uterus: A Report of 6 Unusual Cases With Prominent Cysts Including 4 With Diffuse Myometrial Involvement, 4 With Uterine Serosal Involvement, and 2 Presenting in Curettage Specimens.

Int J Gynecol Pathol 2021 May;40(3):248-256

We evaluated the clinicopathologic features of 6 adenomatoid tumors of the uterus with unusual features. All the tumors differed grossly from the usual adenomatoid tumor, typically being ill-defined and occupying >50% of the myometrium, essentially replacing it in 4. The neoplasm extended to the endometrium in 2 cases and in one of these it formed an intracavitary mass; in both the tumor was first diagnosed in a curettage. In the other 4 cases, the adenomatoid tumor was discovered in a hysterectomy specimen performed for irregular vaginal bleeding (3 patients), and the finding of a pelvic mass on a computed tomography scan in a patient with right lower quadrant pain. The tumors extended to the uterine serosa in the form of small grape-like vesicles or cysts in 4 cases. All tumors contained the typical small often irregularly shaped spaces but also had prominent cysts. When cysts involved the serosa, the microscopic appearance mimicked that of peritoneal inclusion cysts. In one case with serosal involvement, a prominent papillary pattern was also present. The cysts were typically closely packed with minimal intervening stroma but were occasionally separated by conspicuous smooth muscle bundles. The stroma in one case was extensively hyalinized. Two tumors were focally infarcted. A striking, but minor, solid growth in which the tumor cells were arranged in tightly packed nests or interanastomosing cords and trabeculae was seen in 2 tumors. The unusual gross and microscopic features of these tumors can cause significant diagnostic difficulty and bring into the differential diagnosis entities that are usually not realistic considerations. The presentation of 2 tumors in a curettage specimen represents an unusual clinical aspect.
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http://dx.doi.org/10.1097/PGP.0000000000000685DOI Listing
May 2021

Impact of fibroblast growth factor receptor 1 (FGFR1) amplification on the prognosis of breast cancer patients.

Breast Cancer Res Treat 2020 Nov 27;184(2):311-324. Epub 2020 Aug 27.

Department of Obstetrics and Gynecology, Comprehensive Cancer Center EMN, Erlangen University Hospital, Friedrich Alexander University of Erlangen-Nuremberg (FAU), Erlangen, Germany.

Purpose: Various aberrations in the fibroblast growth factor receptor genes FGFR1, FGFR2, and FGFR3 are found in different cancers, including breast cancer (BC). This study analyzed the impact of FGFR amplification on the BC prognosis.

Methods: The study included 894 BC patients. The amplification rates of FGFR1, FGFR2, and FGFR3 were evaluated on tissue microarrays using fluorescence in situ hybridization (FISH). Associations between these parameters and prognosis were analyzed using multivariate Cox regression analyses.

Results: FGFR1 FISH was assessable in 503 samples, FGFR2 FISH in 447, and FGFR3 FISH in 562. The FGFR1 amplification rate was 6.6% (n = 33). Increased FGFR2 copy numbers were seen in 0.9% (n = 4); only one patient had FGFR3 amplification (0.2%). Most patients with FGFR1 amplification had luminal B-like tumors (69.7%, n = 23); only 32.6% (n = 153) of patients without FGFR1 amplification had luminal B-like BC. Other patient and tumor characteristics appeared similar between these two groups. Observed outcome differences between BC patients with and without FGFR1 amplification did not achieve statistical significance; however, there was a trend toward poorer distant metastasis-free survival in BC patients with FGFR1 amplification (HR = 2.08; 95% CI 0.98 to 4.39, P = 0.05).

Conclusion: FGFR1 amplification occurs most frequently in patients with luminal B-like BC. The study showed a nonsignificant correlation with the prognosis, probably due to the small sample size. Further research is therefore needed to address the role of FGFR1 amplifications in early BC patients. FGFR2 and FGFR3 amplifications are rare in patients with primary BC.
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http://dx.doi.org/10.1007/s10549-020-05865-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599145PMC
November 2020

[Reporting and handling of lymphonodectomy specimens in gynecologic malignancies and sentinel lymph nodes].

Pathologe 2021 May;42(3):319-327

Institut für Pathologie, Arbeitsgruppe Mamma‑, Gynäko- & Perinatalpathologie, Universitätsklinikum Leipzig AöR, Liebigstraße 26, 04103, Leipzig, Deutschland.

The handling and reporting of resected lymph nodes in gynecologic cancer follows the recommendations of the German national guidelines and the recommendations of the International Collaboration of Cancer Reporting (ICCR) and the International Society of Gynecologic Pathologists (ISGyP). The definitions of micrometastases and isolated tumor cells are in accordance with the definition of the UICC (Union Internationale Contre le Cancer) and TNM system. Both findings must be reported as part of the pathology report and final tumor classification. It is mandatory to examine all excised lymph nodes with complete processing of all nodes up to 0.3 cm and slicing of all larger nodes in 0.2-cm wide intervals with complete processing of all lamellae. The amount of the resected lymph nodes in correlation to positive nodes, the metric dimension of the largest lymph node metastasis per lymph node region, and the presence of extracapsular extension of the lymph node deposits must be part of the pathology report. The handling and cutting of sentinel lymph nodes are similar to nonsentinel nodes. Within frozen section analyses and final processing from paraffin-embedded sentinel nodes, all nodes should be examined by three-step sections with an interval of about 200 µm. In cases of negative sentinel nodes on H&E staining, immunohistochemical ultrastaging should be performed.
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http://dx.doi.org/10.1007/s00292-020-00805-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084808PMC
May 2021

Targeted sequencing of FH-deficient uterine leiomyomas reveals biallelic inactivating somatic fumarase variants and allows characterization of missense variants.

Mod Pathol 2020 11 1;33(11):2341-2353. Epub 2020 Jul 1.

Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.

Uterine leiomyomas (ULs) constitute a considerable health burden in the general female population. The fumarate hydratase (FH) deficient subtype is found in up to 1.6% and can occur in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. We sequenced 13 FH deficient ULs from a previous immunohistochemical screen using a targeted panel and identified biallelic FH variants in all. In eight, we found an FH point mutation (two truncating, six missense) with evidence for loss of the second allele. Variant allele-frequencies in all cases with a point mutation pointed to somatic variants. Spatial clustering of the identified missense variants in the lyase domain indicated altered fumarase oligomerization with subsequent degradation as explanation for the observed FH deficiency. Biallelic FH deletions in five tumors confirm the importance of copy number loss as mutational mechanism. By curating all pathogenic FH variants and calculating their population frequency, we estimate a carrier frequency of up to 1/2,563. Comparing with the prevalence of FH deficient ULs, we conclude that most are sporadic and estimate 2.7-13.9% of females with an FH deficient UL to carry a germline FH variant. Further prospective tumor/normal sequencing studies are needed to develop a reliable screening strategy for HLRCC in women with ULs.
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http://dx.doi.org/10.1038/s41379-020-0596-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581509PMC
November 2020

Clinical and pathological associations of PTEN expression in ovarian cancer: a multicentre study from the Ovarian Tumour Tissue Analysis Consortium.

Br J Cancer 2020 09 18;123(5):793-802. Epub 2020 Jun 18.

Department of Oncology, Strangeways Research Laboratory, University of Cambridge, Cambridge, England.

Background: PTEN loss is a putative driver in histotypes of ovarian cancer (high-grade serous (HGSOC), endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous (LGSOC)). We aimed to characterise PTEN expression as a biomarker in epithelial ovarian cancer in a large population-based study.

Methods: Tumours from 5400 patients from a multicentre observational, prospective cohort study of the Ovarian Tumour Tissue Analysis Consortium were used to evaluate associations between immunohistochemical PTEN patterns and overall survival time, age, stage, grade, residual tumour, CD8+ tumour-infiltrating lymphocytes (TIL) counts, expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) by means of Cox proportional hazard models and generalised Cochran-Mantel-Haenszel tests.

Results: Downregulation of cytoplasmic PTEN expression was most frequent in ENOC (most frequently in younger patients; p value = 0.0001) and CCOC and was associated with longer overall survival in HGSOC (hazard ratio: 0.78, 95% CI: 0.65-0.94, p value = 0.022). PTEN expression was associated with ER, PR and AR expression (p values: 0.0008, 0.062 and 0.0002, respectively) in HGSOC and with lower CD8 counts in CCOC (p value < 0.0001). Heterogeneous expression of PTEN was more prevalent in advanced HGSOC (p value = 0.019) and associated with higher CD8 counts (p value = 0.0016).

Conclusions: PTEN loss is a frequent driver in ovarian carcinoma associating distinctly with expression of hormonal receptors and CD8+ TIL counts in HGSOC and CCOC histotypes.
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http://dx.doi.org/10.1038/s41416-020-0900-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463007PMC
September 2020

Identification and characterization of a GLMN splice site variant in a family with glomuvenous malformations.

Eur J Dermatol 2020 Apr;30(2):179-181

Department of Human Genetics, University Medicine Greifswald, and Interfaculty Institute of Genetics and Functional Genomics, University of Greifswald, Fleischmannstraße 43, 17475 Greifswald, Germany.

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http://dx.doi.org/10.1684/ejd.2020.3716DOI Listing
April 2020

Prominent entrapment of respiratory epithelium in primary and metastatic intrapulmonary non-epithelial neoplasms: a frequent morphological pattern closely mimicking adenofibroma and other biphasic pulmonary lesions.

Virchows Arch 2020 Aug 19;477(2):195-205. Epub 2020 Mar 19.

Institute of Pathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), University Hospital, Krankenhausstrasse 8-10, 91054, Erlangen, Germany.

As one of the most common target organs for hematogenous spread from diverse cancers, biopsy interpretation of lung tumors is complicated by the challenging question of primary versus metastatic and by frequent entrapment of native respiratory glands. Nevertheless, the literature dealing with this issue is surprisingly sparse and no single study has been devoted to this topic. We reviewed 47 surgical lung specimens of non-epithelial neoplasms (38 metastases, mainly from sarcomas and 9 primary lesions) for frequency and pattern of intralesional epithelial entrapment. Respiratory epithelium entrapment was noted in 23/47 (49%) cases (diffuse in 15 and peripheral in 8). Entrapped glands frequently showed prominent regenerative and reactive changes mimicking neoplastic glands. Based on cellularity of the mesenchymal component and the extent, distribution and shape of entrapped respiratory glands, four morphological patterns were recognized: paucicellular sclerosing low-grade neoplasms containing leaflet-like glands indistinguishable from adenofibroma and fibroepithelial hamartomas (n = 11), and biphasic cellular lesions mimicking adenomyoepithelioma (n = 1), biphasic synovial sarcoma (n = 2), and pleuropulmonary blastoma (n = 1). Only a single genuine pulmonary adenofibroma was identified. This study highlights frequent respiratory epithelium entrapment in diverse non-epithelial lung tumors, both primary and metastatic. Recognition of this finding and use of adjunct IHC combined with clinical history should help to avoid misinterpretation as primary pulmonary biphasic neoplasm or as harmless adenofibroma. The vast majority of morphologically defined lung adenofibromas represent adenofibroma-like variants of histogenetically diverse entities so that a diagnosis of adenofibroma should be rendered only very restrictively and then as a diagnosis by exclusion.
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http://dx.doi.org/10.1007/s00428-020-02796-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371666PMC
August 2020

Is Ovarian Tissue Transport at Supra-zero Temperatures Compared to Body Temperature Optimal for Follicle Survival?

In Vivo 2020 Mar-Apr;34(2):533-541

Department of Obstetrics and Gynecology, Erlangen University Hospital, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.

Background/aim: Transportation of ovarian cortex prior to freezing is used clinically; however, basic investigations of ovarian storage are limited and the question remains what temperature is optimal for transport over long distances and time periods. The aim of this study was to evaluate the rate of follicular loss over various time periods under two different temperatures and assess whether ovarian follicle viability is affected following cryopreservation and thawing subsequent to the transportation of ovarian tissue.

Materials And Methods: Pig ovaries were transported at 4°C (n=10) or at 38°C (n=10) prior to cryopreservation. At 0, 4, 12 and 24 h tissues were fixed for histological examination and a LIVE/DEAD Assay. At the same time-points ovarian tissues were cryopreserved and analysed after thawing.

Results: Histological evaluation and LIVE/DEAD Assay of freshly transported ovarian tissue showed significantly better follicle survival at 4°C during transportation duration. In cryopreserved ovarian tissues the LIVE/DEAD Assay showed a significant difference in the number of intact and dead follicles at 24 h in favor of 4°C (p<0.05).

Conclusion: Ovarian tissue transportation should be kept at a minimum to prevent potential damage.
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http://dx.doi.org/10.21873/invivo.11805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7157863PMC
December 2020

Accelerated Partial Breast Irradiation: Macrophage Polarisation Shift Classification Identifies High-Risk Tumours in Early Hormone Receptor-Positive Breast Cancer.

Cancers (Basel) 2020 Feb 14;12(2). Epub 2020 Feb 14.

Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsstraße 27, D-91054 Erlangen, Germany.

Studies have demonstrated correlations between accumulations of tumour-associated macrophages (TAMs), especially of M2-like phenotype, and increased mortality in advanced breast cancer. We investigated the prognostic potential of both main macrophage phenotypes in early hormone receptor-positive (HR+) breast cancer. The studied cohort of 136 patients participated in an institutional APBI phase II trial. Patient selection was characterized by HR+, small tumour size and no metastasis. Tissue microarrays from pre-RT resection samples were double stained for CD68/CD163 using immunohistochemistry. CD68+/CD163- cells were considered M1-like macrophages and CD68+/CD163+ was representative of M2-like macrophages. M1 and M2 macrophage densities were analysed semi-automatically in the stromal and intraepithelial tumour compartment. Low M1 and high M2 densities were strongly associated with decreased disease-free survival (DFS). Combined TAM phenotype densities were studied after defining a macrophage shift classification: M1-shifted (M1 high, M2 low) and non-shifted (M1 low, M2 low; M1 high, M2 high) tumours entailed a favourable outcome. In contrast, M2-shifted (M1 low, M2 high) TAM populations were associated with extremely reduced DFS. Thus, the full predictive potential of TAMs was revealed in a combined analysis of both phenotypes. The M2-shifted subgroup of tumours is classified as high-risk and probably not suitable for partial breast irradiation.
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http://dx.doi.org/10.3390/cancers12020446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072550PMC
February 2020

Discrimination analysis of breast calcifications using x-ray dark-field radiography.

Med Phys 2020 Apr 21;47(4):1813-1826. Epub 2020 Feb 21.

Erlangen Centre for Astroparticle Physics (ECAP), Friedrich-Alexander-University Erlangen-Nuremberg, Erwin-Rommel-Str. 1, D-91058, Erlangen, Germany.

Background: X-ray dark-field radiography could enhance mammography by providing more information on imaged tissue and microcalcifications. The dark field signal is a measure of small angle scattering and can thus provide additional information on the imaged materials. This information can be useful for material distinction of calcifications and the diagnosis of breast cancer by classifying benign and malign association of these calcifications.

Methods: For this study, institutional review board approval was obtained. We present the evaluation of images acquired with interferometric grating-based x-ray imaging of 323 microcalcifications (166 malign and 157 benign associated) in freshly dissected breast tissue and compare the results to the information extracted in follow-up pathological evaluation. The number of imaged calcifications is sufficiently higher than in similar previous studies. Fourteen calcification properties were extracted from the digital images and used as predictors in three different models common in discrimination analysis namely a simple threshold model, a naive Bayes model and a linear regression model, which classify the calcifications as associated with a benign or suspicious finding. Three of these fourteen predictors have been newly defined in this work and are independent from the tissue background surrounding the microcalcifications. Using these predictors no background correction is needed, as in previous works in this field. The new predictors are the length of the first and second principle component of the absorption and dark-field data, as well as the angle between the first principle component and the dark-field axis. We called these predictors data length, data width, and data orientation.

Results: In fourfold cross-validation malignancy of the imaged tissue was predicted. Models that take only classical absorption predictors into account reached a sensitivity of 53.3% at a specificity of 81.1%. For a combination of predictors that also include dark field information, a sensitivity of 63.2% and specificity of 80.8% were obtained. The included dark field information consisted of the newly introduced parameters, data orientation and data width.

Conclusions: While remaining at a similar specificity, the sensitivity, with which a trained model was able to distinguish malign from benign associated calcifications, was increased by 10% on including dark-field information. This suggests grating-based x-ray imaging as a promising clinical imaging method in the field of mammography.
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http://dx.doi.org/10.1002/mp.14043DOI Listing
April 2020

Nuclear NR4A3 Immunostaining Is a Specific and Sensitive Novel Marker for Acinic Cell Carcinoma of the Salivary Glands.

Am J Surg Pathol 2019 09;43(9):1264-1272

Institute of Pathology.

Recently, we discovered the recurrent genomic rearrangement [t(4;9)(q13;q31)] enabling upregulation of the transcription factor Nuclear Receptor Subfamily 4 Group A Member 3 (NR4A3) through enhancer hijacking as the oncogenic driver event in acinic cell carcinoma (AciCC) of the salivary glands. In the current study, we evaluated the usefulness of NR4A3 immunostaining and NR4A3 fluorescence in situ hybridization (FISH) in the differential diagnosis of AciCC, comparing a total of 64 AciCCs including 17% cases with high-grade transformation, 29 secretory (mammary analog) carcinomas (MASC), and 70 other salivary gland carcinomas. Nuclear NR4A3 immunostaining was a highly specific (100%) and sensitive (98%) marker for AciCC with only 1 negative case, whereas NR4A3 FISH was less sensitive (84%). None of the MASCs or other salivary gland carcinomas displayed any nuclear NR4A3 immunostaining. The recently described HTN3-MSANTD3 gene fusion was observed in 4 of 49 (8%) evaluable AciCCs, all with nuclear NR4A3 immunostaining. In summary, NR4A3 immunostaining is a highly specific and sensitive marker for AciCC, which may be especially valuable in cases with high-grade transformation and in "zymogen granule"-poor examples within the differential diagnostic spectrum of AciCC and MASC.
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http://dx.doi.org/10.1097/PAS.0000000000001279DOI Listing
September 2019

Prognostic effect of Ki-67 in common clinical subgroups of patients with HER2-negative, hormone receptor-positive early breast cancer.

Breast Cancer Res Treat 2019 Jun 13;175(3):617-625. Epub 2019 Mar 13.

Comprehensive Cancer Center Erlangen-EMN, Institute of Pathology, Erlangen University Hospital, Friedrich Alexander University of Erlangen-Nuremberg, Nuremberg, Germany.

Purpose: Several clinical trials have investigated the prognostic and predictive usefulness of molecular markers. With limited predictive value, molecular markers have mainly been used to identify prognostic subgroups in which the indication for chemotherapy is doubtful and the prognosis is favorable enough for chemotherapy to be avoided. However, limited information is available about which groups of patients may benefit from additional therapy. This study aimed to describe the prognostic effects of Ki-67 in several common subgroups of patients with early breast cancer.

Methods: This retrospective study analyzed a single-center cohort of 3140 patients with HER2-, hormone receptor-positive breast cancer. Five-year disease-free survival (DFS) rates were calculated for low (< 10%), intermediate (10-19%), and high (≥ 20%) Ki-67 expression levels, as assessed by immunohistochemistry, and for subgroups relative to age, body mass index, disease stage, tumor grade, and (neo-)adjuvant chemotherapy. It was also investigated whether Ki-67 had different effects on DFS in these subgroups.

Results: The 5-year DFS rates for patients with low, intermediate, and high levels of Ki-67 expression were 0.90, 0.89, and 0.77, respectively. Ki-67 was able to further differentiate patients with an intermediate prognosis into different prognostic groups relative to common clinical parameters. Patients with stage II breast cancer had 5-year DFS rates of 0.84, 0.88, and 0.79 for low, intermediate, and high levels of Ki-67 expression. Ki-67 had different prognostic effects in subgroups defined by age and tumor grade.

Conclusions: Ki-67 may help identify patients in intermediate prognostic groups with an unfavorable prognosis who may benefit from further therapy.
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http://dx.doi.org/10.1007/s10549-019-05198-9DOI Listing
June 2019

BAP1 Loss is a Useful Adjunct to Distinguish Malignant Mesothelioma Including the Adenomatoid-like Variant From Benign Adenomatoid Tumors.

Appl Immunohistochem Mol Morphol 2020 01;28(1):67-73

Institute of Pathology, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen.

Malignant mesothelioma (MM) can show areas closely mimicking reactive mesothelial proliferations or recapitulating benign adenomatoid tumors (ATs) making distinction on occasion impossible on morphologic ground alone, particularly in limited biopsy material. Recently, loss of BAP1 by immunohistochemistry (IHC) has been suggested as a potential marker for identifying MM, but data is still limited. We studied 264 MM cases (257 using tissue microarrays; 7 on conventional slides) and 42 genital ATs for BAP1 immunohistochemical expression. Loss of BAP1 protein expression was observed in 119/211 of MM cases (56.4%). Taken by histologic type, 64.3% of biphasic, 55.4% of epithelioid, and 41.7% of sarcomatoid MM were BAP1-deficient. In contrast, all 42 ATs showed retained BAP1 immunoreactivity. Notably, all 4 MM cases with variable adenomatoid-like features were BAP1-deficient. Surface components of MM of the pleura showed concordant loss as the invasive tumor suggesting a potential role for BAP1 loss for recognizing so-called early mesothelioma. In conclusion, BAP1 loss demonstrated by IHC is seen in more than half of MM cases but none of ATs. Thus, BAP1 IHC represents a potential adjunct for distinguishing MM from benign mesothelial proliferations including in particular "MM with bland adenomatoid-like pattern versus benign ATs" on biopsy material and early mesothelioma with limited invasion.
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http://dx.doi.org/10.1097/PAI.0000000000000700DOI Listing
January 2020

Prediction of pathological complete response and prognosis in patients with neoadjuvant treatment for triple-negative breast cancer.

BMC Cancer 2018 Oct 29;18(1):1051. Epub 2018 Oct 29.

Department of Gynecology and Obstetrics, Erlangen University Hospital, University Breast Center for Franconia, Comprehensive Cancer Center Erlangen-EMN, Friedrich Alexander University of Erlangen-Nuremberg, Universitätsstrasse 21-23, 91054, Erlangen, Germany.

Background: It has been reported that pathological complete response is an important surrogate marker for disease-free survival and overall survival in patients with triple-negative breast cancer. This study investigates predictors of the response to neoadjuvant platinum-based or anthracycline-based treatment, and of the prognosis, in patients with triple-negative breast cancer.

Methods: A total of 121 patients with triple-negative breast cancer received neoadjuvant treatment with either platinum or anthracycline between 2008 and 2013. Pathological complete response was assessed relative to different treatments using logistic regression models with age, clinical tumor stage, grading, and Ki-67 as predictors and interaction terms, to obtain adjusted and subgroup-specific results. The impact of the pathological complete response rate on disease-free survival and overall survival was also analyzed.

Results: The pathological complete response rate was higher after platinum/taxane treatment compared with anthracycline/taxane (50.0% vs. 41.8%), but this was not significant in the adjusted analysis (OR 1.44; 95% CI, 0.68 to 3.09). A high histological grade (G3) was a predictor for higher pathological complete response in platinum-based therapy (OR 2.27; 95% CI, 1.00 to 5.30). The effect of neoadjuvant chemotherapy on pathological complete response was significantly different for G1-2 vs. G3 (P = 0.013), and additional subgroup-specific differences were noted. Pathological complete response was a predictor for improved disease-free survival and overall survival in both treatment groups, with and without platinum chemotherapy.

Conclusions: This retrospective study of patients with triple-negative breast cancer adds to the evidence that the treatment effect of platinum may be greatest particularly in G3 tumors. In addition, the effect of pathological complete response on the prognosis does not depend on the treatment used.
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http://dx.doi.org/10.1186/s12885-018-4925-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6206705PMC
October 2018

Using Probability for Pathological Complete Response (pCR) as a Decision Support Marker for Neoadjuvant Chemotherapy in HER2 Negative Breast Cancer Patients - a Survey Among Physicians.

Geburtshilfe Frauenheilkd 2018 Jul 25;78(7):707-714. Epub 2018 Jul 25.

Department of Gynecology and Obstetrics, Erlangen University Hospital, Comprehensive Cancer Center Erlangen-EMN, Friedrich Alexander University of Erlangen-Nuremberg, Erlangen, Germany.

Background: In women with early breast cancer, a pathological complete response (pCR) after neoadjuvant chemotherapy is reported to be associated with an improvement of the survival. The aim of this survey among physicians was to investigate whether the probability of achieving pCR in patients with a hormone receptor-positive, HER2-negative disease encourages physicians to recommend neoadjuvant chemotherapy.

Methods: The study was conducted via an online survey that was sent to 493 physicians, who were either known as members of national guideline committees, heads of breast cancer centers, being high recruiters in clinical trials or leading a private practice. Participants were asked about a specific case that should resemble patients for whom it is unclear, whether they should be treated with chemotherapy.

Results: 113 (24.5%) physicians participated at the survey, out of which 96.5% had a work experience of more than 10 years and 94.7% were board certified in their specialty. A total of 84.1% would consider pCR for a decision concerning neoadjuvant chemotherapy. With regard to the pCR probability, 2.7 and 10.6% of the participants demanded at least a pCR rate of 5 and 10%, respectively, while 25.7% were satisfied with 20% probability, and another 25.7% with a pCR rate of 30%.

Conclusions: The vast majority of the long-term experienced physicians would embrace the implementation of a further method such as the prediction of pCR probability in clinical routine to support decision making regarding the necessity of neoadjuvant chemotherapy. The cut-off of around 30% pCR probability seems to be a realizable rate to distinguish patient groups.
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http://dx.doi.org/10.1055/a-0642-9462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6059863PMC
July 2018

Breast Tumor Analysis Using Shifted-Excitation Raman Difference Spectroscopy (SERDS).

Technol Cancer Res Treat 2018 01;17:1533033818782532

1 Lehrstuhl für Technische Thermodynamik, Friedrich-Alexander-Universität (FAU), Erlangen-Nürnberg, Germany.

We used a shifted-excitation Raman difference spectroscopy method for the ex vivo classification of resected and formalin-fixed breast tissue samples as normal (healthy) tissue, fibroadenoma, or invasive carcinoma. We analyzed 8 tissue samples containing invasive carcinoma that were surrounded by normal tissue and 3 tissue samples with fibroadenoma only. We made various measurement sites on various tissue samples, in total 240 measurements for each type of tissue. Although the acquired raw spectra contain enough information to clearly differentiate between normal and tumor (fibroadenoma and invasive carcinoma) tissue, the differentiation between fibroadenoma and invasive carcinoma was possible only after the shifted-excitation Raman difference spectroscopy isolation of pure Raman spectra from the heavily fluorescence interfered raw spectra. We used 784 and 785 nm as excitation wavelengths for the shifted-excitation Raman difference spectroscopy method. The differences in the obtained pure Raman spectra are assigned to the different chemical compositions of normal breast tissue, fibroadenoma, and invasive breast carcinoma. Principal component analysis and linear discriminant analysis showed excellent classification results in the Raman shift range between 1000 and 1800 cm. Invasive breast carcinoma was identified with 99.15% sensitivity, and the absence of invasive carcinoma was identified with 90.40% specificity. Tumor tissue in tumor-containing tissue was identified with 100% sensitivity, and the absence of tumor in no-tumor containing tissue was identified with 100% specificity. As gold standard for the determination of the sensitivity and the specificity, we considered the conventional histopathological classification. In summary, shifted-excitation Raman difference spectroscopy could be potentially very useful to support histopathological diagnosis in breast pathology.
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http://dx.doi.org/10.1177/1533033818782532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048663PMC
January 2018

TILGen: A Program to Investigate Immune Targets in Breast Cancer Patients - First Results on the Influence of Tumor-Infiltrating Lymphocytes.

Breast Care (Basel) 2018 Mar 15;13(1):8-14. Epub 2018 Feb 15.

Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander-University Erlangen-Nuremberg (FAU), Erlangen, Germany.

Background: Despite advancements in the treatment of primary and metastatic breast cancer, many patients lack a durable response to these treatments. Patients with triple-negative breast cancer (TNBC) and human epidermal growth factor receptor 2(HER2)-positive breast cancer who do not have a pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) have a very poor prognosis. Tumor-infiltrating lymphocytes (TILs) have been identified as a predictive marker for pCR after NACT in TNBC and HER2-positive breast cancer. These patient populations could also be suitable for novel treatment strategies including neoepitope-based therapies. This work analyses the effect of TILs on the pCR in neoadjuvantly treated patients in the TILGen study and presents the procedures aimed at establishing neoepitope-based therapies in this study.

Methods: Neoadjuvantly treated HER2-positive and TNBC patients were eligible for the presented analysis concerning the association between TILs and pCR. A total of 146 patients could be identified within the TILGen study. TILs were evaluated as percentage of stromal tumor tissue in core biopsies at primary diagnosis. The phenotype 'lymphocyte-predominant breast cancer' (LPBC) was associated with pCR by logistic regression adjusted for estrogen receptor status, progesterone receptor status, HER2 status, age at diagnosis, and grading.

Results: LPBC was seen in 24 (16.4%) patients. In this patient group, 66.7% achieved a pCR, while the pCR rate was 32.8% in patients with a low TIL count. The adjusted odds ratio was 6.60 (95% confidence interval 2.02-21.56; p < 0.01).

Conclusion: TILs are a strong predictor of pCR in TNBC and HER2-positive breast cancer patients. Implications for the use of this information including the effect on prognosis might help to identify patients most likely to benefit from a neoepitope-based therapy approach.
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http://dx.doi.org/10.1159/000486949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6016056PMC
March 2018

Risk, Prediction and Prevention of Hereditary Breast Cancer - Large-Scale Genomic Studies in Times of Big and Smart Data.

Geburtshilfe Frauenheilkd 2018 May 4;78(5):481-492. Epub 2018 Jun 4.

Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.

Over the last two decades genetic testing for mutations in and has become standard of care for women and men who are at familial risk for breast or ovarian cancer. Currently, genetic testing more often also includes so-called panel genes, which are assumed to be moderate-risk genes for breast cancer. Recently, new large-scale studies provided more information about the risk estimation of those genes. The utilization of information on panel genes with regard to their association with the individual breast cancer risk might become part of future clinical practice. Furthermore, large efforts have been made to understand the influence of common genetic variants with a low impact on breast cancer risk. For this purpose, almost 450 000 individuals have been genotyped for almost 500 000 genetic variants in the OncoArray project. Based on first results it can be assumed that - together with previously identified common variants - more than 170 breast cancer risk single nucleotide polymorphisms can explain up to 18% of familial breast cancer risk. The knowledge about genetic and non-genetic risk factors and its implementation in clinical practice could especially be of use for individualized prevention. This includes an individualized risk prediction as well as the individualized selection of screening methods regarding imaging and possible lifestyle interventions. The aim of this review is to summarize the most recent developments in this area and to provide an overview on breast cancer risk genes, risk prediction models and their utilization for the individual patient.
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http://dx.doi.org/10.1055/a-0603-4350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5986564PMC
May 2018

BRCA mutations and their influence on pathological complete response and prognosis in a clinical cohort of neoadjuvantly treated breast cancer patients.

Breast Cancer Res Treat 2018 Aug 3;171(1):85-94. Epub 2018 May 3.

Department of Gynecology and Obstetrics, Erlangen University Hospital, Comprehensive Cancer Center Erlangen-EMN, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany.

Purpose: BRCA1/2 mutations influence the molecular characteristics and the effects of systemic treatment of breast cancer. This study investigates the impact of germline BRCA1/2 mutations on pathological complete response and prognosis in patients receiving neoadjuvant systemic chemotherapy.

Methods: Breast cancer patients were tested for a BRCA1/2 mutation in clinical routine work and were treated with anthracycline-based or platinum-based neoadjuvant chemotherapy between 1997 and 2015. These patients were identified in the tumor registry of the Breast Center of the University of Erlangen (Germany). Logistic regression and Cox regression analyses were performed to investigate the associations between BRCA1/2 mutation status, pathological complete response, disease-free survival, and overall survival.

Results: Among 355 patients, 59 had a mutation in BRCA1 or in BRCA2 (16.6%), 43 in BRCA1 (12.1%), and 16 in BRCA2 (4.5%). Pathological complete response defined as "ypT0; ypN0" was observed in 54.3% of BRCA1/2 mutation carriers, but only in 22.6% of non-carriers. The adjusted odds ratio was 2.48 (95% CI 1.26-4.91) for BRCA1/2 carriers versus non-carriers. Patients who achieved a pathological complete response had better disease-free survival and overall survival rates compared with those who did not achieve a pathological complete response, regardless of BRCA1/2 mutation status.

Conclusions: BRCA1/2 mutation status leads to better responses to neoadjuvant chemotherapy in breast cancer. Pathological complete response is the main predictor of disease-free survival and overall survival, independently of BRCA1/2 mutation status.
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http://dx.doi.org/10.1007/s10549-018-4797-8DOI Listing
August 2018

Misses and near misses in diagnosing nodular fasciitis and morphologically related reactive myofibroblastic proliferations: experience of a referral center with emphasis on frequency of USP6 gene rearrangements.

Virchows Arch 2018 Sep 5;473(3):351-360. Epub 2018 Apr 5.

Institute of Pathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Krankenhausstrasse 8-10, 91054, Erlangen, Germany.

Although harmless, reactive and benign neoplastic myo-/fibroblastic proliferations represent a diagnostic challenge in routine surgical pathology practice as reflected by their frequency among consultation cases. In addition to resembling each other, the prototypical nodular fasciitis (NF) and NF-like lesions can be mistaken for low-grade or aggressive sarcomas. USP6 translocation was reported recently as the molecular driver and potential diagnostic marker of NF. We reviewed 71 lesions with a diagnosis of NF (n = 48) or NF-like myofibroblastic proliferations (n = 23) and screened them for USP6 translocation by fluorescence in situ hybridization (FISH). Only one third of NFs were correctly diagnosed by submitting pathologists while one third was initially judged as malignant. NF was mentioned in the differential diagnosis in only half of the cases. A high Ki67/mitotic index, misleading immunohistochemistry (false-positive h-caldesmon), and unusual sites/circumscription were main causes behind overdiagnosis as malignant. FISH analysis revealed USP6 translocation in 74.4% of NF cases. None of the reactive/reparative myofibroblastic proliferations showed USP6 translocation. NF is still significantly misdiagnosed by general surgical pathologists, with a higher tendency toward overdiagnosis of malignancy. Inclusion of NF in the differential diagnosis of any fibromyxoid soft tissue lesion and awareness of its diverse morphology are mandatory to avoid misdiagnoses with the risk of disastrous overtreatment. In the appropriate clinicopathological context, USP6 gene translocation is a valuable adjunct for diagnosis of NF, particularly in limited biopsies. Absence of the USP6 gene translocation in NF-like reparative pseudosarcomatous myofibroblastic proliferations underlines their reactive nature and distinguishes them from NF which is currently considered a benign neoplasm with a self-limiting "transient" growth phase.
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http://dx.doi.org/10.1007/s00428-018-2350-0DOI Listing
September 2018

Fumarate hydratase (FH) deficiency in uterine leiomyomas: recognition by histological features versus blind immunoscreening.

Virchows Arch 2018 May 13;472(5):789-796. Epub 2018 Jan 13.

Institute of Pathology, University Hospital Erlangen, Comprehensive Cancer Center ER-EMN, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome is a rare autosomal dominant disease caused by germline mutations in the fumarate hydratase (FH) gene. Affected individuals develop cutaneous and uterine leiomyomas and aggressive RCC. To date, only few publications described the frequency and morphology of FH-deficient uterine leiomyomas. We reviewed 22 cases collected over 8 years from routine and consultation files based on distinctive histological features. In addition, we screened 580 consecutive uterine leiomyomas from 484 patients, 23 extra-uterine and 8 uterine leiomyosarcomas, and 6 leiomyomas with bizarre nuclei for FH loss using immunohistochemistry (IHC) on tissue microarrays (TMAs). All 22 FH-deficient cases were suspected on H&E sections and confirmed by FH IHC. Patients' ages ranged from 25 to 70 years (median 36). Seventeen patients had multiple nodules (2-14) measuring up to 11.8 cm. None of the patients had stigmata or family history of the HLRCC syndrome. Histologically, all FH-deficient tumors showed consistent and reproducible features as reported previously. FH loss was detected in 2/534 evaluable leiomyomas (0.4%), but in none of leiomyosarcomas. Two of six leiomyomas with bizarre nuclei were FH-deficient. FH-deficient uterine leiomyomas are rare in routine material (= 0.4%). They can be reliably identified or suspected by consistent morphological features. Our data showed predictive morphology to be superior to blind IHC screening for detecting them. The relationship of FH-deficient uterine smooth muscle tumors to the HLRCC syndrome needs further clarification.
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http://dx.doi.org/10.1007/s00428-018-2292-6DOI Listing
May 2018

Comparison of mRNA Expression Measured with the CheckPoint Typer® Assay with PD-L1 Protein Expression Assessed with Immunohistochemistry in Non-small Cell Lung Cancer.

Anticancer Res 2017 12;37(12):6771-6778

Department of Respiratory Medicine, Allergology and Sleep Medicine, Paracelsus Medical University Nuernberg, General Hospital Nuernberg, Nürnberg, Germany.

Background: Immunohistochemical (IHC) assessment of programmed death-ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC) has become important since the development of anti-PD-1/-PD-L1 directed drugs. Various PD-L1 antibodies and cut-offs have been used in different trials to predict response to these drugs, thus comparison of those studies is difficult. We compared PD-L1 mRNA expression measured by RT-qPCR with PD-L1 protein expression evaluated by IHC. Moreover, we investigated the impact of different tumour tissue acquisition methods on the reliability of PD-L1 measurement techniques.

Materials And Methods: NSCLC cases (N=22), including n=9 mediastinal lymph node biopsies acquired by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and n=5 metastases, were evaluated prospectively for PD-L1 protein on tumor cells (TC) and immune cells (IC) using E1L3N and 28-8 antibodies and PD-L1 mRNA using the CheckPoint TYPER® assay.

Results: In primary NSCLC tissues, agreement between PD-L1 mRNA and TC staining using the 28-8 antibody was excellent (ĸ=0.85, p=0.0002). Comparing both PD-L1 antibodies against each other showed a kappa value of 0.58 (p=0.0106). In EBUS-TBNA, PD-L1 mRNA correlated perfectly with the 28-8 antibody (ĸ=1.0, p=0.0023). PD-L1 mRNA levels significantly differed when comparing 28-8 TC staining of tumours >49% with 1-49% and 0% (p=0.0040; p=0.0081, respectively). In metastatic lesions, differences between PD-L1 mRNA and IHC became apparent (ĸ=0.2, p=0.2525).

Conclusion: Testing of PD-L1 mRNA and 28-8 IHC showed an excellent agreement in NSCLC samples including mediastinal lymph node biopsies. Since PD-L1 expression in >50% TC detected by 28-8 IHC can be reliably detected by RT-qPCR, quantitative PD-L1 mRNA determination should be considered as an alternative to IHC as there is no interobserver variability in RNA results.
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http://dx.doi.org/10.21873/anticanres.12137DOI Listing
December 2017

Impact of postoperative radiotherapy and HER2/new overexpression in salivary duct carcinoma : A monocentric clinicopathologic analysis.

Strahlenther Onkol 2017 Nov 21;193(11):961-970. Epub 2017 Aug 21.

Institute of Pathology, University Hospital of Erlangen, Erlangen, Germany.

Aim: Retrospective Investigation of the prognostic relevance of clinicopathologic parameters in patients with salivary duct carcinoma (SDC).

Methods: An experienced pathologist reviewed 67 patients with de novo SDC or SDC ex pleomorphic adenoma. Paraffin-embedded tumor samples were examined by immunohistochemistry for expression of HER2/neu, androgen (AR), progesterone (PR), estrogen (ER), epidermal growth factor (EGFR) and programmed death ligand 1 (PD-L1-R) receptor. In 45 patients who had cM0 and follow-up data available, survival rates were calculated (Kaplan-Meier method) and prognostic variables were analyzed (univariate analysis: log-rank test; multivariate analysis: Cox-regression analysis).

Results: Overexpression of HER2/neu, AR, ER, PR, EGFR, PD-L1-R was found in 25.4%, 84%, 0%, 0%, 17.9%, 16.4% of patients. Overall (OS), disease-free (DFS), distant-metastases-free survival (DMFS) and locoregional control (LRC) were 92.3/72.4/56.9%, 78.2/58.1/58.1%, 85.4/65.2/65.2% and 89.7/81.9/81.9% after 1/3/5 years (medial follow-up 26 months). In univariate analysis a positive resection margin (p = 0.008) and no postoperative radiotherapy (p = 0.001) predict an increased locoregional recurrence rate. In multivariate analysis only postoperative radiotherapy is statistically significant (p = 0.004). Presence of lymph node metastases, a lymph node density >4 and HER2/neu overexpression predict decreased DFS and DMFS. In multivariate HER2/neu overexpression was the only significant predictor for reduced DFS (p = 0.04) and DMFS (p = 0.02).

Conclusion: Postoperative radiotherapy is the only significant predictor for LRC. HER2/neu receptor expression is an independent prognostic factor for decreased DFS and DMFS in patients with SDC. In addition to radio(chemo)therapy, intensified first-line treatment regimens should also be evaluated in the future.
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http://dx.doi.org/10.1007/s00066-017-1196-8DOI Listing
November 2017
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