Publications by authors named "Ronald Simon"

441 Publications

MUC5AC Expression in Various Tumor Types and Nonneoplastic Tissue: A Tissue Microarray Study on 10 399 Tissue Samples.

Technol Cancer Res Treat 2021 Jan-Dec;20:15330338211043328

Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Mucin 5AC (MUC5AC) belongs to the glycoprotein family of secreted gel-forming mucins and is physiologically expressed in some epithelial cells. Studies have shown that MUC5AC is also expressed in several cancer types suggesting a potential utility for the distinction of tumor types and subtypes. To systematically determine MUC5AC expression in normal and cancerous tissues, a tissue microarray containing 10 399 samples from 111 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. MUC5AC was expressed in normal mucus-producing cells of various organs. At least weak MUC5AC positivity was seen in 44 of 111 (40%) tumor entities. Of these 44 tumor entities, 28 included also tumors with strong positivity. MUC5AC immunostaining was most commonly seen in esophageal adenocarcinoma (72%), colon adenoma (62%), ductal adenocarcinoma of the pancreas (64%), mucinous carcinoma of the ovary (46%), diffuse gastric adenocarcinoma (44%), pancreatic ampullary adenocarcinoma (41%), intestinal gastric adenocarcinoma (39%), and bronchioloalveolar carcinoma (33%). Clinically relevant tumors with complete or almost complete absence of MUC5AC staining included small cell carcinoma of the lung (0% of 17), clear cell renal cell carcinoma (0% of 507), papillary thyroid carcinoma (0% of 359), breast cancer (2% of 1097), prostate cancer (2% of 228), soft tissue tumors (0.1% of 968), and hematological neoplasias (0% of 111). The highly standardized analysis of a broad range of cancers identified a ranking order of tumors according to their relative prevalence of MUC5AC expression.
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http://dx.doi.org/10.1177/15330338211043328DOI Listing
September 2021

High mitochondrial content is associated with breast cancer aggressiveness.

Mol Clin Oncol 2021 Oct 8;15(4):203. Epub 2021 Aug 8.

Institute of Pathology, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.

Mitochondria are relevant for cancer initiation and progression. Antibodies against mitochondrially encoded cytochrome oxidase II (MTCO2), targeting a mitochondria specific epitope, can be used to quantitate the mitochondria content of tumor cells. The present study evaluated the impact of the cellular mitochondrial content on the prognosis of patients with breast cancer using immunohistochemical analysis on 2,197 arrayed breast cancer specimens. Results were compared with histological tumor parameters, patient overall survival, tumor cell proliferation using Ki67 labeling index (Ki67LI) and various other molecular features. Tumor cells exhibited stronger MTCO2 expression than normal breast epithelial cells. MTCO2 immunostaining was largely absent in normal breast epithelium, but was observed in 71.9% of 1,797 analyzable cancer specimens, including 34.6% tumors with weak expression, 22.3% with moderate expression and 15.0% with strong expression. High MTCO2 expression was significantly associated with advanced tumor stage, high Bloom-Richardson-Elston/Nottingham (BRE) grade, nodal metastasis and shorter overall survival (P<0.0001 each). In multivariate analysis, MTCO2 expression did not provide prognostic information independent of BRE grade, pathological tumor and pathological lymph node status. Additionally, significant associations were observed for high MTCO2 expression and various molecular features, including high Ki67LI, amplifications of , , and , deletions of , 8p21 and 9p, low estrogen receptor expression (P<0.0001 each) and progesterone receptor expression (P<0.0001). The present study demonstrated that high MTCO2 expression was strongly associated with a poor prognosis and unfavorable phenotypical and molecular tumor features in patients with breast cancer. This suggests that the mitochondrial content may have a pivotal role in breast cancer progression.
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http://dx.doi.org/10.3892/mco.2021.2365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375016PMC
October 2021

Immunohistochemically detectable thyroglobulin expression in extrathyroidal cancer is 100% specific for thyroidal tumor origin.

Ann Diagn Pathol 2021 Jul 15;54:151793. Epub 2021 Jul 15.

Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Thyroglobulin is a secreted 660 kDa glycoprotein produced by thyroid follicular cells used in diagnostic pathology to secure or exclude a thyroidal origin of metastases of unknown primary tumors. This study was performed to estimate specificity of thyroglobulin immunohistochemistry. 9974 tumor samples from 109 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types were analyzed by immunohistochemistry in a tissue microarray format. Thyroglobulin was strongly expressed in all normal thyroid samples but not in any other normal tissues. Thyroglobulin immunostaining was detected in 99.1% of 106 thyroid adenomas, 98.1% of 364 papillary, 95.2% of 147 follicular, and 7.5% of 40 anaplastic thyroid cancers. Twelve of 15 thyroid samples that were thyroglobulin negative on TMAs showed at least a weak focal thyroglobulin positivity in corresponding large sections, suggesting higher sensitivity of large section analysis. Thyroglobulin positivity in one diffuse large B-cell lymphoma of the thyroid, one chondrosarcoma metastasis to the thyroid, and 42.4% of 92 medullary thyroid cancers was considered to be caused by diffusion of thyroidal colloid from destroyed or even intact adjacent follicles. Thyroglobulin positivity was, however, not seen in 6403 extrathyroidal tumors from 104 different tumor types and subtypes. Our data demonstrate a complete specificity of positive thyroglobulin immunostaining for thyroid origin in tumor tissues obtained from extrathyroidal locations. However, for all tumors located within the thyroid, false positivity can occur as a result of tissue contamination by thyroglobulin rich thyroid colloid from adjacent normal tissue.
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http://dx.doi.org/10.1016/j.anndiagpath.2021.151793DOI Listing
July 2021

DOG1 is commonly expressed in pancreatic adenocarcinoma but unrelated to cancer aggressiveness.

PeerJ 2021 3;9:e11905. Epub 2021 Aug 3.

University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: DOG1 (ANO1; TMEM16A) is a voltage-gated calcium-activated chloride and bicarbonate channel. DOG1 is physiologically expressed in Cajal cells, where it plays an important role in regulating intestinal motility and its expression is a diagnostic hallmark of gastrointestinal stromal tumors (GIST). Data on a possible role of DOG1 in pancreatic cancer are rare and controversial. The aim of our study was to clarify the prevalence of DOG1 expression in pancreatic cancer and to study its association with parameters of cancer aggressiveness.

Methods: DOG1 expression was analyzed by immunohistochemistry in 599 pancreatic cancers in a tissue microarray format and in 12 cases of pancreatitis on large tissue sections.

Results: DOG1 expression was always absent in normal pancreas but a focal weak expression was seen in four of 12 cases of pancreatitis. DOG1 expression was, however, common in pancreatic cancer. Membranous and cytoplasmic DOG1 expression in tumor cells was highest in pancreatic ductal adenocarcinomas (61% of 444 interpretable cases), followed by cancers of the ampulla Vateri (43% of 51 interpretable cases), and absent in 6 acinus cell carcinomas. DOG1 expression in tumor associated stroma cells was seen in 76 of 444 (17%) pancreatic ductal adenocarcinomas and in seven of 51 (14%) cancers of the ampulla Vateri. Both tumoral and stromal DOG1 expression were unrelated to tumor stage, grade, lymph node and distant metastasis, mismatch repair protein deficiency and the density of CD8 positive cytotoxic T-lymphocytes in the subgroups of ductal adenocarcinomas and cancers of ampulla Vateri. Overall, the results of our study indicate that DOG1 may represent a potential biomarker for pancreatic cancer diagnosis and a putative therapeutic target in pancreatic cancer. However, DOG1 expression is unrelated to pancreatic cancer aggressiveness.
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http://dx.doi.org/10.7717/peerj.11905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8344676PMC
August 2021

Pattern of placental alkaline phosphatase (PLAP) expression in human tumors: a tissue microarray study on 12,381 tumors.

J Pathol Clin Res 2021 Aug 7. Epub 2021 Aug 7.

Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Placental alkaline phosphatase (PLAP) is commonly expressed at high levels in testicular germ cell tumors. PLAP immunohistochemistry (IHC) is thus often used to confirm this diagnosis, especially in cases of putative metastasis. However, other tumors can also express PLAP. To comprehensively determine PLAP expression in normal and tumor tissue, a tissue microarray containing 16,166 samples from 131 different tumor types and subtypes as well as 608 samples from 76 different normal tissue types was analyzed by IHC. Moderate to strong PLAP positivity was found in 27 (21%) of 131 different tumor types including seminoma (96%), embryonal carcinoma (85%), and yolk sac tumors of the testis (56%); endometrioid carcinoma of the endometrium (28%) and the ovary (20%); gastric adenocarcinoma (22%); serous carcinoma (not otherwise specified) of the ovary (17%) and the uterus (11%); adenocarcinoma of the ampulla of Vater (15%); carcinosarcoma of the ovary (11%) and the uterus (8%); esophageal adenocarcinoma (10%); invasive urothelial carcinoma (4%); cholangiocarcinoma (2%); and adenocarcinoma of the lung (1%). Low-level PLAP immunostaining, often involving only a small fraction of tumor cells, was seen in 21 additional tumor entities. The clinical significance of PLAP expression may vary between tumor types as high PLAP expression was linked to advanced pathological tumor stage (p = 0.0086), nodal metastasis (p = 0.0085), and lymphatic (p = 0.0007) and blood vessel invasion (p = 0.0222) in colorectal cancer, but to low pathological tumor stage in endometrial cancer (p = 0.0043). In conclusion, our data identify several tumor entities that can show PLAP expression at comparable levels to testicular germ cell tumors. These tumor entities need to be considered in cases of PLAP-positive metastasis. Low-level PLAP expression can be found in various other tumor entities and should generally not be viewed as a strong argument for germ cell neoplasia.
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http://dx.doi.org/10.1002/cjp2.237DOI Listing
August 2021

Lorlatinib Induces Durable Disease Stabilization in a Pancreatic Cancer Patient with a ROS1 p.L1950F Mutation: Case Report.

Oncol Res Treat 2021 28;44(9):495-502. Epub 2021 Jul 28.

Department of Hematology, Oncology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Introduction: The prognosis of pancreatic cancer has improved only modestly in recent years. This is partly due to the lack of development in precision oncology including immune oncology in this entity. Rearrangements of the proto-oncogene tyrosine protein kinase ROS1 gene represent driver alterations found especially in lung cancer. Tyrosine kinase inhibitors (TKI) with activity against ROS1 including lorlatinib substantially improved the outcome of this patient population. Anecdotal evidence reports treatment of pancreatic cancer harboring ROS1 fusions with ROS1 TKI, but data concerning treatment of patients with ROS1 point mutations are lacking.

Case Presentation: This case describes a pancreatic cancer patient harboring a ROS1 point mutation that occurred without an underlying ROS1 rearrangement and thus not in the resistance situation. The heavily pretreated patient showed a strong decrease of the tumor biomarkers (CA19-9 and CEA) and radiologically a durable stable disease to the targeted treatment with lorlatinib, thereby achieving a progression-free survival of 12 months.

Conclusion: Our data are the first to show a clinical benefit from targeted treatment with ROS1 TKI in a cancer patient with a thus far undescribed ROS1 point mutation without a concomitant ROS1 rearrangement. Furthermore, they indicate that ROS1 could be an oncogenic driver in pancreatic cancer. This subgroup could be eligible for targeted treatments, which may contribute to the urgently needed improvement in patient outcome.
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http://dx.doi.org/10.1159/000517616DOI Listing
July 2021

Napsin A Expression in Human Tumors and Normal Tissues.

Pathol Oncol Res 2021 20;27:613099. Epub 2021 Apr 20.

Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Novel aspartic proteinase of the pepsin family A (Napsin A, TAO1/TAO2) is a functional aspartic proteinase which is involved in the maturation of prosurfactant protein B in type II pneumocytes and the lysosomal protein catabolism in renal cells. Napsin A is highly expressed in adenocarcinomas of the lung and is thus commonly used to affirm this diagnosis. However, studies have shown that other tumors can also express Napsin A. To comprehensively determine Napsin A expression in normal and tumor tissue, 11,957 samples from 115 different tumor types and subtypes as well as 500 samples of 76 different normal tissue types were evaluable by immunohistochemistry on tissue microarrays. Napsin A expression was present in 16 different tumor types. Adenocarcinoma of the lung (85.6%), clear cell adenocarcinoma of the ovary (71.7%), clear cell adenocarcinoma of the endometrium (42.8%), papillary renal cell carcinoma (40.2%), clear cell (tubulo) papillary renal cell carcinoma (16.7%), endometrial serous carcinoma (9.3%), papillary thyroid carcinoma (9.3%) and clear cell renal cell carcinoma (8.2%) were among the tumors with the highest prevalence of Napsin A positivity. In papillary and clear cell renal cell carcinoma, reduced Napsin A expression was linked to adverse clinic-pathological features ( ≤ 0.03). This methodical approach enabled us to identify a ranking order of tumors according to their relative prevalence of Napsin A expression. The data also show that loss of Napsin A is linked to tumor dedifferentiation in renal cell carcinomas.
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http://dx.doi.org/10.3389/pore.2021.613099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262149PMC
April 2021

MUC5AC expression is linked to mucinous/endometroid subtype, absence of nodal metastasis and mismatch repair deficiency in ovarian cancer.

Pathol Res Pract 2021 Aug 21;224:153533. Epub 2021 Jun 21.

Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Institute of Pathology, Clinical Center Osnabrueck, Osnabrueck, Germany.

Mucin 5AC (MUC5AC) is a secreted gel-forming mucin which is expressed by mucus producing cells of several organs but can also be found in cancer cells of the ovary, pancreas, and gastrointestinal tract. This study aimed to characterize the expression of MUC5AC and its potential prognostic implications in different ovarian cancer subtypes. MUC5AC expression was analyzed by immunohistochemistry on a tissue microarray containing 603 ovarian cancers. MUC5AC was commonly expressed in mucinous (27/36; 75%) and endometrioid (12/39; 31%) carcinomas, whereas malignant mixed Mullerian tumors (2/27; 7%), high-grade serous (20/373; 5%) and clear cell carcinomas (1/28; 4%) were only rarely MUC5AC positive and also showed lower expression levels. MUC5AC positive endometroid carcinomas and high-grade serous carcinomas lacked lymph node metastases (p = 0.0495 and p = 0.0216) suggesting a more favorable prognosis. Deficient mismatch repair (dMMR), associated with a favorable prognosis in different cancer types, was found in 4/39 (10%) MUC5AC positive cancers but in only 5/375 (1%) of MUC5AC negative cancers (p = 0.0052). In subgroup analyses MUC5AC positive endometroid carcinomas more frequently showed dMMR (4/10; 40%) as opposed to MUC5AC negative endometroid carcinomas (3/23; 13%; p = 0.0932). In summary, the results of our study show that MUC5AC expression is associated with mucinous and endometrioid ovarian carcinomas, lack of nodal metastases and dMMR. MUC5AC expressing ovarian cancers should be evaluated for dMMR.
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http://dx.doi.org/10.1016/j.prp.2021.153533DOI Listing
August 2021

Increased lysophosphatidylcholine acyltransferase 1 expression is unrelated to prognosis of esophageal cancer patients.

J Cancer Res Clin Oncol 2021 Oct 19;147(10):2879-2884. Epub 2021 Jun 19.

General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Introduction: Lysophosphatidylcholine acyltransferase 1 (LPCAT1) has repeatedly been suggested to be associated with tumorigenesis. To evaluate the role of LPCAT1 in esophageal cancer, LPCAT1 immunostaining was analyzed on a tissue microarray containing samples from esophageal cancer patients.

Results: In benign esophageal tissue, LPCAT1 staining was detectable in low intensities. LPCAT1 staining was increased in malignant as compared to benign esophageal tissue and was found in high intensity in 26.4% of 288 interpretable esophageal adenocarcinomas (EACs) and in 23.2% of 211 squamous cell carcinomas (ESCCs). Increased LPCAT1 staining was linked to undifferentiated tumor grading in both subtypes of EACs and ESCCs (p = 0.0273 and p = 0.0085).

Conclusion: However, LPCAT1 was not associated with prognosis of EAC and ESCC patients (p = 0.6838 and p = 0.4695) and thus cannot be considered a prognostic biomarker in esophageal cancers.
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http://dx.doi.org/10.1007/s00432-021-03686-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397628PMC
October 2021

Mesothelin is Commonly Expressed in Pancreatic Adenocarcinoma but Unrelated to Cancer Aggressiveness.

Cancer Invest 2021 Oct 18;39(9):711-720. Epub 2021 Aug 18.

General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Data on Mesothelin (MSLN) expression in human normal and cancerous tissues is controversial. We employed immunohistochemistry (IHC) on a tissue microarray (TMA) from 599 pancreatic cancers and 12 large tissue sections of pancreatitis. MSLN expression was highest in pancreatic adenocarcinomas (89%) and adenocarcinomas of the ampulla Vateri (79%), infrequent in pancreatitis and absent in 6 acinus cell carcinomas and normal pancreas. MSLN expression was unrelated to pathological tumor stage, grade, metastasis, and tumor-infiltrating CD8+ lymphocytes. In conclusion, pancreatic cancer may be ideally suited for putative anti- MSLN therapies, and MSLN may represent a suitable biomarker for pancreatic cancer diagnosis, especially on small biopsies.
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http://dx.doi.org/10.1080/07357907.2021.1943747DOI Listing
October 2021

Diagnostic and prognostic impact of cytokeratin 19 expression analysis in human tumors: a tissue microarray study of 13,172 tumors.

Hum Pathol 2021 Sep 6;115:19-36. Epub 2021 Jun 6.

Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.

To evaluate cytokeratin 19 (CK19) expression in normal and cancerous tissues, 15,977 samples from 122 tumor types and 608 samples of 76 normal tissue types were analyzed by immunohistochemistry (IHC). In normal tissues, CK19 expression occurred in epithelial cells of most glandular organs but was strictly limited to the basal cell layer of nonkeratinizing squamous epithelium and absent in the skin. CK19 expression in ≥90% of cases was seen in 34% of the tumor entities including the adenocarcinomas of the pancreas (99.4%), colorectum (99.8%), esophagus (98.7%), and stomach (97.7%), as well as breast cancer (90.0%-100%), high-grade serous (99.1%) or endometrioid (97.8%) ovarian cancer, and urothelial carcinoma (92.6%-100%). A low CK19 positivity rate (0.1-10%) was seen in 5 of 122 tumor entities including hepatocellular carcinoma and seminoma. A comparison of tumor versus normal tissue findings demonstrated that upregulation and downregulation of CK19 can occur in cancer and that both alterations can be linked to unfavorable phenotypes. CK19 downregulation was linked to high grade (p = 0.0017) and loss of estrogen receptor- and progesterone receptor-expression (p < 0.0001 each) in invasive breast carcinoma of no special type. CK19 upregulation was linked to nodal metastases in neuroendocrine tumors and papillary thyroid carcinomas (p < 0.05 each) and to poor grade in clear cell renal cell carcinoma (p < 0.05). CK19 upregulation was particularly common in squamous cell carcinomas. We concluded that CK19 IHC might separate primary liver cell carcinoma from liver metastases, seminoma from other testicular tumors, and helps in the detection of early neoplastic transformation in squamous epithelium.
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http://dx.doi.org/10.1016/j.humpath.2021.05.012DOI Listing
September 2021

High density of cytotoxic T-lymphocytes is linked to tumoral PD-L1 expression regardless of the mismatch repair status in colorectal cancer.

Acta Oncol 2021 Sep 5;60(9):1210-1217. Epub 2021 Jun 5.

Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: Immune checkpoint-inhibitors targeting the PD-1/PD-L1 system are FDA approved in microsatellite instable (MSI) or mismatch repair deficient (dMMR) colorectal cancer (CRC). PD-L1 expression is tightly linked to features connected to immune checkpoint inhibitor response, but studies on large subsets of cancers analyzing the correlation between different status of MSI/dMMR, tumor infiltrating lymphocytes and PD-L1 expression are still lacking.

Methods: More than 1800 CRC were analyzed for PD-L1 by immunohistochemistry in a tissue microarray format. Data were compared to MMR, the number of intratumoral CD8 cytotoxic T-cells, and adverse clinico-pathological parameters. Different cutoff levels for defining PD-L1 positivity in tumor cells (1%, 5%, 10%, and 50%) yielded comparable results.

Results: At a cutoff level of 5%, PD-L1 positivity was seen in 5.1% of tumors. PD-L1 was more often positive in dMMR (18.6%) than in MMR proficient (pMMR) cancers (4.1%;  < 0.0001). The number of intratumoral CD8 lymphocytes was strikingly higher in PD-L1 positive (939.5 ± 118.2) than in PD-L1 negative cancers (310.5 ± 24.8). A higher number of intratumoral CD8 lymphocytes was found in dMMR CRC (PD-L1 positive: 1999.7 ± 322.0; PD-L1 negative: 398.6 ± 128.0;  < 0.0001) compared to pMMR CRC (PD-L1 positive: 793.2 ± 124.8; PD-L1 negative: 297.2 ± 24.2;  < 0.0001). In dMMR and pMMR CRC, PD-L1 expression in tumor cells was unrelated to tumor stage, lymph node status or lymphatic/venous invasion. PD-L1 positivity in tumor associated immune cells was seen in 47.5% of cases and was significantly linked to high numbers of tumor infiltrating CD8, low tumor stage, and absence of lymph node metastasis and lymphatic/venous invasion ( < 0.0001 each).

Conclusion: The data support the previously suggested fact that PD-L1 expression in tumor cells is driven by extensive cytotoxic T-cell infiltration in highly immunogenic dMMR and pMMR CRC. Frequent and intense PD-L1 expression in tumor cells of dMMR CRC may contribute to the high response rates of dMMR CRC to immune checkpoint-inhibitors.
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http://dx.doi.org/10.1080/0284186X.2021.1933585DOI Listing
September 2021

E-Cadherin expression in human tumors: a tissue microarray study on 10,851 tumors.

Biomark Res 2021 Jun 5;9(1):44. Epub 2021 Jun 5.

Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.

Background: The E-Cadherin gene (CDH1, Cadherin 1), located at 16q22.1 encodes for a calcium-dependent membranous glycoprotein with an important role in cellular adhesion and polarity maintenance.

Methods: To systematically determine E-Cadherin protein expression in normal and cancerous tissues, 14,637 tumor samples from 112 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types were analyzed by immunohistochemistry in a tissue microarray format.

Results: E-Cadherin was strongly expressed in normal epithelial cells of most organs. From 77 tumor entities derived from cell types normally positive for E-Cadherin, 35 (45.5%) retained at least a weak E-Cadherin immunostaining in ≥99% of cases and 61 (79.2%) in ≥90% of cases. Tumors with the highest rates of E-Cadherin loss included Merkel cell carcinoma, anaplastic thyroid carcinoma, lobular carcinoma of the breast, and sarcomatoid and small cell neuroendocrine carcinomas of the urinary bladder. Reduced E-Cadherin expression was linked to higher grade (p = 0.0009), triple negative receptor status (p = 0.0336), and poor prognosis (p = 0.0466) in invasive breast carcinoma of no special type, triple negative receptor status in lobular carcinoma of the breast (p = 0.0454), advanced pT stage (p = 0.0047) and lymph node metastasis in colorectal cancer (p < 0.0001), and was more common in recurrent than in primary prostate cancer (p < 0.0001). Of 29 tumor entities derived from E-Cadherin negative normal tissues, a weak to strong E-Cadherin staining could be detected in at least 10% of cases in 15 different tumor entities (51.7%). Tumors with the highest frequency of E-Cadherin upregulation included various subtypes of testicular germ cell tumors and renal cell carcinomas (RCC). E-Cadherin upregulation was more commonly seen in malignant than in benign soft tissue tumors (p = 0.0104) and was associated with advanced tumor stage (p = 0.0276) and higher grade (p = 0.0035) in clear cell RCC, and linked to advanced tumor stage (p = 0.0424) and poor prognosis in papillary RCC (p ≤ 0.05).

Conclusion: E-Cadherin is consistently expressed in various epithelial cancers. Down-regulation or loss of E-Cadherin expression in cancers arising from E-Cadherin positive tissues as well as E-Cadherin neo-expression in cancers arising from E-Cadherin negative tissues is linked to cancer progression and may reflect tumor dedifferentiation.
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http://dx.doi.org/10.1186/s40364-021-00299-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8180156PMC
June 2021

Prevalence of proliferating CD8 cells in normal lymphatic tissues, inflammation and cancer.

Aging (Albany NY) 2021 06 3;13(11):14590-14603. Epub 2021 Jun 3.

Institute of Pathology, University Medical Centre Hamburg-Eppendorf, Hamburg D-20246, Germany.

CD8 cytotoxic T-lymphocytes are essential components of the anti-tumor immunity. To better understand the expansion of CD8 T-cells we used multiplex fluorescence immunohistochemistry to study Ki67CD8 cells in normal lymphoid tissues, selected inflammatory diseases and cancers in 41 large sections/ microenvironment tissue microarrays (TMAs) as well as 765 samples in a conventional TMA format. The evaluation of more than 20 different compartments of normal lymphoid tissues revealed that the percentage of proliferating (ki67) CD8 cells did commonly not exceed 3%. In inflammations, the percentage of Ki67CD8 cells was more variable and higher compared to normal tissues. In cancers, the percentage of Ki67CD8 cells was higher in the tumor center than at the invasive margin. In the tumor center of 765 colorectal cancers, the density of Ki67CD8 cells and the percentage of proliferating CD8 cytotoxic T-cells was significantly associated with microsatellite instability (p<0.0001), pT (p<0.0002) and pN category (p<0.0098). In summary, these data show that the percentage of Ki67CD8 cells is usually at a baseline proliferation rate below 3% in healthy secondary lymphoid organs. This rate is often markedly higher in inflammatory and neoplastic diseases compared to normal tissues. The striking link with unfavorable tumor features in colorectal cancer suggest a potential clinical utility of assessing the percentage of Ki67CD8 cells to predict patients outcome.
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http://dx.doi.org/10.18632/aging.203113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221353PMC
June 2021

Mesothelin Expression in Human Tumors: A Tissue Microarray Study on 12,679 Tumors.

Biomedicines 2021 Apr 7;9(4). Epub 2021 Apr 7.

Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20357 Hamburg, Germany.

Mesothelin (MSLN) represents an attractive molecule for targeted cancer therapies. To identify tumors that might benefit from such therapies, tissue microarrays including 15,050 tumors from 122 different tumor types and 76 healthy organs were analyzed for MSLN expression by immunohistochemistry. Sixty-six (54%) tumor types showed at least occasional weak staining, including 50 (41%) tumor types with at least one strongly positive sample. Highest prevalence of MSLN positivity had ovarian carcinomas (serous 97%, clear cell 83%, endometrioid 77%, mucinous 71%, carcinosarcoma 65%), pancreatic adenocarcinoma (ductal 75%, ampullary 81%), endometrial carcinomas (clear cell 71%, serous 57%, carcinosarcoma 50%, endometrioid 45%), malignant mesothelioma (69%), and adenocarcinoma of the lung (55%). MSLN was rare in cancers of the breast (7% of 1138), kidney (7% of 807), thyroid gland (1% of 638), soft tissues (0.3% of 931), and prostate (0 of 481). High expression was linked to advanced pathological tumor (pT) stage ( < 0.0001) and metastasis ( < 0.0001) in 1619 colorectal adenocarcinomas, but unrelated to parameters of malignancy in 1072 breast-, 386 ovarian-, 174 lung-, 757 kidney-, 171 endometrial-, 373 gastric-, and 925 bladder carcinomas. In summary, numerous important cancer types with high-level MSLN expression might benefit from future anti-MSLN therapies, but MSLN's prognostic relevance appears to be limited.
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http://dx.doi.org/10.3390/biomedicines9040397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067734PMC
April 2021

Prognostic role of proliferating CD8 cytotoxic Tcells in human cancers.

Cell Oncol (Dordr) 2021 Aug 17;44(4):793-803. Epub 2021 Apr 17.

Institute of Pathology, University Medical Centre Hamburg-Eppendorf, Martinistraße 52, D-20246, Hamburg, Germany.

Purpose: Expansion of CD8 cytotoxic Tlymphocytes is a prerequisite for anti-cancer immune activity and has gained interest in the era of immune checkpoint therapy.

Methods: To understand the CD8 T cell dynamics in the tumor microenvironment, we used multiplex fluorescence immunohistochemistry to quantitate CD8 proliferation (Ki67 co-expression) in tissue microarrays from 1107 colorectal, 642 renal cell, 1066 breast, 375 ovarian, 451 pancreatic and 347 gastric cancer samples.

Results: The density and the percentage of proliferating (Ki67) CD8 T cells were both highly variable between tumor types as well as between patients with the same tumor type. Elevated density and percentage of proliferating CD8 cytotoxic T cells were significantly associated with favorable tumor parameters such as low tumor stage, negative nodal stage (p ≤ 0.0041 each), prolonged overall survival (p ≤ 0.0028 each) and an inflamed immune phenotype (p = 0.0025) in colorectal cancer and, in contrast, linked to high tumor stage, advanced ISUP/Fuhrman/Thoenes grading (each p ≤ 0.003), shorter overall survival (p ≤ 0.0330 each) and an immune inflamed phenotype (p = 0.0094) in renal cell cancer. In breast, ovarian, pancreatic and gastric cancer the role of (Ki67)CD8 Tcells was not linked to clinicopathological data.

Conclusion: Our data demonstrate a tumor type dependent prognostic impact of proliferating (Ki67)CD8 Tcells and an inverse impact in colorectal and renal cell cancer.
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http://dx.doi.org/10.1007/s13402-021-00601-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8338812PMC
August 2021

Mismatch repair deficiency occurs very rarely in seminomas.

Transl Androl Urol 2021 Mar;10(3):1048-1055

Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: Dense tumor-associated lymphocyte infiltration is linked to mismatch repair (MMR) deficiency in colorectal and endometrial cancer. MMR deficiency is of high clinical importance as MMR deficient cancers tend to react favorably to treatment with immune checkpoint inhibitors. Strong lymphocytic infiltration is a morphological hallmark of seminomas. We thus asked whether seminomas may exhibit MMR deficiency at relevant frequency.

Methods: To screen for tumors with MMR deficiency, protein expression of MLH1, PMS2, MSH2, and MSH6 was analyzed by immunohistochemistry (IHC) on a tissue microarray (TMA) containing 574 seminomas.

Results: In total, 536 cases were evaluable resulting in 481 seminomas with unequivocally intact MMR protein expression. In 55 cancers, one or several IHC stains were equivocal and lacked detectable MMR protein in both tumor and stromal cells. Large section IHC analysis of all 55 equivocal cases demonstrated substantial staining issues due to improper fixation in 54 cases and identified one tumor with clear-cut MLH1 and PMS2 protein loss. This seminoma showed homogeneous loss of MLH1 and PMS2 in the entire tumor mass whereas minor adjacent foci of associated germ cell neoplasia in situ (GCNIS) were MMR intact. Polymerase chain reaction (PCR) analysis using the 5 microsatellite loci of the "Bethesda Panel" revealed instability in 1 of 4 interpretable loci ("MSI-low") and additional instability of the complex tetra-penta repeat locus MYCL1 in this tumor.

Conclusions: In summary, one single seminoma with MMR deficiency, characterized by protein loss of MLH1 and PMS2, was identified among 536 interpretable seminomas (0.19%). MMR deficiency is not a relevant determinant of lymphocyte influx in seminoma.
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http://dx.doi.org/10.21037/tau-20-1355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039613PMC
March 2021

Tumor cell PD-L1 expression is a strong predictor of unfavorable prognosis in immune checkpoint therapy-naive clear cell renal cell cancer.

Int Urol Nephrol 2021 Apr 1. Epub 2021 Apr 1.

Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.

Background: PD-L1 expression predicts response to immune checkpoint inhibitors in renal cell carcinomas (RCC), but has also been suggested to be linked to poor patient outcome.

Methods: We analyzed PD-L1 in > 1400 RCC in a tissue microarray format by immunohistochemistry. Results were compared with histological tumor type, parameters of cancer aggressiveness, and intratumoral CD8 cytotoxic cells.

Result: At a cut-off level of 5% PD-L1 positive tumor cells, PD-L1 positivity was seen in 6.3% of 633 clear cell RCC (ccRCC), 18.2% of 165 papillary RCC, 18.8% of 64 chromophobe RCC, and 41.7% of 103 oncocytomas. In ccRCC, PD-L1 positivity was significantly linked to high ISUP (p < 0.0001), Fuhrman (p < 0.0001), Thoenes grade (p < 0.0001), distant metastasis (p = 0.0042), short recurrence-free (p < 0.0001), and overall survival (p = 0.0002). Intratumoral CD8 lymphocytes were more frequent in PD-L1 positive (1055 ± 109) than in PD-L1 negative ccRCC (407 ± 28; p < 0.0001). PD-L positive immune cells were seen in 8.2% of all RCC and 13.9% of papillary RCC. In ccRCC, PD-L1 positive immune cells were linked to high numbers of tumor-infiltrating CD8 cells (p < 0.0001), high ISUP (p < 0.0001), Fuhrman (p = 0.0027), and Thoenes grade (p < 0.0001), and poor tumor-specific survival (p = 0.0280).

Conclusions: These data suggest that PD-L1 expression in highly immunogenic RCCs facilitates immune evasion and contributes to cancer aggressiveness.
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http://dx.doi.org/10.1007/s11255-021-02841-7DOI Listing
April 2021

Y-chromosome loss is frequent in male renal tumors.

Ann Transl Med 2021 Feb;9(3):209

Department of Urology, University Medical Center Hamburg-Eppendorf, Martinistr. 52 D-20246 Hamburg, Germany.

Background: Loss of the Y-chromosome is a common event in different tumor types but its prevalence and clinical relevance in renal cell tumors is still not understood.

Methods: It was the aim of this study to estimate the frequency and clinical relevance of Y-loss in kidney neoplasms. A cohort of 1,252 male renal tumors was analyzed in a tissue microarray format by fluorescence in-situ hybridization (FISH).

Results: Y-loss was found in 47% of tumors. The frequency of this alteration varied markedly between kidney tumor subtypes. Y-loss was most prevalent in papillary renal cell carcinoma (RCC) (77%) followed by chromophobe RCC (60%), oncocytoma (51%), clear cell RCC (39%) and clear cell (tubulo)papillary RCC (19%). Y-loss was linked to higher patient age and smaller tumor size at diagnosis. Mean age (95% CI) was 65 (64-66) years in patients with Y-loss in their tumor compared to 60 (58-61) years in patients without Y-loss (P<0.0001). Significant correlations between Y-loss and tumor phenotype were found only for papillary carcinomas (P=0.002), especially for type 1 (P=0.03).

Conclusions: Y-loss is present in different histologic subtypes of renal neoplasm. The highest frequency is in papillary RCC, where it may represent a potentially relevant prognostic biomarker suggesting favorable disease outcome.
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http://dx.doi.org/10.21037/atm-20-3061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940894PMC
February 2021

Reduced anoctamin 7 (ANO7) expression is a strong and independent predictor of poor prognosis in prostate cancer.

Cancer Biol Med 2021 02;18(1):245-255

Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.

Objective: Anoctamin 7 (ANO7) is a calcium-dependent chloride ion channel protein. Its expression is restricted to prostate epithelial cells. The exact function is unknown. This study aimed to analyze ANO7 expression and its clinical significance in prostate cancer (PCa).

Methods: ANO7 expression was assessed by immunohistochemistry in 17,747 clinical PCa specimens.

Results: ANO7 was strongly expressed in normal prostate glandular cells but often less abundant in cancer cells. ANO7 staining was interpretable in 13,594 cancer tissues and considered strong in 34.4%, moderate in 48.7%, weak in 9.3%, and negative in 7.6%. Reduced staining was tightly linked to adverse tumor features [high classical and quantitative Gleason grade, lymph node metastasis, advanced tumor stage, high Ki67 labeling index, positive surgical margin, and early biochemical recurrence ( < 0.0001 each)]. The univariate Cox hazard ratio for prostate-specific antigen (PSA) recurrence after prostatectomy in patients with negative strong ANO7 expression was 2.98 (95% confidence interval 2.61-3.38). The prognostic impact was independent of established pre- or postoperatively available parameters ( < 0.0001). Analysis of annotated molecular data showed that low ANO7 expression was linked to G fusions ( < 0.0001), elevated androgen receptor expression ( < 0.0001), as well as presence of 9 of 11 chromosomal deletions ( < 0.05 each). A particularly strong association of low ANO7 expression with phosphatase and tensin homolog (PTEN) deletion may indicate a functional relationship with the PTEN/AKT pathway.

Conclusions: These data identify reduced ANO7 protein expression as a strong and independent predictor of poor prognosis in PCa. ANO7 measurement, either alone or in combination, might provide clinically useful prognostic information in PCa.
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http://dx.doi.org/10.20892/j.issn.2095-3941.2019.0324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877177PMC
February 2021

Diagnostic and prognostic impact of cytokeratin 18 expression in human tumors: a tissue microarray study on 11,952 tumors.

Mol Med 2021 02 15;27(1):16. Epub 2021 Feb 15.

Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.

Background: Cytokeratin 18 (CK18) is an intermediate filament protein of the cytokeratin acidic type I group and is primarily expressed in single-layered or "simple" epithelial tissues and carcinomas of different origin.

Methods: To systematically determine CK18 expression in normal and cancerous tissues, 11,952 tumor samples from 115 different tumor types and subtypes (including carcinomas, mesenchymal and biphasic tumors) as well as 608 samples of 76 different normal tissue types were analyzed by immunohistochemistry in a tissue microarray format.

Results: CK18 was expressed in normal epithelial cells of most organs but absent in normal squamous epithelium. At least an occasional weak CK18 positivity was seen in 90 of 115 (78.3%) tumor types. Wide-spread CK18 positivity was seen in 37 (31.9%) of tumor entities, including adenocarcinomas of the lung, prostate, colon and pancreas as well as ovarian cancer. Tumor categories with variable CK18 immunostaining included cancer types arising from CK18 positive precursor cells but show CK18 downregulation in a fraction of cases, tumor types arising from CK18 negative precursor cells occasionally exhibiting CK18 neo-expression, tumors derived from normal tissues with variable CK18 expression, and tumors with a mixed differentiation. CK18 downregulation was for example seen in renal cell cancers and breast cancers, whereas CK18 neo-expression was found in squamous cell carcinomas of various origins. Down-regulation of CK18 in invasive breast carcinomas of no special type and clear cell renal cell carcinomas (ccRCC) was related to adverse tumor features in both tumors (p ≤ 0.0001) and poor patient prognosis in ccRCC (p = 0.0088). Up-regulation of CK18 in squamous cell carcinomas was linked to high grade and lymph node metastasis (p < 0.05). In summary, CK18 is consistently expressed in various epithelial cancers, especially adenocarcinomas.

Conclusions: Down-regulation or loss of CK18 expression in cancers arising from CK18 positive tissues as well as CK18 neo-expression in cancers originating from CK18 negative tissues is linked to cancer progression and may reflect tumor dedifferentiation.
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http://dx.doi.org/10.1186/s10020-021-00274-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885355PMC
February 2021

Opposing prognostic relevance of junction plakoglobin in distinct prostate cancer patient subsets.

Mol Oncol 2021 Jul 17;15(7):1956-1969. Epub 2021 Feb 17.

Institute of Anatomy and Experimental Morphology, Center for Experimental Medicine, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Germany.

Both oncogenic and tumor suppressor functions have been described for junction plakoglobin (JUP), also known as γ-catenin. To clarify the role of JUP in prostate cancer, JUP protein expression was immunohistochemically detected in a tissue microarray containing 11 267 individual prostatectomy specimens. Considering all patients, high JUP expression was associated with adverse tumor stage (P = 0.0002), high Gleason grade (P < 0.0001), and lymph node metastases (P = 0.011). These associations were driven mainly by the subset without TMPRSS2:ERG fusion, in which high JUP expression was an independent predictor of poor prognosis (multivariate analyses, P = 0.0054) and early biochemical recurrence (P = 0.0003). High JUP expression was further linked to strong androgen receptor expression (P < 0.0001), high cell proliferation, and PTEN and FOXP1 deletion (P < 0.0001). In the ERG-negative subset, high JUP expression was additionally linked to MAP3K7 (P = 0.0007) and CHD1 deletion (P = 0.0021). Contrasting the overall prognostic effect of JUP, low JUP expression indicated poor prognosis in the fraction of CHD1-deleted patients (P = 0.039). In this subset, the association of high JUP and high cell proliferation was specifically absent. In conclusion, the controversial biological roles of JUP are reflected by antagonistic prognostic effects in distinct prostate cancer patient subsets.
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http://dx.doi.org/10.1002/1878-0261.12922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253102PMC
July 2021

p63 expression in human tumors and normal tissues: a tissue microarray study on 10,200 tumors.

Biomark Res 2021 Jan 25;9(1). Epub 2021 Jan 25.

Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.

Background: Tumor protein 63 (p63) is a transcription factor of the p53 gene family involved in differentiation of several tissues including squamous epithelium. p63 immunohistochemistry is broadly used for tumor classification but published data on its expression in cancer is conflicting.

Methods: To comprehensively catalogue p63 expression, tissue microarrays (TMAs) containing 12,620 tissue samples from 115 tumor entities and 76 normal tissue types were analyzed.

Results: p63 expression was seen in various normal tissues including squamous epithelium and urothelium. At least occasional weak p63 positivity could be detected in 61 (53%) of 115 different tumor types. The frequencies of p63 positivity was highest in squamous cell carcinomas irrespective of their origin (96-100%), thymic tumors (100%), urothelial carcinomas (81-100%), basal type tumors such as basal cell carcinomas (100%), and various salivary gland neoplasias (81-100%). As a rule, p63 was mostly expressed in cancers derived from p63 positive normal tissues and mostly not detectable in tumors derived from p63 negative cancers. However, exceptions from this rule occurred. A positive p63 immunostaining in cancers derived from p63 negative tissues was unrelated to aggressive phenotype in 422 pancreatic cancers, 160 endometrium cancers and 374 ovarian cancers and might be caused by aberrant squamous differentiation or represent stem cell properties. In 355 gastric cancers, aberrant p63 expression occurred in 4% and was linked to lymph node metastasis (p = 0.0208). Loss of p63 in urothelial carcinomas - derived from p63 positive urothelium - was significantly linked to advanced stage, high grade (p < 0.0001 each) and poor survival (p < 0.0001) and might reflect clinically relevant tumor dedifferentiation.

Conclusion: The high prevalence of p63 expression in specific tumor types makes p63 immunohistochemistry a suitable diagnostic tool. Loss of p63 expression might constitute a feature of aggressive cancers.
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http://dx.doi.org/10.1186/s40364-021-00260-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830855PMC
January 2021

Overexpression of the TRIM24 E3 Ubiquitin Ligase is Linked to Genetic Instability and Predicts Unfavorable Prognosis in Prostate Cancer.

Appl Immunohistochem Mol Morphol 2021 04;29(4):e29-e38

General, Visceral and Thoracic Surgery Department and Clinic.

Tripartite motif containing 24 (TRIM24) is a multifunctional protein involved in p53 degradation, chromatin binding, and transcriptional modulation of nuclear receptors. Emerging research has revealed that upregulation of TRIM24 in numerous tumor types is linked to poor prognosis, attributing an important role to TRIM24 in tumor biology. In order to better understand the role of TRIM24 in prostate cancer, we analyzed its immunohistochemical expression on a tissue microarray containing >17,000 prostate cancer specimens. TRIM24 immunostaining was detectable in 61% of 15,321 interpretable cancers, including low expression in 46% and high expression in 15% of cases. TRIM24 upregulation was associated with high Gleason grade, advanced pathologic tumor stage, lymph node metastasis, higher preoperative prostate-specific antigen level, increased cell proliferation as well as increased genomic instability, and predicted prognosis independent of clinicopathologic parameters available at the time of the initial biopsy (all P<0.0001). TRIM24 upregulation provides additional prognostic information in prostate cancer, particularly in patients with low Gleason grade tumors who may be eligible for active surveillance strategies, suggesting promising potential for TRIM24 in the routine diagnostic work-up of these patients.
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http://dx.doi.org/10.1097/PAI.0000000000000901DOI Listing
April 2021

Dysbiosis in aspirin-exacerbated respiratory disease.

Int Forum Allergy Rhinol 2021 07 12;11(7):1116-1120. Epub 2021 Jan 12.

Division of Allergy, National Jewish Hospital, Denver, CO.

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http://dx.doi.org/10.1002/alr.22762DOI Listing
July 2021

CHD1 loss negatively influences metastasis-free survival in R0-resected prostate cancer patients and promotes spontaneous metastasis in vivo.

Cancer Gene Ther 2021 Jan 7. Epub 2021 Jan 7.

Institute of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.

The outcome of prostate cancer (PCa) patients is highly variable and depends on whether or not distant metastases occur. Multiple chromosomal deletions have been linked to early tumor marker PSA recurrence (biochemical relapse, BCR) after radical prostatectomy (RP), but their potential role for distant metastasis formation is largely unknown. Here, we specifically analyzed whether deletion of the tumor suppressor CHD1 (5q21) influences the post-surgical risk of distant metastasis and whether CHD1 loss directly contributes to metastasis formation in vivo. By considering >6800 patients we found that the CHD1 deletion negatively influences metastasis-free survival in R0 patients (HR: 2.32; 95% CI: 1.61, 3.33; p < 0.001) independent of preoperative PSA, pT stage, pN status, Gleason Score, and BCR. Moreover, CHD1 deletion predicts shortened BCR-free survival in pT2 patients and cancer-specific survival in all patients. In vivo, CHD1 loss increases spontaneous pulmonary metastasis formation in two distinct PCa models coupled with a higher number of multicellular colonies as compared to single-cell metastases. Transcriptome analyses revealed down-regulation of the PCa-specific metastasis suppressor and TGFβ signaling regulator PMEPA1 after CHD1 depletion in both tested PCa models. CHD1 loss increases the risk of postoperative metastasis in R0-resected PCa patients and promotes spontaneous metastasis formation in vivo.
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http://dx.doi.org/10.1038/s41417-020-00288-zDOI Listing
January 2021

Elevated MUC5AC expression is associated with mismatch repair deficiency and proximal tumor location but not with cancer progression in colon cancer.

Med Mol Morphol 2021 Jun 29;54(2):156-165. Epub 2020 Dec 29.

Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.

Mucin 5AC (MUC5AC) is a secreted gel-forming mucin expressed by several epithelia. In the colon, MUC5AC is expressed in scattered normal epithelial cells but can be abundant in colorectal cancers. To clarify the relationship of MUC5AC expression with parameters of tumor aggressiveness and mismatch repair deficiency (dMMR) in colorectal cancer, a tissue microarray containing 1812 colorectal cancers was analyzed by immunohistochemistry. MUC5AC expression was found in 261 (15.7%) of 1,667 analyzable colorectal cancers. MUC5AC expression strongly depended on the tumor location and gradually decreased from proximal (27.4% of cecum cancers) to distal (10.6% of rectal cancers; p < 0.0001). MUC5AC expression was also strongly linked to dMMR. dMMR was found in 21.3% of 169 cancers with MUC5AC positivity but in only 4.6% of 1051 cancers without detectable MUC5AC expression (p < 0.0001). A multivariate analysis showed that dMMR status and tumor localization predicted MUC5AC expression independently (p < 0.0001 each). MUC5AC expression was unrelated to pT and pN status. This also applied to the subgroups of 1136 proficient MMR (pMMR) and of 84 dMMR cancers. The results of our study show a strong association of MUC5AC expression with proximal and dMMR colorectal cancers. However, MUC5AC expression is unrelated to colon cancer aggressiveness.
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http://dx.doi.org/10.1007/s00795-020-00274-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139930PMC
June 2021

Epithelial splicing regulatory protein 1 and 2 (ESRP1 and ESRP2) upregulation predicts poor prognosis in prostate cancer.

BMC Cancer 2020 Dec 18;20(1):1220. Epub 2020 Dec 18.

Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.

Background: Epithelial splicing regulatory protein 1 (ESRP1) and 2 (ESRP2) regulate alternative splicing events of various pre-mRNAs. Some of these targets play a role in cancer-associated processes, including cytoskeleton reorganization and DNA-repair processes. This study was undertaken to estimate the impact of ESRP1 and ESRP2 alterations on prostate cancer patient prognosis.

Methods: A tissue microarray made from 17,747 individual cancer samples with comprehensive, pathological, clinical and molecular data was analyzed by immunohistochemistry for ESRP1 and ESRP2.

Results: Nuclear staining for ESRP1 was seen in 38.6% (36.0% low, 2.6% high) of 12,140 interpretable cancers and in 41.9% (36.4% low, 5.3% high) of 12,962 interpretable cancers for ESRP2. Nuclear protein expression was linked to advanced tumor stage, high Gleason score, presence of lymph node metastasis, early biochemical recurrence, and ERG-positive cancers (p < 0.0001 each). Expression of ESRPs was significantly linked to 11 (ESRP1)/9 (ESRP2) of 11 analyzed deletions in all cancers and to 8 (ESRP1)/9 (ESRP2) of 11 deletions in ERG-negative cancers portending a link to genomic instability. Combined ESRPs expression analysis suggested an additive effect and showed the worst prognosis for cancers with high ESRP1 and ESRP2 expression. Multivariate analyses revealed that the prognostic impact of ESRP1, ESRP2 and combined ESRP1/ESRP2 expression was independent of all established pre- and postoperative prognostic features.

Conclusions: Our data show a striking link between nuclear ESRP expression and adverse features in prostate cancer and identifies expression of ESRP1 and/or ESRP2 as independent prognostic markers with a potential for routine application.
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http://dx.doi.org/10.1186/s12885-020-07682-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749503PMC
December 2020

Aspirin-exacerbated respiratory disease: Update on medical management.

World J Otorhinolaryngol Head Neck Surg 2020 Dec 15;6(4):241-247. Epub 2020 Oct 15.

Scripps Clinic, Division of Allergy, Asthma and Immunology, Scripps Green Hospital, San Diego, CA, USA.

Aspirin-exacerbated respiratory disease (AERD) is frequently diagnosed in patients with severe type 2 airway inflammation presenting with nasal polyps and severe asthma. It has been associated with a recalcitrant course with high medical and surgical requirements. The advent of recent biological and other targeted treatments show promise in the medical management of patient with AERD. The goal of complete disease control where patients no longer require recurrent surgical procedures, systemic corticosteroid exposure and may live with a stable and relatively normal quality of life is now within reach. Further work is necessary to identify biomarkers predictive of treatment response.
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http://dx.doi.org/10.1016/j.wjorl.2020.07.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729248PMC
December 2020

Increased Cytoplasmic CD138 Expression Is Associated with Aggressive Characteristics in Prostate Cancer and Is an Independent Predictor for Biochemical Recurrence.

Biomed Res Int 2020 28;2020:5845374. Epub 2020 Oct 28.

General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.

Syndecan-1 (CD138) is a transmembrane proteoglycan expressed in various normal and malignant tissues. It is of interest due to a possible prognostic effect in tumors and its role as a target for the antibody-drug conjugate indatuximab ravtansine. Here, we analyzed 17,747 prostate cancers by immunohistochemistry. Membranous and cytoplasmic CD138 staining was separately recorded. In normal prostate glands, CD138 staining was limited to basal cells. In cancers, membranous CD138 positivity was seen in 19.6% and cytoplasmic CD138 staining in 11.2% of 12,851 interpretable cases. A comparison with clinico-pathological features showed that cytoplasmic CD138 staining was more linked to unfavorable tumor features than membranous staining. Cytoplasmic CD138 immunostaining was associated with high tumor stage ( < 0.0001), high Gleason grade ( < 0.0001), nodal metastases ( < 0.0001), positive surgical margin ( < 0.0001), and biochemical recurrence ( < 0.0001). This also holds true for both V-ets avian erythroblastosis virus E26 oncogene homolog (ERG) fusion positive and ERG fusion negative tumors although the cytoplasmic CD138 expression was markedly more frequent in ERG positive than in ERG negative tumors ( < 0.0001). Comparison with 11 previously analyzed chromosomal deletions identified a conspicuous association between cytoplasmic CD138 expression and 8p deletions ( < 0.0001) suggesting a possible functional interaction of CD138 with one or several 8p genes. Multivariate analysis revealed the cytoplasmic CD138 expression as an independent prognostic parameter in all cancers and in the ERG positive subgroup. In summary, our study indicates the cytoplasmic CD138 expression as a strong and independent predictor of poor prognosis in prostate cancer. Immunohistochemical measurement of CD138 protein may thus-perhaps in combination with other parameters-become clinically useful in the future.
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http://dx.doi.org/10.1155/2020/5845374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641694PMC
May 2021
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