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Suster DI, Mejbel H, Mackinnon AC, Suster S. Desmoplastic Adamantinoma-like Thymic Carcinoma: Clinicopathologic, Immunohistochemical, and Molecular Study of 5 Cases. Am J Surg Pathol 2022; 46:1722-1731. [PMID: 35993584 DOI: 10.1097/pas.0000000000001947] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Five cases of a heretofore unreported rare variant of thymic carcinoma characterized by a striking resemblance to adamantinoma of the mandible are described. The tumors occurred in 4 women and 1 man aged 58 to 76 years (mean: 67.8 y); they arose in the anterior mediastinum and measured from 5.3 to 12.0 cm in greatest diameter (mean: 8.9 cm). Presenting symptoms included chest pain, shortness of breath, and in 2 patients, pleural effusion. One tumor was asymptomatic and discovered incidentally. Histologically, the tumors were extensively desmoplastic, and the cellular proliferation was characterized by multiple islands of squamous epithelium with striking peripheral palisading of nuclei and central areas containing clear cells resembling a stellate reticulum. Areas of preexisting spindle cell thymoma were identified in 2 cases; these areas gradually merged with the higher-grade component of the lesion. Cystic changes were noted in 3 cases. Immunohistochemical studies in 3 cases showed the tumor cells were positive for cytokeratins, p40 and p63, and all showed a high proliferation rate (>50% nuclear positivity) with Ki-67. Next-generation sequencing was performed in 2 cases that showed amplification of the AKT1 gene (copy numbers 6 and 13). Clinical follow-up in 3 patients showed recurrence and metastasis after 1 and 2 years; 1 patient passed away 2 years after diagnosis due to the tumor. Desmoplastic adamantinoma-like thymic carcinoma represents an unusual histologic variant of thymic carcinoma that needs to be distinguished from metastases from similar tumors to the mediastinum.
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Affiliation(s)
- David I Suster
- Department of Pathology, Rutgers University New Jersey Medical School, Newark, NJ
| | - Haider Mejbel
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL
| | | | - Saul Suster
- Department of Pathology, Medical College of Wisconsin, Milwaukee, WI
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Menz A, Bauer R, Kluth M, Marie von Bargen C, Gorbokon N, Viehweger F, Lennartz M, Völkl C, Fraune C, Uhlig R, Hube-Magg C, De Wispelaere N, Minner S, Sauter G, Kind S, Simon R, Burandt E, Clauditz T, Lebok P, Jacobsen F, Steurer S, Wilczak W, Krech T, Marx AH, Bernreuther C. Diagnostic and prognostic impact of cytokeratin 19 expression analysis in human tumors: a tissue microarray study of 13,172 tumors. Hum Pathol 2021; 115:19-36. [PMID: 34102222 DOI: 10.1016/j.humpath.2021.05.012] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 05/27/2021] [Indexed: 12/13/2022]
Abstract
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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Affiliation(s)
- Anne Menz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Rifka Bauer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Martina Kluth
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Clara Marie von Bargen
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Natalia Gorbokon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Florian Viehweger
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Maximilian Lennartz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Cosima Völkl
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Christoph Fraune
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Ria Uhlig
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Claudia Hube-Magg
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Noémi De Wispelaere
- Department and Clinic of Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Sarah Minner
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Guido Sauter
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Simon Kind
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Ronald Simon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
| | - Eike Burandt
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Till Clauditz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Patrick Lebok
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Frank Jacobsen
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Stefan Steurer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Waldemar Wilczak
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Till Krech
- Institute of Pathology, Clinical Center Osnabrueck, 49076 Osnabrueck, Germany
| | - Andreas H Marx
- Department of Pathology, Academic Hospital Fuerth, 90766 Fuerth Germany
| | - Christian Bernreuther
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
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Sharma A, Sharma KL, Gupta A, Yadav A, Kumar A. Gallbladder cancer epidemiology, pathogenesis and molecular genetics: Recent update. World J Gastroenterol 2017; 23:3978-3998. [PMID: 28652652 PMCID: PMC5473118 DOI: 10.3748/wjg.v23.i22.3978] [Citation(s) in RCA: 250] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2016] [Revised: 02/01/2017] [Accepted: 06/01/2017] [Indexed: 02/06/2023] Open
Abstract
Gallbladder cancer is a malignancy of biliary tract which is infrequent in developed countries but common in some specific geographical regions of developing countries. Late diagnosis and deprived prognosis are major problems for treatment of gallbladder carcinoma. The dramatic associations of this orphan cancer with various genetic and environmental factors are responsible for its poorly defined pathogenesis. An understanding to the relationship between epidemiology, molecular genetics and pathogenesis of gallbladder cancer can add new insights to its undetermined pathophysiology. Present review article provides a recent update regarding epidemiology, pathogenesis, and molecular genetics of gallbladder cancer. We systematically reviewed published literature on gallbladder cancer from online search engine PubMed (http://www.ncbi.nlm.nih.gov/pubmed). Various keywords used for retrieval of articles were Gallbladder, cancer Epidemiology, molecular genetics and bullion operators like AND, OR, NOT. Cross references were manually searched from various online search engines (http://www.ncbi.nlm.nih.gov/pubmed,https://scholar.google.co.in/, http://www.medline.com/home.jsp). Most of the articles published from 1982 to 2015 in peer reviewed journals have been included in this review.
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Batmunkh E, Shimada M, Morine Y, Imura S, Kanemura H, Arakawa Y, Hanaoka J, Kanamoto M, Sugimoto K, Nishi M. Expression of hypoxia-inducible factor-1 alpha (HIF-1alpha) in patients with the gallbladder carcinoma. Int J Clin Oncol 2010; 15:59-64. [PMID: 20082206 DOI: 10.1007/s10147-009-0011-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2009] [Accepted: 08/19/2009] [Indexed: 01/05/2023]
Abstract
BACKGROUND Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that plays a central role in biologic processes under hypoxic conditions, especially concerning tumor angiogenesis. Vascular endothelial growth factor (VEGF) is a potent proangiogenic agent and a multifunctional angiogenic cytokine in many malignant tumors. METHODS This study was conducted to clarify the role of HIF-1 expression in gallbladder carcinoma. Thirty-one patients with gallbladder carcinoma underwent surgical treatment between 1994 and 2003 at the Department of Surgery, University of Tokushima, Japan. Both HIF-1alpha and VEGF were evaluated by immunohistochemistry, and correlations between the expression of these factors and clinicopathological features including prognosis were analyzed. RESULTS Among 31 specimens from patients with gallbladder carcinoma, 22 (70%) and 9 (30%) were positive for HIF-1alpha and VEGF expression, respectively. Expression of HIF-1alpha was significantly correlated with stage, tumor curability, lymph node metastasis, venous invasion, hepatic infiltration, and lymphatic invasion (P < 0.05). The survival rate for patients with HIF-1alpha positive staining was significantly lower than that for patients with HIF-1alpha negative staining. However, VEGF overexpression did not correlate with clinical outcomes. We demonstrated that HIF-1alpha expression was associated with a malignant behavior risk category in gallbladder cancer. CONCLUSION Expression of HIF-1alpha was correlated with the poor prognostic indicators, such as lymph node metastasis and venous invasion. Therefore, HIF-1alpha could serve as an auxiliary parameter for predicting malignant behavior for gallbladder carcinomas.
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Affiliation(s)
- Erdenebulgan Batmunkh
- Department of Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Kuramoto-cho, Tokushima, Japan
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Artico M, Bronzetti E, Alicino V, Ionta B, Bosco S, Grande C, Bruno M, Tranquilli Leali FM, Ionta G, Fumagalli L. Human gallbladder carcinoma: Role of neurotrophins, MIB-1, CD34 and CA15-3. Eur J Histochem 2010; 54:e10. [PMID: 20353905 PMCID: PMC3167291 DOI: 10.4081/ejh.2010.e10] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2010] [Accepted: 01/28/2010] [Indexed: 12/19/2022] Open
Abstract
Gallbladder carcinoma is the most common biliary tract tumor and the fifth most common gastrointestinal tract cancer. The prognosis of gallbladder carcinoma is poor and less than 5% of the patients are still alive five years postoperatively. Gallbladder specimens were obtained during surgical operations performed in eleven patients for resection of a gallbladder carcinoma, and during five autopsies (control cases selected among patients who died from for other causes, excluding those suffering from biliary or hepatic diseases). Immunohistochemical characterization and distribution of neurotrophins, with their respective receptors, were analyzed. The actual role played by these neurotrophic factors in the general regulation, vascular permeability, algic responsiveness, release of locally active substances and potential tumorigenesis in the gallbladder and biliary ducts compartment remains controversial. Our study revealed an increased immunohistochemical expression of NGF and TrKA in the epithelium and in the epithelial glands of the gallbladder carcinoma together with an evident immunoreactivity for BDNF in the same neoplastic areas. An evident immunoreactivity for NGF, TrKA and BDNF was observed in control specimens of gallbladder obtained during autopsies, whereas a weak or quite absent immunoreactivity was observed in the same specimens for NT4, TrKC and p75. On the contrary an appreciable immunoreactivity for p75 was observed in the specimens harvested from patients with gallbladder carcinoma. We also investigated the expression of some known tumor markers such as MIB-1 (anti Ki-67), CD34 and CA15-3, to identify a possible correlation between the expression of these molecular factors and the prognosis of gallbladder carcinoma. They resulted highly expressed in the stroma (CD34 and CA 15-3) and in the epithelium/epithelial glands (MIB-1) of the neoplastic areas and appeared to be almost absent in the control cases, suggesting that these markers, taken together, could be adopted as a panel of prognostic factors in the evaluation of the gallbladder carcinoma.
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Affiliation(s)
- M Artico
- Department of Otorhinolaringology, Audiology and Phoniatry G. Ferreri, University of Rome La Sapienza, Rome, Italy.
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Svoboda M, Sellner F, Ekmekcioglu C, Klimpfinger M, Jaeger W, Thalhammer T. Expression of estrogen-metabolizing enzymes and estrogen receptors in cholelithiasis gallbladder. Biomed Pharmacother 2008; 62:690-6. [PMID: 18440760 DOI: 10.1016/j.biopha.2008.03.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2008] [Accepted: 03/13/2008] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND Estrogen exposure is a risk factor for gallstone disease (cholelithiasis), which often leads to chronic inflammation (cholecystitis). Studies in various estrogen-sensitive tissues showed that key enzymes involved in the inactivation and activation of estrogens as well as expression of estrogen receptors alpha and beta determine the amount of active estrogen. In estrogen-sensitive tissues, e.g. the female breast, estrone sulfate (E1S), present at high concentrations in the circulation, is converted into the biologically active estrone (E1) by steroid sulfatase (STS) and again reverted into E1S by estrogen sulfotransferase (SULT1E1) providing a local estrogen storage. AIMS To assess whether this might also apply for gallbladder epithelia, we determined expression of these two enzymes and of ERalpha and ERbeta in 15 cholelithiasis specimens from tissues with/or without inflammation. METHODS Quantitative (Real-time) PCR and immunofluorescence were used as methods. RESULTS We demonstrate mRNA expression of SULT1E1, STS, and ERalpha in all specimens with mean enrichment of 3.53- vs. 1.72-fold (n.s.), 3.5- vs. 0.91-fold (n.s.), and 3.04- vs. 1.6-fold (n.s.) in the inflammatory and non-inflammatory groups, respectively. Although high expression levels were seen in many specimens (means 4.88-fold vs. 5.77-fold), ERbeta mRNA was below the detection limit in two specimens from cholecystitis patients. To further investigate this varying expression pattern of ERbeta, immunohistological studies were performed, which indeed showed low expression levels of ERbeta in the damaged mucosa, while in specimens with well preserved mucosa, high ERbeta levels were seen in the cytosol and in the nucleus. CONCLUSION The data show expression of an estrogen network of activating STS and inactivating SULT1E1. Together with ERalpha and ERbeta, these enzymes could regulate estrogen concentrations in human gallbladder.
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Affiliation(s)
- Martin Svoboda
- Institute of Pathophysiology, Center for Physiology, Pathophysiology and Immunology, Medical University of Vienna, A-1090 Vienna, Austria
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