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Soltani H, Ahmadinejad M, Shafiee A, Afshar Rezaee F, Beik Mohamadi M, Bahrambeigi A, Hajialigol AH, Fattan S, Zebarjadi Bagherpour J. Expression rate and comparison of immunohistochemistry biomarkers in appendiceal neuroendocrine and other epithelial cell neoplasms: Systematic review and meta-analysis. Rare Tumors 2025; 17:20363613251330179. [PMID: 40182058 PMCID: PMC11967222 DOI: 10.1177/20363613251330179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 02/13/2025] [Accepted: 03/10/2025] [Indexed: 04/05/2025] Open
Abstract
Background: Immunohistochemistry (IHC) provides comprehensive information for morphology and pathologic characteristics and is a valuable tool for establishing the correct cancer diagnosis in clinical diagnostic pathology and determining prognosis. Objectives: The current study analyzes and compares the expression of Immunohistochemistry biomarkers on neuroendocrine and epithelial cell types of appendiceal neoplasms. Design: This systematic review adhered to the recommendations in the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. We performed a meta-analysis employing a random effects model with proportions to gauge the proportion of positive cases. Method: A comprehensive systematic search in PubMed, Web of Science, and Scopus databases was conducted based on the PRISMA statement up to August 2023. Studies reporting the immunohistochemistry biomarkers expression performed in patients with primary appendiceal neuroendocrine and epithelial cell neoplasms according to the most recent World Health Organization classification of malignant tumors were included. Results: Our systematic search included 56 observational articles that meet the eligibility criteria. Meta-analysis revealed an expression rate of 93%, 91%, 87%, 71%, 94%, 99%, 32%, 76%, 25%, and 91% for non-specific enolase (NSE), chromaffin A, synaptophysin, Serotonin, SATB2, Caudal-type homeobox 2 (CDX2), β-catenin, Carcinoembryonic antigen (CEA), Cytokeratin 7, and Cytokeratin 20, respectively. CDX2 and SATB2 were the most expressed markers. The expression rate had a significant association with tumor type. NSE and synaptophysin were the highest in neuroendocrine tumors, whereas CEA was more elevated in gablet cell carcinoids. Cytokeratin 20 is suitable for identifying epithelial cell neoplasms. Conclusion: The study indicates the proportion of positive cases in patients with primary neuroendocrine and epithelial cell appendiceal neoplasms.
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Affiliation(s)
- Hedieh Soltani
- School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
| | - Mojtaba Ahmadinejad
- Department of General Surgery, Alborz University of Medical Sciences, Karaj, Iran
| | - Arman Shafiee
- School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
| | | | | | | | | | - Saeedeh Fattan
- School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
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Ladenheim A, Zheng JX, Teklu A, Matsukuma K. PCSK2 can be Useful in a Panel Approach to Distinguish Foregut and Midgut Neuroendocrine Tumors. Int J Surg Pathol 2025; 33:76-84. [PMID: 39034588 DOI: 10.1177/10668969241260208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/23/2024]
Abstract
INTRODUCTION A number of immunohistochemical stains have been examined for utility in establishing the site of origin for metastatic well-differentiated neuroendocrine tumors (NETs). In the gastrointestinal (GI) tract, distinguishing metastatic duodenal NETs from jejunoileal and other GI NETs is important for clinical work-up, prognosis, and therapy. A recent study indicated that prohormone convertase 2 (PCSK2 or PC2) had broad expression in small intestine and appendiceal NETs. Because the study did not include duodenal NETs, we examined PCSK2 expression in duodenal and other GI NETs. METHODS GI NETs (n = 69) and 13 corresponding lymph node metastases from stomach, duodenum, pancreas, ileum, appendix, and rectum were evaluated for the expression of PCSK2, along with ISL1, NKX2.2, CDX2, SATB2, and PAX8. Expression of each stain was evaluated using the H-score system, and differences in expression by site were evaluated by the chi square test. RESULTS PCSK2 was expressed at similar frequency in duodenal (50%), pancreatic (59%), and ileal NETs (40%). PCSK2 was infrequently expressed in stomach (0%), appendiceal (8%), and rectal (25%) NETs. However, incorporating PCSK2 into a panel including ISL1, NKX2.2, CDX2, and SATB2 allowed development of an algorithm which had 87% sensitivity and 93% specificity for classification of ileal NETs; and 68% sensitivity and 98% specificity for pancreaticoduodenal NETs. CONCLUSIONS In contrast to previous findings, PCSK2 does not show specificity for any particular GI site. An algorithmic approach incorporating the expression of PCSK2 with that of ISL1, NKX2.2, CDX2, and SATB2 is useful in discriminating pancreatic, duodenal, ileal, appendiceal, and rectal NETs.
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Affiliation(s)
- Alexander Ladenheim
- Department of Pathology and Laboratory Medicine, University of California, Davis School of Medicine, Sacramento, CA, USA
| | - Jasper X Zheng
- Department of Pathology and Laboratory Medicine, University of California, Davis School of Medicine, Sacramento, CA, USA
| | - Abebe Teklu
- Department of Pathology and Laboratory Medicine, University of California, Davis School of Medicine, Sacramento, CA, USA
| | - Karen Matsukuma
- Department of Pathology and Laboratory Medicine, University of California, Davis School of Medicine, Sacramento, CA, USA
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Lin X, Antic T, Hou T, Nezami BG. Cytopathology and clinicopathological correlation of renal neuroendocrine neoplasms. J Am Soc Cytopathol 2024; 13:406-412. [PMID: 38981825 DOI: 10.1016/j.jasc.2024.06.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 05/23/2024] [Accepted: 06/05/2024] [Indexed: 07/11/2024]
Abstract
INTRODUCTION There is a lack of documentation regarding cytopathology of renal neuroendocrine neoplasms (NENs) due to their rarity. MATERIALS AND METHODS Five cytology cases were gathered from 3 institutes. RESULTS Cohort consisted of 4 females and 1 male. Fine needle aspiration biopsy and touch preparation slides of core needle biopsy revealed cellular samples, composed of round, plasmacytoid, or columnar cells. Tumor cells were present in nested, acinar, 3D cluster, and individual cell patterns. Tumor cells in 3 cases exhibited uniformly round to oval small nuclei with inconspicuous nucleoli, finely granular chromatin, and smooth nuclear membranes, whereas 2 other cases showed pleomorphic nuclei with conspicuous nucleoli, nuclear molding, and irregular nuclear membranes. Tumor cells displayed pale or granular cytoplasm, with 1 case showing small vacuoles. Examination of cores and cell blocks demonstrated tumor cells in sheets, nests, or acini. All tumor cells were positive for neuroendocrine immunomarkers. Based on mitotic count, Ki-67 index and morphology, 3 tumors were graded as well-differentiated neuroendocrine tumor (WDNET) (1 grade [G] 3, 1 G2, 1 G1) and 2 as large cell neuroendocrine carcinoma. Deletion of 7q, 10q, and 19q was detected in WDNETs. Two patients with large cell neuroendocrine carcinoma and 1 with WDNET G3 underwent chemotherapy due to aggressiveness, whereas nephrectomy was performed for patients with WDNET G1 and 2 without metastasis. CONCLUSIONS Cytopathological characteristics of renal NENs closely resemble those affecting other organs. Despite its rarity, renal NENs should be kept in mind when confronted with morphological resemblances to NENs, to prevent misdiagnosis and inappropriate therapeutic interventions.
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Affiliation(s)
- Xiaoqi Lin
- Department of Pathology, Northwestern University, Chicago, Illinois.
| | - Tatjana Antic
- Department of Pathology, University of Chicago, Chicago, Illinois
| | - Tieying Hou
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Behtash G Nezami
- Department of Pathology, Northwestern University, Chicago, Illinois
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Grass A, Kasajima A, Foersch S, Kriegsmann M, Brobeil A, Schmitt M, Wagner D, Poppinga J, Wiese D, Maurer E, Kirschbaum A, Muley T, Winter H, Rinke A, Gress TM, Kremer M, Evert M, Märkl B, Quaas A, Eckstein M, Tschurtschenthaler M, Klöppel G, Denkert C, Bartsch DK, Jesinghaus M. PITX2 as a Sensitive and Specific Marker of Midgut Neuroendocrine Tumors: Results from a Cohort of 1157 Primary Neuroendocrine Neoplasms. Mod Pathol 2024; 37:100442. [PMID: 38309431 DOI: 10.1016/j.modpat.2024.100442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Revised: 01/12/2024] [Accepted: 01/25/2024] [Indexed: 02/05/2024]
Abstract
As neuroendocrine tumors (NETs) often present as metastatic lesions, immunohistochemical assignment to a site of origin is one of the most important tasks in their pathologic assessment. Because a fraction of NETs eludes the typical expression profiles of their primary localization, additional sensitive and specific markers are required to improve diagnostic certainty. We investigated the expression of the transcription factor Pituitary Homeobox 2 (PITX2) in a large-scale cohort of 909 NET and 248 neuroendocrine carcinomas (NEC) according to the immunoreactive score (IRS) and correlated PITX2 expression groups with general tumor groups and primary localization. PITX2 expression (all expression groups) was highly sensitive (98.1%) for midgut-derived NET, but not perfectly specific, as non-midgut NET (especially pulmonary/duodenal) were quite frequently weak or moderately positive. The specificity rose to 99.5% for a midgut origin of NET if only a strong PITX2 expression was considered, which was found in only 0.5% (one pancreatic/one pulmonary) of non-midgut NET. In metastases of midgut-derived NET, PITX2 was expressed in all cases (87.5% strong, 12.5% moderate), whereas CDX2 was negative or only weakly expressed in 31.3% of the metastases. In NEC, a fraction of cases (14%) showed a weak or moderate PITX2 expression, which was not associated with a specific tumor localization. Our study independently validates PITX2 as a very sensitive and specific immunohistochemical marker of midgut-derived NET in a very large collective of neuroendocrine neoplasms. Therefore, our data argue toward implementation into diagnostic panels applied for NET as a firstline midgut marker.
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Affiliation(s)
- Albert Grass
- Department of Pathology, Phillips University Marburg und University Hospital Marburg, Marburg, Germany
| | - Atsuko Kasajima
- Department of Pathology, Technical University of Munich, Munich, Germany
| | | | - Mark Kriegsmann
- Department of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Alexander Brobeil
- Department of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Maxime Schmitt
- Department of Pathology, Phillips University Marburg und University Hospital Marburg, Marburg, Germany
| | - Daniel Wagner
- Department of Pathology, University Hospital Mainz, Mainz, Germany
| | - Jelte Poppinga
- Department of Surgery, Phillips University Marburg and University Hospital Marburg, Marburg, Germany
| | - Dominik Wiese
- Department of Surgery, Phillips University Marburg and University Hospital Marburg, Marburg, Germany
| | - Elisabeth Maurer
- Department of Surgery, Phillips University Marburg and University Hospital Marburg, Marburg, Germany
| | - Andreas Kirschbaum
- Department of Surgery, Phillips University Marburg and University Hospital Marburg, Marburg, Germany
| | - Thomas Muley
- Translational Lung Research Center Heidelberg (TLRC-H), Heidelberg, Germany; Translational Research Unit, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany
| | - Hauke Winter
- Translational Lung Research Center Heidelberg (TLRC-H), Heidelberg, Germany; Translational Research Unit, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany; Department of Thoracic Surgery, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany
| | - Anja Rinke
- Department of Gastroenterology, Endocrinology and Infectious Diseases, Phillips University Marburg and University Hospital Marburg, Marburg, Germany
| | - Thomas M Gress
- Department of Gastroenterology, Endocrinology and Infectious Diseases, Phillips University Marburg and University Hospital Marburg, Marburg, Germany
| | - Markus Kremer
- Institute of Pathology, Städtisches Klinikum München, Munich, Germany
| | - Matthias Evert
- Department of Pathology, University Hospital Regensburg, Regensburg, Germany
| | - Bruno Märkl
- Institute of Pathology, University Hospital Augsburg, Augsburg, Germany
| | - Alexander Quaas
- Institute of Pathology, University Hospital Cologne, Cologne, Germany
| | - Markus Eckstein
- Department of Pathology, University Hospital Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Markus Tschurtschenthaler
- Institute for Translational Cancer Research, German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
| | - Günter Klöppel
- Department of Pathology, Technical University of Munich, Munich, Germany
| | - Carsten Denkert
- Department of Pathology, Phillips University Marburg und University Hospital Marburg, Marburg, Germany
| | - Detlef K Bartsch
- Department of Surgery, Phillips University Marburg and University Hospital Marburg, Marburg, Germany
| | - Moritz Jesinghaus
- Department of Pathology, Phillips University Marburg und University Hospital Marburg, Marburg, Germany.
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Soukup J, Manethova M, Stejskal V, Hornychova H, Cesak T, Netuka D, Ryska A, Gabalec F. Immunoreactivity of HOXB13 in Neuroendocrine Neoplasms Is a Sensitive and Specific Marker of Rectal Well-Differentiated Neuroendocrine Tumors. Endocr Pathol 2023; 34:333-341. [PMID: 37552455 DOI: 10.1007/s12022-023-09779-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/25/2023] [Indexed: 08/09/2023]
Abstract
HoxB13 is a transcription factor involved in defining of posterior endodermal derivatives, including prostate and rectum. While it is used as a marker of prostatic adenocarcinoma, it has not been studied systematically in neuroendocrine neoplasms. Thus, we performed HoxB13 immunohistochemistry in tissue microarrays and the whole sections of 232 neuroendocrine neoplasms. These included 34 paragangliomas (PGs), 20 cauda equina neuroendocrine tumors (CENETs), 123 well-differentiated neuroendocrine tumors (WDNETs), and 55 neuroendocrine carcinomas (NECs). WDNETs were additionally analyzed with SATB2, and colorectal WDNETs with CDX2 and serotonin immunohistochemistry. In total, HoxB13 immunoreactivity was observed in 95% (19/20) CENETs, 10.6% (13/123) WDNETs, and 12.9% (7/54) NECs. No PGs were positive. Large intestine WDNETs expressed HoxB13 in 68.4% (13/19); five negative tumors originated in cecum and one in rectum. In rectum, 92.9% (13/14) WDNETs expressed HoxB13. HoxB13 was 92.9% sensitive and 100% specific, showing 100% positive predictive value for the rectal origin of WDNET. In NECs, HoxB13 was positive in 15.4% (2/13) GIT tumors and 80% (4/5) prostatic NECs, but in none of urinary bladder NECs (0/8). SATB2 was positive in 17.1% (21/123) WDNETs, including 78.9% (15/19) of colorectal WDNETs, 71.4% (5/7) appendiceal WDNETs, and 2.9% (1/34) small intestine WDNETs. All 4 SATB2-negative large bowel tumors originated in the cecum. When both markers combined, HoxB13+/SATB2+ immunoprofile was seen exclusively in rectal WDNETs (positive predictive value 100%), while HoxB13-/SATB2+ immunoprofile was highly suggestive of the appendiceal origin (positive predictive value 71.4%). Therefore, HoxB13 can be useful as an immunohistochemical marker of rectal WDNETs and prostatic NECs.
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Affiliation(s)
- Jiri Soukup
- Department of Pathology, Military University Hospital Prague, Prague, Czech Republic.
- The Fingerland Department of Pathology, Charles University, Faculty of Medicine in Hradec Králové and University Hospital Hradec Králové, Sokolska 581, Prague, 500 05, Czech Republic.
| | - Monika Manethova
- The Fingerland Department of Pathology, Charles University, Faculty of Medicine in Hradec Králové and University Hospital Hradec Králové, Sokolska 581, Prague, 500 05, Czech Republic
| | - Vaclav Stejskal
- The Fingerland Department of Pathology, Charles University, Faculty of Medicine in Hradec Králové and University Hospital Hradec Králové, Sokolska 581, Prague, 500 05, Czech Republic
| | - Helena Hornychova
- The Fingerland Department of Pathology, Charles University, Faculty of Medicine in Hradec Králové and University Hospital Hradec Králové, Sokolska 581, Prague, 500 05, Czech Republic
| | - Tomas Cesak
- Department of Neurosurgery, Charles University, Faculty of Medicine in Hradec Králové and University Hospital Hradec Králové, Prague, Czech Republic
| | - David Netuka
- Department of Neurosurgery and Neurooncology, 1st Medical Faculty, Military University Hospital Prague, Charles University, Prague, Czech Republic
| | - Ales Ryska
- The Fingerland Department of Pathology, Charles University, Faculty of Medicine in Hradec Králové and University Hospital Hradec Králové, Sokolska 581, Prague, 500 05, Czech Republic
| | - Filip Gabalec
- 4th Department of Internal Medicine, Charles University, Faculty of Medicine in Hradec Králové and University Hospital Hradec Králové, Prague, Czech Republic
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Rossi RE, Corti F, Pusceddu S, Milione M, Coppa J, Masoni B, Oldani S, Sabella G, Cafaro P, Repici A. Multidisciplinary Approach to the Diagnosis of Occult Primary Neuroendocrine Neoplasm: A Clinical Challenge. J Clin Med 2023; 12:5537. [PMID: 37685605 PMCID: PMC10488469 DOI: 10.3390/jcm12175537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 07/31/2023] [Accepted: 08/23/2023] [Indexed: 09/10/2023] Open
Abstract
Approximately 11% to 14% of subjects with neuroendocrine neoplasms (NENs) have metastatic lesions with unknown primary origin (UPO), with the majority of UPO-NENs found in the small bowel. Herein, we assessed the available literature on UPO-NENs, focusing on clinical presentation and diagnostic techniques to identify the primary site. The identification of the primary tumor is important as it affects the prognosis; however, the clinical presentation can be non-specific in non-functioning forms. In the presence of metastatic disease, the histological sample is fundamental to obtain immunohistochemical markers that might orientate the clinician in the search for the primary tumor through radiology, functional imaging and endoscopic techniques. In summary, multidisciplinary management plays a key role in UPO-NENs, even more than in other NENs. Molecular biology and gene-expression profiling represent areas of great interest which might be developed in the near future for both the diagnosis and the treatment of these neoplasms.
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Affiliation(s)
- Roberta Elisa Rossi
- Gastroenterology and Endoscopy Unit, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy; (B.M.); (A.R.)
| | - Francesca Corti
- Medical Oncology Unit, Fondazione IRCCS San Gerardo dei Tintori Monza, Via G.B. Pergolesi, 20900 Monza, Italy; (F.C.); (P.C.)
| | - Sara Pusceddu
- Gastro-Entero-Pancreatic and Neuroendocrine Tumor Unit 1, Department of Medical Oncology, ENETS Center of Excellence, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy; (S.P.); (S.O.)
| | - Massimo Milione
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS–Istituto Nazionale dei Tumori, 20133 Milan, Italy; (M.M.); (G.S.)
| | - Jorgelina Coppa
- Hepatology and Hepato-Pancreatic-Biliary Surgery and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy;
| | - Benedetta Masoni
- Gastroenterology and Endoscopy Unit, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy; (B.M.); (A.R.)
| | - Simone Oldani
- Gastro-Entero-Pancreatic and Neuroendocrine Tumor Unit 1, Department of Medical Oncology, ENETS Center of Excellence, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy; (S.P.); (S.O.)
| | - Giovanna Sabella
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS–Istituto Nazionale dei Tumori, 20133 Milan, Italy; (M.M.); (G.S.)
| | - Pietro Cafaro
- Medical Oncology Unit, Fondazione IRCCS San Gerardo dei Tintori Monza, Via G.B. Pergolesi, 20900 Monza, Italy; (F.C.); (P.C.)
| | - Alessandro Repici
- Gastroenterology and Endoscopy Unit, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy; (B.M.); (A.R.)
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20090 Milan, Italy
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Marando A, Di Blasi E, Tucci F, Aquilano MC, Bonoldi E. DOG1 expression in neuroendocrine neoplasms: Potential applications and diagnostic pitfalls. Pathol Res Pract 2023; 248:154623. [PMID: 37331184 DOI: 10.1016/j.prp.2023.154623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 06/13/2023] [Accepted: 06/14/2023] [Indexed: 06/20/2023]
Abstract
Neuroendocrine neoplasms represent a heterogeneous group of rare tumors, more frequently arising from gastroenteropancreatic tract and lungs. At the time of diagnosis, 20% of cases are metastatic, and 10% of cases are considered as cancer of unknown primary origin. Several immunohistochemical markers are routinely used to confirm the neuroendocrine differentiation, first among all Synaptophysin and Chromogranin-A; on the other hand, different immunohistochemical markers are used to establish primary anatomical site, as TTF1, CDX2, Islet-1 and Calcitonin, but no marker is available in order to distinguish among different sites of the digestive tract. DOG1 (discovered on GIST-1) is a gene normally expressed in interstitial cells of Cajal and, in routine practice, DOG1 immunostaining is used in diagnosis of GIST (gastrointestinal stromal tumor). DOG1 expression has been described in several neoplasms other than GIST, both in mesenchymal and epithelial neoplasms. In the present study, DOG1 immunostaining has been performed in a large cohort of neuroendocrine neoplasms, including neuroendocrine tumors and neuroendocrine carcinomas, in order to evaluate frequency, intensity and pattern of expression in different anatomical site and in different tumor grade. DOG1 expression was detected in a large percentage of neuroendocrine tumors, with statistically significant association between DOG1 expression and gastrointestinal tract neuroendocrine tumors. As a consequence, DOG1 could be included in marker panel for the identification of primary site in neuroendocrine metastases of unknown primary origin; moreover, these results recommend careful evaluation of DOG1 expression in gastrointestinal neoplasms, in particular in differential diagnosis between epithelioid GIST and neuroendocrine tumors.
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Affiliation(s)
- A Marando
- Department of Surgical Pathology, Niguarda Hospital, Milano, Italy.
| | - E Di Blasi
- School of Pathology, University of Milan, Milan, Italy
| | - F Tucci
- School of Pathology, University of Milan, Milan, Italy
| | - M C Aquilano
- Department of Surgical Pathology, Niguarda Hospital, Milano, Italy
| | - E Bonoldi
- Department of Surgical Pathology, Niguarda Hospital, Milano, Italy
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CDX2 expression in primary skin tumors-case series and review of the literature. Hum Pathol 2022; 129:1-10. [PMID: 35926811 DOI: 10.1016/j.humpath.2022.07.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 07/10/2022] [Accepted: 07/12/2022] [Indexed: 12/14/2022]
Abstract
CDX2 expression characterizes tumors of gastrointestinal origin, including those of intestinal-type differentiation. In dermatopathology, CDX2 expression is reported in 4 settings: cutaneous metastases from carcinomas of intestinal origin or differentiation, extramammary Paget's disease associated with an underlying colorectal or urothelial tumor, pilomatricomas and pilomatrical carcinomas, and rare primary cutaneous (adeno)squamous carcinomas with intestinal immunophenotype. Over 4 years (10/2017-10/2021), 252 dermatopathology cases with CDX2 immunostain were reviewed, revealing 46 cases with confirmed positive staining. Among them, 11 cases confirmed as primary nonintestinal type cutaneous carcinoma with definitively positive CDX2 nuclear staining were further studied. All cases demonstrated basaloid morphology with atypia, variable necrosis, and brisk mitotic activity. Cases 1-5 had heterogeneous features that cannot be further classified, including 2 cases with neuroendocrine or pseudoglandular/pseudopapillary features, and 1 case with human papillomavirus high-risk E6/E7 ISH positivity. In cases 6 through 11, the diagnosis of pilomatrical carcinoma was supported morphologically. This study substantiates the association of CDX2 with pilomatrical carcinoma. In addition, CDX2 positivity was observed in a subset of basaloid cutaneous carcinomas of ambiguous classification. However, this finding also raises a diagnostic pitfall in clinical diagnostic specificity of the CDX2 immunostain in skin cancers, which can be observed in rare while heterogeneous subsets of primary cutaneous carcinomas with primitive cytomorphology.
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Pongsuvareeyakul T, Garcia-Moliner M, Lokich E, Dizon DS, Singh K. Small cell neuroendocrine carcinoma of vagina: Report of a unique case with literature review. Cancer Treat Res Commun 2022; 33:100645. [PMID: 36274474 DOI: 10.1016/j.ctarc.2022.100645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 08/12/2022] [Accepted: 10/02/2022] [Indexed: 11/27/2022]
Abstract
Small cell carcinoma (SCC) of vagina is extremely rare. The association between this tumor and high-risk HPV infection is unclear. To our knowledge, HPV status has been reported in only 3 previous cases of SCC of vagina. Herein, we present a unique case of vaginal small cell carcinoma with discordant HPV testing results between vaginal and cervical samples. We also review and discuss findings from previously reported cases of small cell carcinoma of vagina.
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Affiliation(s)
- Tip Pongsuvareeyakul
- Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island, United States
| | - Maria Garcia-Moliner
- Department of Pathology and Laboratory Medicine Rhode Island Hospital, Providence, Rhode Island, United States
| | - Elizabeth Lokich
- Department of Women Oncology Women & Infants Hospital of Rhode Island, Brown University, Providence, Rhode Island, United States
| | - Don S Dizon
- Department of Medicine Warren Alpert Medical School of Brown University, Providence, Rhode Island, United States
| | - Kamaljeet Singh
- Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island, United States.
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Soukup J, Manethova M, Faistova H, Krbal L, Vitovcova B, Hornychova H, Drugda J, Cesak T, Netuka D, Gabalec F, Ryska A. Pitx2 is a useful marker of midgut‐derived neuroendocrine tumours ‐ an immunohistochemical study of 224 cases. Histopathology 2022; 81:799-807. [DOI: 10.1111/his.14789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Revised: 08/03/2022] [Accepted: 08/26/2022] [Indexed: 11/29/2022]
Affiliation(s)
- Jiri Soukup
- The Fingerland Department of Pathology, Charles University Faculty of Medicine in Hradec Králové and University Hospital Hradec Králové Czech Republic
| | - Monika Manethova
- The Fingerland Department of Pathology, Charles University Faculty of Medicine in Hradec Králové and University Hospital Hradec Králové Czech Republic
| | - Hana Faistova
- The Fingerland Department of Pathology, Charles University Faculty of Medicine in Hradec Králové and University Hospital Hradec Králové Czech Republic
| | - Lukas Krbal
- The Fingerland Department of Pathology, Charles University Faculty of Medicine in Hradec Králové and University Hospital Hradec Králové Czech Republic
| | - Barbora Vitovcova
- Department of Medical Biology and Genetics Charles University Faculty of Medicine Hradec Kralove Czech Republic
| | - Helena Hornychova
- The Fingerland Department of Pathology, Charles University Faculty of Medicine in Hradec Králové and University Hospital Hradec Králové Czech Republic
| | - Jan Drugda
- 4th Department of Internal Medicine, Charles University Faculty of Medicine in Hradec Králové and University Hospital Hradec Králové Czech Republic
| | - Tomas Cesak
- Department of Neurosurgery, Charles University Faculty of Medicine in Hradec Králové and University Hospital Hradec Králové Czech Republic
| | - David Netuka
- Department of Neurosurgery and Neurooncology, 1st Medical Faculty, Charles University Military University Hospital Prague Prague Czech Republic
| | - Filip Gabalec
- 4th Department of Internal Medicine, Charles University Faculty of Medicine in Hradec Králové and University Hospital Hradec Králové Czech Republic
| | - Ales Ryska
- The Fingerland Department of Pathology, Charles University Faculty of Medicine in Hradec Králové and University Hospital Hradec Králové Czech Republic
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11
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Explainability and Causability for Artificial Intelligence-Supported Medical Image Analysis in the Context of the European In Vitro Diagnostic Regulation. N Biotechnol 2022; 70:67-72. [DOI: 10.1016/j.nbt.2022.05.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 05/02/2022] [Accepted: 05/03/2022] [Indexed: 01/02/2023]
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12
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Vrana JA, Boland JM, Terra SBSP, Xie H, Jenkins SM, Mansfield AS, Molina JR, Cassivi SD, Roden AC. SATB2 Is Expressed in a Subset of Pulmonary and Thymic Neuroendocrine Tumors. Am J Clin Pathol 2021; 156:853-865. [PMID: 33978159 DOI: 10.1093/ajcp/aqab038] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVES To evaluate SATB2 expression and prognostic implications in a large cohort of thoracic neuroendocrine tumors. METHODS Surgical pathology files (1995-2017) and an institutional thymic epithelial tumor database (2010-2020) were searched for resected neuroendocrine tumors. Cases were stained with SATB2 (clone EP281). Percent SATB2-positive tumor cells and expression intensity were scored. RESULTS In the lung, SATB2 was expressed in 5% or more of tumor cells in 29 (74.4%) of 39 small cell carcinomas and 9 (22.5%) of 40 atypical and 26 (40.6%) of 64 typical carcinoid tumors. SATB2 percent tumor cell expression and intensity were higher in small cell carcinomas than in carcinoid tumors (both P < .001, respectively). After adjusting for tumor subtype, SATB2 expression did not correlate with outcome. In the thymus, four (100%) of four atypical carcinoid tumors and one large cell neuroendocrine carcinoma but no small cell carcinoma (n = 2) expressed SATB2 in 5% or more of tumor cells. CONCLUSIONS SATB2 (clone EP281) is expressed in a large subset of pulmonary and thymic neuroendocrine tumors and therefore does not appear to be a useful marker to identify the origin of neuroendocrine tumors. Validation studies are needed, specifically including thymic neuroendocrine tumors, as the expression pattern might be different in those tumors.
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Affiliation(s)
- Julie A Vrana
- Department of Laboratory Medicine and Pathology, Rochester, MN, USA
| | | | | | - Hao Xie
- Division of Medical Oncology, Department of Oncology, Rochester, MN, USA
| | | | - Aaron S Mansfield
- Division of Medical Oncology, Department of Oncology, Rochester, MN, USA
| | - Julian R Molina
- Division of Medical Oncology, Department of Oncology, Rochester, MN, USA
| | - Stephen D Cassivi
- Division of Thoracic Surgery, Mayo Clinic Rochester, Rochester, MN, USA
| | - Anja C Roden
- Department of Laboratory Medicine and Pathology, Rochester, MN, USA
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13
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Yan F, Zhou Q, Lin Y, Yu C, Chang H, Li Y. Clinicopathological analysis of primary carcinoid tumour of the ovary arising in mature cystic teratomas. J Int Med Res 2021; 49:3000605211034666. [PMID: 34459278 PMCID: PMC8408898 DOI: 10.1177/03000605211034666] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
OBJECTIVE To investigate the clinicopathological features, diagnosis and differential diagnosis of patients with primary ovarian carcinoid tumours arising in mature cystic teratomas. METHODS This retrospective case series analysed the data from patients with primary ovarian carcinoid tumours arising in mature cystic teratomas. RESULTS The study enrolled four patients. Histopathological analysis of the tumours identified the following subtypes: insular (n = 1), trabecular (n = 1) and strumal (n = 2). All four primary ovarian carcinoid tumours originated from a mature teratoma. The morphology of the primary ovarian carcinoids was similar to other neuroendocrine tumours. Strumal carcinoids were composed of different proportions of thyroid tissue intimately admixed with carcinoid tumour. Tumour tissue was arranged in insular and/or trabecular patterns. The nucleus of tumour cells displayed exquisite chromatin without obvious mitotic figures. Tumour tissues were positively stained for neuroendocrine markers chromogranin A, synaptophysin and CD56 to varying degrees. Strumal carcinoid tumours were cytokeratin 19 positive and thyroid transcription factor 1 negative. No recurrence or metastasis occurred during follow-up (12-71 months). CONCLUSION Primary ovarian carcinoid tumours arising in mature cystic teratomas are rare. Diagnosis and differential diagnosis should be confirmed by clinical features, histopathological characteristics and specific immunophenotyping.
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Affiliation(s)
- Fengcai Yan
- Department of Pathology, 117968Beijing Shijitan Hospital, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Quan Zhou
- Department of Pathology, 117968Beijing Shijitan Hospital, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Yulin Lin
- Department of Peritoneal Cancer Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Chunkai Yu
- Department of Pathology, 117968Beijing Shijitan Hospital, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Hong Chang
- Department of Pathology, 117968Beijing Shijitan Hospital, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Yan Li
- Department of Peritoneal Cancer Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
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14
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Laprovitera N, Riefolo M, Ambrosini E, Klec C, Pichler M, Ferracin M. Cancer of Unknown Primary: Challenges and Progress in Clinical Management. Cancers (Basel) 2021; 13:451. [PMID: 33504059 PMCID: PMC7866161 DOI: 10.3390/cancers13030451] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 11/30/2020] [Accepted: 01/19/2021] [Indexed: 12/11/2022] Open
Abstract
Distant metastases are the main cause of cancer-related deaths in patients with advanced tumors. A standard diagnostic workup usually contains the identification of the tissue-of-origin of metastatic tumors, although under certain circumstances, it remains elusive. This disease setting is defined as cancer of unknown primary (CUP). Accounting for approximately 3-5% of all cancer diagnoses, CUPs are characterized by an aggressive clinical behavior and represent a real therapeutic challenge. The lack of determination of a tissue of origin precludes CUP patients from specific evidence-based therapeutic options or access to clinical trial, which significantly impacts their life expectancy. In the era of precision medicine, it is essential to characterize CUP molecular features, including the expression profile of non-coding RNAs, to improve our understanding of CUP biology and identify novel therapeutic strategies. This review article sheds light on this enigmatic disease by summarizing the current knowledge on CUPs focusing on recent discoveries and emerging diagnostic strategies.
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Affiliation(s)
- Noemi Laprovitera
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40126 Bologna, Italy; (N.L.); (M.R.); (E.A.)
- Department of Life Sciences and Biotechnologies, University of Ferrara, 44121 Ferrara, Italy
| | - Mattia Riefolo
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40126 Bologna, Italy; (N.L.); (M.R.); (E.A.)
| | - Elisa Ambrosini
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40126 Bologna, Italy; (N.L.); (M.R.); (E.A.)
| | - Christiane Klec
- Division of Oncology, Medical University of Graz, 8036 Graz, Austria; (C.K.); (M.P.)
| | - Martin Pichler
- Division of Oncology, Medical University of Graz, 8036 Graz, Austria; (C.K.); (M.P.)
| | - Manuela Ferracin
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40126 Bologna, Italy; (N.L.); (M.R.); (E.A.)
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15
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Metovic J, Barella M, Harari S, Pattini L, Albini A, Sonzogni A, Veronesi G, Papotti M, Pelosi G. Clinical implications of lung neuroendocrine neoplasm classification. Expert Rev Anticancer Ther 2020; 21:377-387. [PMID: 33306420 DOI: 10.1080/14737140.2021.1862654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
INTRODUCTION Neuroendocrine neoplasms of the lung (Lung NENs) encompass NE tumors (NETs), which are in turn split into typical and atypical carcinoids, and NE carcinomas (NECs), which group together small-cell carcinoma and large-cell NE carcinoma. This classification is the current basis for orienting the daily practice of these patients, with diagnostic, prognostic, and predictive inferences. AREAS COVERED The clinical implications of lung NEN classification are addressed according to three converging perspectives, which were dissected through an extensive literature overview: (1) how to put intratumor heterogeneity into the context of the current classification; (2) how to contextualize immunohistochemistry markers to improve diagnosis, prognosis, and therapy prediction; and (3) how to use immuno-oncology strategies for life-threatening NECs, which still account for 90% or more of lung NENs. EXPERT OPINION We provide practical insights to account for intratumor heterogeneity, practice the choice of immunohistochemistry markers, and emphasize once again the added value of immuno-oncology in the setting of personalized medicine of lung NENs.
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Affiliation(s)
- Jasna Metovic
- Department of Oncology, University of Turin, Turin, Italy
| | - Marco Barella
- Inter-Hospital Pathology Division, IRCCS MultiMedica, Milan, Italy
| | - Sergio Harari
- Department of Medical Sciences and Community Health, University of Milan, Milan, Italy.,Division of Pneumology, San Giuseppe Hospital, IRCCS MultiMedica, Milan, Italy
| | - Linda Pattini
- Department of Electronics, Information and Bioengineering, Politecnico Di Milano, Milan, Italy
| | - Adriana Albini
- Laboratory of Vascular Biology and Angiogenesis, IRCCS MultiMedica, Milan, Italy
| | - Angelica Sonzogni
- Department of Pathology and Laboratory Medicine, IRCCS Istituto Nazionale Dei Tumori, Milan, Italy
| | - Giulia Veronesi
- Division of Thoracic Surgery, San Raffaele Scientific Institute - IRCCS, Milan, Italy.,School of Medicine, Vita-Salute San Raffaele University, Milan, Italy
| | - Mauro Papotti
- Department of Oncology, University of Turin, Turin, Italy
| | - Giuseppe Pelosi
- Inter-Hospital Pathology Division, IRCCS MultiMedica, Milan, Italy.,Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
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16
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Mohanty SK, Tiwari A, Bhardwaj N, Chuang F, Kim E, Lugo H, Yuan X, Diffalha SA, Peralta-Venturina M, Balzer B, Dhall D. Positivity for SATB2 distinguishes Islet1 positive rectal neuroendocrine tumours from pancreaticoduodenal neuroendocrine tumours. J Clin Pathol 2020; 74:582-588. [PMID: 32934105 DOI: 10.1136/jclinpath-2020-206645] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 07/14/2020] [Accepted: 08/02/2020] [Indexed: 12/19/2022]
Abstract
AIMS Determining the site of origin of a metastatic neuroendocrine tumour (NET) can be challenging and has important prognostic and therapeutic implications. An immunohistochemical (IHC) panel consisting of TTF1, CDX2, PAX8/PAX6 and Islet1 is often employed. However, there can be a significant IHC overlap among different primary sites. Herein, we sought to determine the utility of including Special AT-rich sequence binding protein-2 (SATB2) in the IHC panel that is used for determining the site of origin of a metastatic NET. METHODS Paraffin tissue microarrays consisting of 137 primary NETs (26 lung, 22 jejunoileal, 8 appendix, 5 stomach, 4 duodenum, 17 rectum and 55 pancreas) were stained for SATB2, in addition to the well-described lineage-associated markers, such as TTF1, CDX2, PAX6 and Islet1. Additionally, a tissue microarray consisting of 21 metastatic NETs (1 lung, 1 stomach, 8 jejunoileal and 11 pancreas) was stained for TTF1, CDX2, SATB2 and Islet1. The results were recorded as no staining, weak staining and moderate to strong staining. RESULTS All appendiceal NETs and majority (88%) of the rectal NETs were positive for SATB2. All primary foregut NETs (stomach, pancreas, duodenum and lung) were negative for SATB2, except for one pulmonary NET with weak staining. However, among the metastatic tumours, 5 of 11 pancreatic NETs, 1 stomach NET, 1 lung NET and 2 of 8 jejunoileal NETs showed weak staining. Receiver operating characteristic analysis incorporating sensitivity and specificity data of IHC panel, considering moderate to strong staining as truly positive cases, showed that inclusion of SATB2 to the previously described NET IHC panel outperformed the panel without SATB2, raising the specificity for pancreaticoduodenal NETs from 81.2% to 100%, with a positive predictive value (PPV) of 100% and negative predictive value (NPV) of 82.22% (p<0.0001); for appendiceal NETs the specificity changed from 99.1% to 98.5% and sensitivity increased from 11.8% to 80%, with a PPV and NPV of 66.67% and 99.26%, respectively (p<0.0001); and for rectal NETs the specificity increased from 97.6% to 99.3% and sensitivity raised from 7.1% to 66.7%, with a PPV and NPV of 80% and 98.53%, respectively (p<0.0001). CONCLUSIONS SATB2 stain is useful in differentiatingIslet1/PAX6 positive pancreatic and rectal NETs, as rectal NETs are typically moderately to strongly positive for SATB2 and pancreatic NETs are usually negative or weakly positive for SATB2. Moderate to strong staining for SATB2 is suggestive of an appendiceal or a rectal primary. SATB2 may complement the panel of CDX2, TTF1 and Islet1 in determining the site of origin of an NET in a metastatic setting.
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Affiliation(s)
- Sambit Kumar Mohanty
- Pathology and Laboratory Medicine, Advanced Medical Research Institute, Bhubaneswar, Odisha, India.,Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Ankit Tiwari
- Pathology and Laboratory Medicine, Advanced Medical Research Institute, Bhubaneswar, Odisha, India
| | - Nitin Bhardwaj
- Pathology and Laboratory Medicine, Advanced Medical Research Institute, Bhubaneswar, Odisha, India
| | - Fai Chuang
- Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Evelyn Kim
- Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Hector Lugo
- Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Xiaopu Yuan
- Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Sameer Al Diffalha
- Pathology, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, USA
| | | | - Bonnie Balzer
- Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Deepti Dhall
- Pathology, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, USA
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17
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Chornenkyy Y, Lin X. Aberrant expression of TTF1, p63, and cytokeratins in a diffuse large B-cell lymphoma. Diagn Cytopathol 2020; 49:E75-E79. [PMID: 32870599 DOI: 10.1002/dc.24588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 07/08/2020] [Accepted: 08/03/2020] [Indexed: 11/08/2022]
Abstract
Pancytokeratins and TTF-1 are used in working up carcinomas of unknown primary and p63 is expressed in many cell lineages. We present a case of a TTF-1, p63, and cytokeratins positive small round blue cell lesion presenting in a patient with enlarged right supraclavicular lymph nodes and multiple solid pulmonary nodules. The preliminary report to the clinical team was "suspicious for carcinoma." However, after a complete work up the final diagnosis of diffuse large B-cell lymphoma, nongerminal center B-cell phenotype, "double expressor," was rendered (based on Han's algorithm). This case brings up significant diagnostic dilemma as some lymphoid malignancies can morphologically mimic poorly differentiated carcinoma and stain positive for carcinoma markers. Additionally, the frequently used TTF-1 SPT23 antibody clone has strong nuclear staining in rare cases of DLBCL, which is a diagnostic pitfall. To our best knowledge this is the first reported case of DLBCL staining positive for three carcinoma markers.
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Affiliation(s)
- Yevgen Chornenkyy
- Department of Pathology, Northwestern University, Feinberg School of Medicine, Northwestern Memorial Hospital, Chicago, Illinois, USA
| | - Xiaoqi Lin
- Department of Pathology, Northwestern University, Feinberg School of Medicine, Northwestern Memorial Hospital, Chicago, Illinois, USA
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18
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Bacorn C, Kim E, Borowsky AD, Lin LK. Previously undiagnosed neuroendocrine tumour mimicking breast cancer metastasis to the orbit. BMJ Case Rep 2020; 13:13/5/e234629. [PMID: 32439746 DOI: 10.1136/bcr-2020-234629] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Metastatic neuroendocrine neoplasms to the breast are rare and histopathologic overlap with mammary carcinomas has led to misdiagnosis. We present a case of a middle-aged woman with diplopia and a right medial rectus mass. Metastatic breast cancer was initially suspected based on a history of invasive ductal carcinoma. Detailed immunohistochemistry of the orbital biopsy, gallium-68 dotatate positron emission tomography-CT, and reevaluation of her prior breast specimen, demonstrated that her initial breast carcinoma diagnosis was in error and she was ultimately diagnosed with a previously unknown gastrointestinal neuroendocrine tumour metastatic to both the orbit and breast. This case highlights the challenges of differentiating between metastatic neuroendocrine tumours and invasive mammary carcinomas with neuroendocrine differentiation both in the breast and in the orbit. It is important to recognise the overlap so that a primary neuroendocrine neoplasm is not missed, or treatment significantly delayed.
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Affiliation(s)
- Colin Bacorn
- Department of Ophthalmology and Vision Science, University of California Davis Health Eye Center, Sacramento, California, USA
| | - Esther Kim
- Department of Ophthalmology and Vision Science, University of California Davis Health Eye Center, Sacramento, California, USA
| | - Alexander D Borowsky
- Department of Pathology and Laboratory Medicine, University of California Davis Health System, Sacramento, California, USA
| | - Lily Koo Lin
- Department of Ophthalmology and Vision Science, University of California Davis Health Eye Center, Sacramento, California, USA
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19
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Li C, Huang J, Yang X, Xia J, Xu G, Zheng H. A primary neuroendocrine tumor of the left ventricle presenting with diarrhea-an unusual experience and literature review. Diagn Pathol 2020; 15:32. [PMID: 32245475 PMCID: PMC7119177 DOI: 10.1186/s13000-020-00935-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 02/05/2020] [Indexed: 01/04/2023] Open
Abstract
Background Neuroendocrine tumors (NETs) can secrete bioactive amines in the bloodstream, resulting in the carcinoid syndrome characterized by diarrhea and flushing. The frequency of occurrence of primary cardiac neuroendocrine neoplasms is lesser than that of metastases, and hence, metastases must be adequately ruled out before diagnosis. Cardiac tumors, both primary and metastatic, mainly result in heart-related symptoms, such as heart failure and acquired valvular dysfunction. Here, we report a unique case of a primary left ventricular neuroendocrine tumor presenting with diarrhea. Case presentation A 51-year-old female complaining of intermittent diarrhea for 2 years was admitted to our hospital. Enhancement of total abdominal computed tomography scan, echocardiography, and magnetic resonance imaging indicated a mass in the left ventricle. The indexes of myocardial enzymes were normal. Histologically, round cells with well-differentiated neuroendocrine morphology were arranged in typical pseudo-glandular, trabecular, ribbon-like, and solid nest patterns. Immunohistochemically, the tumor cells were positive for cytokeratin, chromogranin, synaptophysin, and CD56. However, they were negative for caudal type homeobox 2, S100, paired box gene 8, thyroid transcription factor 1, and CD20, which ruled out the origin of gastrointestinal, pancreatic, lung, and Merkel cell carcinomas. The symptoms of diarrhea disappeared after the operation. The patient was asymptomatic at the 9-month follow-up. Conclusion Cardiac neuroendocrine tumors with diarrhea are considerably rare and related clinical research is limited. We presented a case and reviewed related articles to improve the identification, diagnosis, and management of patients with cardiac neuroendocrine tumors. The site of origin of a neuroendocrine tumor is clinically vital, and identification of an occult primary tumor using imaging modalities is necessary. Immunohistochemistry is well-suited to indicate the origin of the tumor. Regular follow-up is necessary for both poorly differentiated and well-differentiated cardiac neuroendocrine tumors. It is suggested to detect some neuroendocrinal markers for patients with unexplained reasons of diarrhea.
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Affiliation(s)
- Chengfang Li
- Department of Pathology, The Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, Guizhou, China
| | - Jiajia Huang
- Department of Pathology, The Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, Guizhou, China
| | - Xiaorong Yang
- Department of Pathology, The Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, Guizhou, China
| | - Jinhua Xia
- Department of Pathology, The Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, Guizhou, China
| | - Gaoqiang Xu
- Department of Imaging, The Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, Guizhou, China
| | - Hong Zheng
- Department of Pathology, The Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, Guizhou, China.
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20
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Maleki Z, Muller S, Layfield L, Siddiqui MT, Rekhtman N, Pantanowitz L. Pulmonary sclerosing pneumocytoma: Cytomorphology and immunoprofile. Cancer Cytopathol 2020; 128:414-423. [PMID: 32022435 DOI: 10.1002/cncy.22251] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 12/18/2019] [Accepted: 01/16/2020] [Indexed: 11/10/2022]
Abstract
BACKGROUND Sclerosing pneumocytoma (SP) is a rare, benign pulmonary neoplasm. To the authors' knowledge, the current study is the first to evaluate the cytomorphology and immunoprofile of SP in a series. METHODS A total of 9 fine-needle aspiration cases of SP (7 of which were computed tomography guided and 2 of which were endobronchial ultrasound guided) including histopathology and immunohistochemistry were collected from 5 institutions. RESULTS The female-to-male ratio was 3.5:1, and the mean age of the patients was 54 years (range, 27-73 years). All cases presented as lung nodules, with a mean size of 2.2 cm (range, 1.1-5 cm), and were interpreted as atypical on rapid on-site evaluation. The final diagnoses were favor adenocarcinoma (1 case), well-differentiated lung adenocarcinoma (2 cases), low-grade epithelial neoplasm (2 cases), and sclerosing pneumocytoma (4 cases). Samples were moderately cellular, and consisted of round epithelioid cells with clear cell features, columnar cells, and spindle cells. A papillary arrangement with prominent hyalinized fibrovascular cores was the most common architectural pattern, followed by flat sheets and acinar formations. Tumor cells demonstrated mild, focally moderate nuclear pleomorphism with prominent nucleoli, hyperchromasia, nuclear elongation, nuclear overlap, and occasional nuclear inclusions and grooves. The background consisted of foamy macrophages (9 cases), hemosiderin pigment (6 cases), and lymphoid aggregates (3 cases) with no mitoses and/or necrosis. The surface cells and underlying round cells were positive for both thyroid transcription factor 1 and epithelial membrane antigen in all cases, which was the most notable immunohistochemical finding. CONCLUSIONS Cytomorphological findings of SP overlap with those of well-differentiated lung adenocarcinoma. Awareness of these cytomorphologic findings and the distinct immunoprofile of the 2 cell types found in SP should prevent a misdiagnosis and aggressive treatment.
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Affiliation(s)
- Zahra Maleki
- Division of Cytopathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Stephanie Muller
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Lester Layfield
- Department of Pathology and Anatomical Sciences, University of Missouri School of Medicine, Columbia, Missouri
| | - Momin T Siddiqui
- Pathology and Laboratory Medicine, Department of Pathology, New York Presbyterian-Weill Cornell Medicine, New York, New York
| | - Natasha Rekhtman
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Liron Pantanowitz
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
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21
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Taggart MW, Foo WC, Lee SM. Tumors of the Gastrointestinal System Including the Pancreas. ONCOLOGICAL SURGICAL PATHOLOGY 2020:691-870. [DOI: 10.1007/978-3-319-96681-6_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Berner AM, Pipinikas C, Ryan A, Dibra H, Moghul I, Webster A, Luong TV, Thirlwell C. Diagnostic Approaches to Neuroendocrine Neoplasms of Unknown Primary Site. Neuroendocrinology 2020; 110:563-573. [PMID: 31658461 DOI: 10.1159/000504370] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Accepted: 10/26/2019] [Indexed: 12/18/2022]
Abstract
Neuroendocrine neoplasms (NENs) arise from cells of neuronal and endocrine differentiation. While they are a rare entity, an increasing proportion of patients with NEN present with metastatic disease and no evident primary site using routine imaging or histopathology. NENs of unknown primary site have a poorer prognosis, often due to the challenge of selecting appropriate evidence-based management. We review the available literature and guidelines for the management of NENs of unknown primary site including clinical features, biochemical tests, histopathology, imaging, surgical exploration and localised and systemic treatments. We also discuss novel molecular techniques currently under investigation to aid primary site identification.
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Affiliation(s)
- Alison May Berner
- Department of Tumour Biology, Barts Cancer Institute, London, United Kingdom,
- Research Department of Oncology, UCL Cancer Institute, London, United Kingdom,
| | | | - Anna Ryan
- Mount Vernon Cancer Centre, East and North Hertfordshire NHS Trust, Northwood, United Kingdom
| | | | - Ismail Moghul
- Research Department of Oncology, UCL Cancer Institute, London, United Kingdom
| | - Amy Webster
- Research Department of Oncology, UCL Cancer Institute, London, United Kingdom
| | - Tu Vinh Luong
- Royal Free Hospitals NHS Trust, London, United Kingdom
| | - Christina Thirlwell
- Research Department of Oncology, UCL Cancer Institute, London, United Kingdom
- University of Exeter School of Medicine and Health, RILD Building, Exeter, United Kingdom
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23
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Baek YB, Ang MJ, Park JG, Yu D, Park S, Lee JH, Choi J, Cho KO. Canine adrenocorticotropic hormone-producing sinusoidal neuroendocrine tumor associated with Cushing's disease. J Vet Med Sci 2019; 81:1863-1867. [PMID: 31656239 PMCID: PMC6943326 DOI: 10.1292/jvms.19-0386] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
An 18-year-old male Yorkshire Terrier was admitted with a history of neurological signs
including dullness and progressive tetraparesis. Physical examination revealed bilaterally
symmetrical alopecia and pot-bellied abdomen. Computed tomography and necropsy examination
showed a mass across the frontal sinus and cerebral frontal lobe, bilateral adrenocortical
hyperplasia, and hepatomegaly. Histopathologically, the tumor lesions consisted of sheets,
nests, or cords of small- to medium-sized round-to-polyhedral cells. Adrenal cortex showed
bilateral diffuse cellular proliferation, and some hepatocytes showed intracytoplasmic
glycogen accumulation. Immunohistochemically, the tumor cells were positive for
pancytokeratin, chromogranin-A, neuron-specific enolase, S100, synaptophysin, and thyroid
transcription factor-1 but negative for microtubule-associated proein-2 and neurofilament,
leading to the diagnosis of neuroendocrine tumor. These tumor cells were also positive for
adrenocorticotropic hormone.
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Affiliation(s)
- Yeong-Bin Baek
- Laboratory of Veterinary Pathology, College of Veterinary Medicine, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - Mary Jasmin Ang
- Laboratory of Veterinary Pathology, College of Veterinary Medicine, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - Jun-Gyu Park
- Laboratory of Veterinary Pathology, College of Veterinary Medicine, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - DoHyeon Yu
- Institute of Animal Medicine, College of Veterinary Medicine, Gyeongsang National University, Jinju, 52828, Republic of Korea
| | - Seungjo Park
- Veterinary Medical Imaging, College of Veterinary Medicine, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - Jae-Hyuk Lee
- Department of Pathology, Chonnam National University Medical School, Hwasun, 58128, Republic of Korea
| | - Jihye Choi
- Veterinary Medical Imaging, College of Veterinary Medicine, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - Kyoung-Oh Cho
- Laboratory of Veterinary Pathology, College of Veterinary Medicine, Chonnam National University, Gwangju, 61186, Republic of Korea
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Kei S, Adeyi OA. Practical Application of Lineage-Specific Immunohistochemistry Markers: Transcription Factors (Sometimes) Behaving Badly. Arch Pathol Lab Med 2019; 144:626-643. [PMID: 31385722 DOI: 10.5858/arpa.2019-0226-ra] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT.— Transcription factors (TFs) are proteins that regulate gene expression and control RNA transcription from DNA. Lineage-specific TFs have increasingly been used by pathologists to determine tumor lineage, especially in the setting of metastatic tumors of unknown primary, among other uses. With experience gathered from its daily application and increasing pitfalls reported from immunohistochemical studies, these often-touted highly specific TFs are not as reliable as once thought. OBJECTIVES.— To summarize the established roles of many of the commonly used TFs in clinical practice and to discuss known and potential sources for error (eg, false-positivity from cross-reactivity, aberrant, and overlap "lineage-specific" expression) in their application and interpretation. DATA SOURCES.— Literature review and the authors' personal practice experience were used. Several examples selected from the University Health Network (Toronto, Ontario, Canada) are illustrated. CONCLUSIONS.— The application of TF diagnostic immunohistochemistry has enabled pathologists to better assess the lineage/origin of primary and metastatic tumors. However, the awareness of potential pitfalls is essential to avoid misdiagnosis.
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Affiliation(s)
- Si Kei
- From the Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada (Dr Lou); and the Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis (Dr Adeyi)
| | - Oyedele A Adeyi
- From the Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada (Dr Lou); and the Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis (Dr Adeyi)
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Zhao LH, Chen C, Mao CY, Xiao H, Fu P, Xiao HL, Wang G. Value of SATB2, ISL1, and TTF1 to differentiate rectal from other gastrointestinal and lung well-differentiated neuroendocrine tumors. Pathol Res Pract 2019; 215:152448. [PMID: 31133441 DOI: 10.1016/j.prp.2019.152448] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2019] [Revised: 04/26/2019] [Accepted: 05/12/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND Management of neuroendocrine tumors (NETs) depends on the primary site, but the location of many well-differentiated (WD) NETs is elusive. Organ-specific markers are required for pathological diagnosis from biopsy. Transcription factors with good organ specificity include TTF1 (thyroid transcription factor 1; lung), CDX2 (caudal type homeobox transcription factor 2; midgut), and ISL1 (ISL LIM homeobox 1) and PAX8 (paired box 8) for the pancreas and rectum. SATB2 (SATB homeobox 2) has shown high sensitivity and specificity in colorectal adenocarcinoma. This study determined the viability of SATB2 and other transcription factors as markers, single or in combination, for WD-NETs of various sites. METHODS Immunohistochemical staining of 81 WD-NETs from 8 organ sites was performed to identify SATB2, TTF1, CDX2, ISL1, and PAX8. Receiver operating characteristic (ROC) curves were constructed for different combinations of the 5 markers to determine sensitivity and specificity. RESULTS Among the WD-NETs, SATB2 was predominantly found in those of the rectum; TTF1 in the lung, larynx, and esophagus; and ISL1 in the duodenum and rectum. PAX8 and CDX2 showed poor organ specificity. ROC profiles showed 50% sensitivity and 96% specificity to lung for TTF1+ ISL1-; and 65% sensitivity and 100% specificity to rectum for SATB2+ ISL1- TTF1-. ISL1+ SATB2- TTF1- showed 83% sensitivity and 85% specificity to the duodenum, and 44% sensitivity and 87% specificity to the pancreas. A literature search showed that there was no significant difference in the expression rates of the five transcription factors (TTF1, CDX2, SATB2, PAX8 and ISL1) between primary and metastatic WD-NETs at the same organ when there was a large sample size. CONCLUSION Among the 5 transcription factors tested, SATB2 may be a viable marker of WE-NETs of the rectum. The combination of SATB2, ISL1, and TTF1 may help estimate the locations of WD-NETs of unknown origin.
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Affiliation(s)
- Lian-Hua Zhao
- Department of Pathology, Daping Hospital and Research Institute of Surgery, Army Military Medical University (Army Special Medical Center), Chongqing, China.
| | - Chuan Chen
- Cancer Center, Daping Hospital and Research Institute of Surgery, Army Military Medical University (Army Medical Center of PLA), Chongqing, China.
| | - Cheng-Yi Mao
- Department of Pathology, Daping Hospital and Research Institute of Surgery, Army Military Medical University (Army Special Medical Center), Chongqing, China.
| | - He Xiao
- Cancer Center, Daping Hospital and Research Institute of Surgery, Army Military Medical University (Army Medical Center of PLA), Chongqing, China.
| | - Ping Fu
- Department of Pathology, Daping Hospital and Research Institute of Surgery, Army Military Medical University (Army Special Medical Center), Chongqing, China.
| | - Hua-Liang Xiao
- Department of Pathology, Daping Hospital and Research Institute of Surgery, Army Military Medical University (Army Special Medical Center), Chongqing, China.
| | - Ge Wang
- Cancer Center, Daping Hospital and Research Institute of Surgery, Army Military Medical University (Army Medical Center of PLA), Chongqing, China.
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Selberherr A, Koperek O, Riss P, Scheuba C, Kaderli R, Perren A, Niederle B. Neuroendocrine Liver Metastasis-a Specific Set of Markers to Detect Primary Tumor Sites. Endocr Pathol 2019; 30:31-34. [PMID: 30456697 DOI: 10.1007/s12022-018-9558-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
The diagnosis of neuroendocrine neoplasia (NEN) is often made at an advanced stage of disease, including hepatic metastasis. At this point, the primary may still be unknown and sometimes cannot even be detected by functional imaging, especially in very small tumors of the pancreas (pan) and small intestinal (si) entities. The site of the primary may be based on biopsy specimens of the liver applying a specific set of markers. Specimens of liver metastases from 87 patients with NENs were studied. In retrospect, 50 patients had si and 37 pan NENs. Tissue samples were evaluated by immunohistochemistry. The markers applied were insulin gene enhancer protein Islet-1 (ISL-1), homeobox protein CDX-2 (CDX2), thyroid transcription factor 1 (TTF-1), and serotonin. Positive stains for CDX2 were documented in 43 (86%) and for serotonin in 45 (90%) of 50 siNENs. Three panNENs were positive for CDX2 and one for serotonin, respectively. ISL-1 was negative throughout in siNENs and also negative in 8 of 50 panNENs (21.6%). TTF-1 was negative in more than 90% of the specimens of either entity. Immunohistochemical markers in liver metastasis can lead the way to the site of the primary NEN. They should always be used in combined clusters.
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Affiliation(s)
- Andreas Selberherr
- Section "Endocrine Surgery", Division of General Surgery, Department of Surgery, Medical University Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
| | - Oskar Koperek
- Department of Pathology, Medical University, Währinger Gürtel 18-20, 1090, Vienna, Austria
| | - Philipp Riss
- Section "Endocrine Surgery", Division of General Surgery, Department of Surgery, Medical University Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
| | - Christian Scheuba
- Section "Endocrine Surgery", Division of General Surgery, Department of Surgery, Medical University Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
| | - Reto Kaderli
- Section "Endocrine Surgery", Division of General Surgery, Department of Surgery, Medical University Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
| | - Aurel Perren
- Institute of Pathology, University of Bern, Murtenstrasse 31, 3012, Bern, Switzerland
| | - Bruno Niederle
- Section "Endocrine Surgery", Division of General Surgery, Department of Surgery, Medical University Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
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27
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The expression of TTF1, CDX2 and ISL1 in 74 poorly differentiated neuroendocrine carcinomas. Ann Diagn Pathol 2018; 37:30-34. [DOI: 10.1016/j.anndiagpath.2018.09.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 08/29/2018] [Accepted: 09/11/2018] [Indexed: 12/26/2022]
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Chae YK, Tamragouri KB, Chung J, Lin X, Miller V, Ali SM, Giles FJ. Large-Cell Neuroendocrine Carcinoma of the Lung: A Focused Analysis of BRAF Alterations and Case Report of a BRAF Non-V600-Mutated Tumor Responding to Targeted Therapy. JCO Precis Oncol 2018; 2:1-12. [PMID: 35135105 DOI: 10.1200/po.17.00150] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
PURPOSE In advanced stages, large-cell neuroendocrine carcinoma of the lung (L-LCNEC) mimics small-cell lung cancer despite its traditional classification as a non-small-cell lung cancer. Here we present a focused analysis of BRAF mutations in this population. PATIENTS AND METHODS Comprehensive genomic profiling of tumor tissues was performed from a cohort of 300 patients with biopsy-proven L-LCNEC. Specimens were either from a primary lung lesion or metastatic site. RESULTS In 13 patients, 14 unique BRAF alterations (amplifications, mutations) were identified. The importance of biomarker-driven therapy is subsequently highlighted with our case of a 69-year-old man diagnosed with metastatic L-LCNEC who did not respond to cisplatin plus etoposide. A significant durable response was then demonstrated with therapy targeted toward a BRAF non-V600E activating mutation (G469R) associated with biomarker response identified through circulating cell-free tumor DNA analysis. A change in clonal allele frequency from nearly 40% to nondetectable was observed. CONCLUSION Although uncommon, L-LCNEC does seem to contain activating and therefore actionable alterations. We thus highlight the value of pursuing next-generation sequencing for patients with this disease.
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Affiliation(s)
- Young Kwang Chae
- Young Kwang Chae, Keerthi B. Tamragouri, and Francis J. Giles, Northwestern University Feinberg School of Medicine; Young Kwang Chae and Francis J. Giles, Robert H. Lurie Comprehensive Cancer Center, Northwestern University; Xiaoqi Lin, Northwestern Memorial Hospital, Northwestern University, Chicago, IL; and Jon Chung, Vincent Miller, and Siraj M. Ali, Foundation Medicine, Cambridge, MA
| | - Keerthi B Tamragouri
- Young Kwang Chae, Keerthi B. Tamragouri, and Francis J. Giles, Northwestern University Feinberg School of Medicine; Young Kwang Chae and Francis J. Giles, Robert H. Lurie Comprehensive Cancer Center, Northwestern University; Xiaoqi Lin, Northwestern Memorial Hospital, Northwestern University, Chicago, IL; and Jon Chung, Vincent Miller, and Siraj M. Ali, Foundation Medicine, Cambridge, MA
| | - Jon Chung
- Young Kwang Chae, Keerthi B. Tamragouri, and Francis J. Giles, Northwestern University Feinberg School of Medicine; Young Kwang Chae and Francis J. Giles, Robert H. Lurie Comprehensive Cancer Center, Northwestern University; Xiaoqi Lin, Northwestern Memorial Hospital, Northwestern University, Chicago, IL; and Jon Chung, Vincent Miller, and Siraj M. Ali, Foundation Medicine, Cambridge, MA
| | - Xiaoqi Lin
- Young Kwang Chae, Keerthi B. Tamragouri, and Francis J. Giles, Northwestern University Feinberg School of Medicine; Young Kwang Chae and Francis J. Giles, Robert H. Lurie Comprehensive Cancer Center, Northwestern University; Xiaoqi Lin, Northwestern Memorial Hospital, Northwestern University, Chicago, IL; and Jon Chung, Vincent Miller, and Siraj M. Ali, Foundation Medicine, Cambridge, MA
| | - Vincent Miller
- Young Kwang Chae, Keerthi B. Tamragouri, and Francis J. Giles, Northwestern University Feinberg School of Medicine; Young Kwang Chae and Francis J. Giles, Robert H. Lurie Comprehensive Cancer Center, Northwestern University; Xiaoqi Lin, Northwestern Memorial Hospital, Northwestern University, Chicago, IL; and Jon Chung, Vincent Miller, and Siraj M. Ali, Foundation Medicine, Cambridge, MA
| | - Siraj M Ali
- Young Kwang Chae, Keerthi B. Tamragouri, and Francis J. Giles, Northwestern University Feinberg School of Medicine; Young Kwang Chae and Francis J. Giles, Robert H. Lurie Comprehensive Cancer Center, Northwestern University; Xiaoqi Lin, Northwestern Memorial Hospital, Northwestern University, Chicago, IL; and Jon Chung, Vincent Miller, and Siraj M. Ali, Foundation Medicine, Cambridge, MA
| | - Francis J Giles
- Young Kwang Chae, Keerthi B. Tamragouri, and Francis J. Giles, Northwestern University Feinberg School of Medicine; Young Kwang Chae and Francis J. Giles, Robert H. Lurie Comprehensive Cancer Center, Northwestern University; Xiaoqi Lin, Northwestern Memorial Hospital, Northwestern University, Chicago, IL; and Jon Chung, Vincent Miller, and Siraj M. Ali, Foundation Medicine, Cambridge, MA
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Vesterinen T, Mononen S, Salmenkivi K, Mustonen H, Räsänen J, Salo JA, Ilonen I, Knuuttila A, Haglund C, Arola J. Clinicopathological indicators of survival among patients with pulmonary carcinoid tumor. Acta Oncol 2018; 57:1109-1116. [PMID: 29463166 DOI: 10.1080/0284186x.2018.1441543] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND Pulmonary carcinoids (PC) are rare malignant neoplasms that cover approximately 1% of all lung cancers. PCs are classified by histological criteria as either typical (TC) or atypical (AC). Histological subtype is the most studied prognostic factor. The aim of this study was to evaluate if other tissue or clinical features are associated with patient outcomes. MATERIAL AND METHODS We retrospectively reviewed clinical records of 133 PC patients who underwent operation in the Helsinki University Hospital between 1990 and 2013. Tissue specimens were re-evaluated, processed into tissue microarray format and stained immunohistochemically with serotonin, calcitonin, adrenocorticotropic hormone (ACTH), thyroid transcription factor-1 (TTF-1) and Ki-67. Survival and risk analyses were performed. RESULTS Based on histology, 75% (n = 100) of the tumors were TCs and 25% (n = 33) ACs. TCs had higher 10-year disease-specific survival (DSS) rate than ACs (99% (95% CI, 93-100%) for TCs vs. 82% (95% CI, 61-92%) for ACs). Hormonally active tumors expressing serotonin, calcitonin or ACTH were noted in 53% of the specimens but hormonal expression was not associated with DSS. TTF-1 was positive in 78% of the specimens but was not associated with DSS. Ki-67 index varied between <1% and 15%. Ki-67 ≥ 2.5% was associated with shorter DSS (p = .004). The presence of metastatic disease (p = .001), tumor size ≥30 mm (p = .021) and atypical histology (p = .011) were also associated with disease-specific mortality. CONCLUSIONS We conclude that PCs are uncommon tumors. When resected, the long-term survival is in general favorable. In this consecutive, single-institution cohort of patients, presence of metastatic disease, tumor size, histological subtype and Ki-67 index were associated with shorter disease-specific survival. As TC and AC have different clinical behaviors, the correct tumor classification at the time of diagnosis is a necessity.
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Affiliation(s)
- Tiina Vesterinen
- HUSLAB, Helsinki Biobank, Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
| | - Sanna Mononen
- Department of Thoracic Surgery, Heart and Lung Center, Helsinki University Hospital, Helsinki, Finland
| | - Kaisa Salmenkivi
- HUSLAB, Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Harri Mustonen
- Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Jari Räsänen
- Department of Thoracic Surgery, Heart and Lung Center, Helsinki University Hospital, Helsinki, Finland
| | - Jarmo A. Salo
- Department of Thoracic Surgery, Heart and Lung Center, Helsinki University Hospital, Helsinki, Finland
| | - Ilkka Ilonen
- Department of Thoracic Surgery, Heart and Lung Center, Helsinki University Hospital, Helsinki, Finland
| | - Aija Knuuttila
- Department of Pulmonary Medicine, Heart and Lung Center, and Cancer Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Caj Haglund
- Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Programs Unit, Translational Cancer Biology, University of Helsinki, Helsinki, Finland
| | - Johanna Arola
- HUSLAB, Helsinki Biobank, Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
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Kyriakopoulos G, Mavroeidi V, Chatzellis E, Kaltsas GA, Alexandraki KI. Histopathological, immunohistochemical, genetic and molecular markers of neuroendocrine neoplasms. ANNALS OF TRANSLATIONAL MEDICINE 2018; 6:252. [PMID: 30069454 DOI: 10.21037/atm.2018.06.27] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Neuroendocrine neoplasms (NENs) arise from cells of the neuroendocrine system located in many sites amongst which most common are the gastrointestinal (GI) system and the lung. The efforts to assess the specific site of origin or predict the biological behavior of NENs is based upon a detailed study of neoplasm's architectural pattern, immunohistochemical, genetic and molecular profile. Immunohistochemistry is used to characterize the aggressivity of NENs, by assessing the proliferation index Ki-67, as well as the neuroendocrine differentiation by assessing chromogranin A (CgA) and CD56. Basal panels of immunohistochemical markers such as CDX-2, Isl-1, TTF-1, PAX6/8 are currently being used to allocate the neoplasms, while in dubious cases new markers are investigating. Unraveling the genetic and molecular mechanisms of NENs pathogenesis along with shedding light on the molecular heterogeneity of neoplasms and the individual patterns of molecular lesions, underlining these neoplasms may provide new tools in terms of diagnostics and therapeutics. Molecular targeted therapies (MTTs) such as everolimus and sunitinib have been the first example of druggable molecular targets implicated in NENs that have been approved for NEN treatment. New investigational drugs are developing along with genetic tests that may allow the identification of the specific subset of patients that will respond to each individual MTT. Multiparametrical molecular and genetic analysis such as the NETest and the MASTER are already in trials shedding light in a step-by-step management of NENs that allow not only the selection of an appropriate therapeutic option but also the identification of response to treatment or early relapse allowing an early amendment of the strategy. Summarizing the combination of histopathological, immunohistochemical, genetic and molecular profile of a NEN opens new horizons in the efficient management of NENs.
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Affiliation(s)
| | - Vasiliki Mavroeidi
- Endocrine Unit, 1st Department of Propaedeutic Medicine, Laiko University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Eleftherios Chatzellis
- Endocrine Unit, 1st Department of Propaedeutic Medicine, Laiko University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Gregory A Kaltsas
- Endocrine Unit, 1st Department of Propaedeutic Medicine, Laiko University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Krystallenia I Alexandraki
- Endocrine Unit, 1st Department of Propaedeutic Medicine, Laiko University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
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31
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Yang MX, Coates RF, Ambaye A, Cortright V, Mitchell JM, Buskey AM, Zubarik R, Liu JG, Ades S, Barry MM. NKX2.2, PDX-1 and CDX-2 as potential biomarkers to differentiate well-differentiated neuroendocrine tumors. Biomark Res 2018; 6:15. [PMID: 29713473 PMCID: PMC5907358 DOI: 10.1186/s40364-018-0129-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 04/02/2018] [Indexed: 12/24/2022] Open
Abstract
Background Well-differentiated neuroendocrine tumors (NET) most frequently arise from the gastrointestinal tract (GI), pancreas, and lung. Patients often present as metastasis with an unknown primary, and the clinical management and outcome depend on multiple factors, including the accurate diagnosis with the tumor primary site. Determining the site of the NET with unknown primary remains challenging. Many biomarkers have been investigated in primary NETs and metastatic NETs, with heterogeneous sensitivity and specificity observed. Methods We used high-throughput tissue microarray (TMA) and immunohistochemistry (IHC) with antibodies against a panel of transcriptional factors including NKX2.2, PDX-1, PTF1A, and CDX-2 on archived formalin-fixed paraffin-embedded NETs, and investigated the protein expression pattern of these transcription factors in 109 primary GI (N = 81), pancreatic (N = 17), and lung (N = 11) NETs. Results Differential expression pattern of these markers was observed. In the GI and pancreatic NETs (N = 98), NKX2.2, PDX-1, and CDX-2 were immunoreactive in 82 (84%), 14 (14%), and 52 (52%) cases, respectively. PDX-1 was expressed mainly in the small intestinal and appendiceal NETs, occasionally in the pancreatic NETs, and not in the colorectal NETs. All three biomarkers including NKX2.2, PDX-1, and CDX-2 were completely negative in lung NETs. PTF1A was expressed in all normal and neuroendocrine tumor cells. Conclusions Our findings suggest that NKX2.2 was a sensitive and specific biomarker for the GI and pancreatic neuroendocrine tumors. We proposed that a panel of immunostains including NKX2.2, PDX-1, and CDX-2 may show diagnostic utility for the most common NETs.
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Affiliation(s)
- Michelle X Yang
- 1Department of Pathology and Laboratory Medicine, University of Vermont Medical Center, 111 Colchester Avenue, Burlington, VT 05401 USA
| | - Ryan F Coates
- 1Department of Pathology and Laboratory Medicine, University of Vermont Medical Center, 111 Colchester Avenue, Burlington, VT 05401 USA
| | - Abiy Ambaye
- 1Department of Pathology and Laboratory Medicine, University of Vermont Medical Center, 111 Colchester Avenue, Burlington, VT 05401 USA
| | - Valerie Cortright
- 1Department of Pathology and Laboratory Medicine, University of Vermont Medical Center, 111 Colchester Avenue, Burlington, VT 05401 USA
| | - Jeannette M Mitchell
- 1Department of Pathology and Laboratory Medicine, University of Vermont Medical Center, 111 Colchester Avenue, Burlington, VT 05401 USA
| | - Alexa M Buskey
- 1Department of Pathology and Laboratory Medicine, University of Vermont Medical Center, 111 Colchester Avenue, Burlington, VT 05401 USA
| | - Richard Zubarik
- 2Gastroenterology, University of Vermont Medical Center, Burlington, VT USA
| | - James G Liu
- Applied Pathology Systems, Worcester, MA USA
| | - Steven Ades
- 4Medical Oncology, University of Vermont Medical Center, Burlington, VT USA
| | - Maura M Barry
- 4Medical Oncology, University of Vermont Medical Center, Burlington, VT USA
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Abstract
Neuroendocrine tumours are uncommon or rare at all sites in the female genital tract. The 2014 World Health Organisation (WHO) Classification of neuroendocrine tumours of the endometrium, cervix, vagina and vulva has been updated with adoption of the terms low-grade neuroendocrine tumour and high-grade neuroendocrine carcinoma. In the endometrium and cervix, high-grade neoplasms are much more prevalent than low-grade and are more common in the cervix than the corpus. In the ovary, low-grade tumours are more common than high-grade carcinomas and the term carcinoid tumour is still used in WHO 2014. The term ovarian small-cell carcinoma of pulmonary type is included in WHO 2014 for a tumour which in other organs is termed high small-cell neuroendocrine carcinoma. Neuroendocrine tumours at various sites within the female genital tract often occur in association with other neoplasms and more uncommonly in pure form.
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Primary breast carcinomas with neuroendocrine features: Clinicopathological features and analysis of tumor growth patterns in 36 cases. Ann Diagn Pathol 2018; 34:122-130. [PMID: 29661717 DOI: 10.1016/j.anndiagpath.2018.03.010] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Accepted: 03/30/2018] [Indexed: 12/17/2022]
Abstract
Primary breast carcinoma with neuroendocrine features (NEBC) is an uncommon tumor. In the classification of WHO 2012, these tumors were categorized as: 1- neuroendocrine tumor, well-differentiated; 2- neuroendocrine carcinoma, poorly differentiated/small cell carcinoma; and 3- invasive breast carcinoma with neuroendocrine differentiation. In this study, we reviewed NEBC except poorly differentiated/small cell carcinoma variant in order to define the morphological growth patterns and cytonuclear details of these tumors. All breast surgical excision materials between 2007 and 2016 were re-evaluated in terms of neuroendocrine differentiation. Thirty-six cases showing positive staining for synaptophysin and/or chromogranin A in ≥50% of tumor cells were included in the study. All cases were female with a mean age of 67.4. Mean tumor diameter was 26 mm. Multifocality was noted in 5 cases. Grossly, they were mostly infiltrative mass lesions. T stages, identified in 34 cases, were as follows: 13 cases with pT1; 19 pT2 and 2 pT3. We described schematically 4 types of patterns depending on predominant growth pattern, except one case: 1) Large-sized solid cohesive groups (6 cases), 2) Small- to medium-sized solid cohesive groups with trabeculae/ribbons and glandular structures (6 cases), 3) Mixed growth patterns (20 cases), 4) Invasive tumor with prominent extracellular and/or intracellular mucin (3 cases). The tumor cells were mostly polygonal-oval with eosinophilic/eosinophilic-granular cytoplasm. The nuclei of tumor cells were mostly round to oval with evenly distributed chromatin. Only 5 cases showed high grade nuclear and histological features. Molecular subtypes of the cases were as follows: 33 luminal A, 2 luminal B, and 1 triple negative. NEBC should come to mind when a tumor display one of the morphological patterns described above, composed of monotonous cells with mild to moderate nuclear pleomorphism and abundant eosinophilic/eosinophilic granular or clear cytoplasm, especially in elderly patients.
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Expression of CDX2 and Thyroid Transcription Factor-1 in Oropharyngeal Undifferentiated Carcinomas: A Potential Diagnostic Pitfall. Appl Immunohistochem Mol Morphol 2018; 26:268-273. [DOI: 10.1097/pai.0000000000000414] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Panse G, Cowper SE, Leffell DJ, Pulitzer M, Ko CJ. Well-differentiated neuroendocrine tumors in skin: Terminology and diagnostic utility of cytokeratin 5/6 and p63. J Cutan Pathol 2018; 44:557-562. [PMID: 28417484 DOI: 10.1111/cup.12952] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Revised: 04/05/2017] [Accepted: 04/06/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND Well-differentiated neuroendocrine tumors (WDNETs) in skin include metastases from visceral primary sites and very uncommonly, primary cutaneous carcinoid tumors. Cutaneous WDNET may present a diagnostic challenge and in particular can be mistaken for a benign skin adnexal tumor. In contrast to cutaneous adnexal tumors, metastatic adenocarcinomas to the skin are cytokeratin 5/6 (CK5/6) and p63 negative in the majority of cases. It is unclear if failure to stain with CK5/6 and p63 would be helpful in differentiating WDNETs from cutaneous adnexal neoplasms. METHODS We reviewed 10 cases of cutaneous WDNETs (8 cases of metastatic disease and 2 presumed primary carcinoid tumors of the skin) and performed immunohistochemical stains for CK5/6 and p63 on all cases. RESULTS All 10 cases were negative with both CK5/6 and p63. CONCLUSION Negative staining for CK5/6 and p63 can be helpful to distinguish WDNETs from cutaneous adnexal neoplasms. It is important to consider WDNETs in the differential diagnosis of cutaneous adnexal neoplasms as low-grade tumors may be the first sign of aggressive metastatic disease.
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Affiliation(s)
- Gauri Panse
- Department of Dermatology, Division of Dermatopathology, Yale School of Medicine, New Haven, Connecticut
| | - Shawn E Cowper
- Department of Dermatology, Division of Dermatopathology, Yale School of Medicine, New Haven, Connecticut.,Department of Pathology, Yale School of Medicine, New Haven, Connecticut
| | - David J Leffell
- Department of Dermatology, Division of Dermatopathology, Yale School of Medicine, New Haven, Connecticut
| | - Melissa Pulitzer
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Christine J Ko
- Department of Dermatology, Division of Dermatopathology, Yale School of Medicine, New Haven, Connecticut.,Department of Pathology, Yale School of Medicine, New Haven, Connecticut
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36
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Wick MR. Primary lesions that may imitate metastatic tumors histologically: A selective review. Semin Diagn Pathol 2018; 35:123-142. [DOI: 10.1053/j.semdp.2017.11.010] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
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Lv Y, Huang C, Xu H, Han X, Zhang L, Mao W, Ji Y, Jin D, Lou W, Xu X. Clinicopathological Characteristics of the primary and metastatic Hepatic Neuroendocrine Tumors and the relevant Prognosis-Related Factors: A Retrospective Study of 81 Cases in a Single Chinese Center. J Cancer 2018; 9:479-487. [PMID: 29483952 PMCID: PMC5820914 DOI: 10.7150/jca.22157] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2017] [Accepted: 10/06/2017] [Indexed: 12/18/2022] Open
Abstract
Aims: We aim to describe the clinicopathological characteristics of hepatic neuroendocrine tumors (HNETs) and evaluate the relevant prognosis-related factors. Methods: The clinical data of 81 consecutive patients with primary or metastatic HNETs from March 2000 to July 2014 were retrospectively analyzed. Results: The mean (SD) age was 59.68 (11.64) years, 69.15% were men. The percentages of Grade G1, G2 and G3 tumors were 4.94%, 25.93% and 69.13%, respectively. Thirty-five cases were primary HNETs. Primary HNETs were more common in patients with larger tumors, lymph nodes invasions, tumor necrosis and portal vein tumor thrombus. The 1-, 3-, and 5-year overall survival rate were 88.89%, 32.10%, and 8.64%, separately. The relapse rate was 81.48% (66/81) and the mean (SD) relapse time was 18.79 (10.99) months. Reduced survival rate was associated with lymph node metastases (P=0.034), tumor necrosis (P=0.048), hard texture of tumor character (P=0.001), multifocality of tumor numbers (P=0.043), and the immunohistochemical expression of NSE (P=0.000) and Syn (P=0.037). Patients with metastatic HNETs were demonstrated with a more decreased period of Progression-free Survival (PFS) and Overall survival (OS) than their primary HNETs counterparts (P<0.05). Conclusion: Primary HNETs cohort patients were more common with aggressive clinical presentation. The hard texture of tumor character, multifocality of tumor numbers, and the immunohistochemical expression of NSE and Syn were independent predictive factors. Patients who were pathologically diagnosed as the primary HNETs seemed to achieve a long-term survival.
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Affiliation(s)
- Yang Lv
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Cheng Huang
- Department of Hepatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Haizhou Xu
- Department of General Surgery, Nantong Second People's Hospital, Nantong, Jiangsu, China
| | - Xu Han
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Lei Zhang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Weilin Mao
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yuan Ji
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Dayong Jin
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wenhui Lou
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xuefeng Xu
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
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38
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Linhas R, Tente D, China N, Conde S, Barroso A. Subcutaneous metastasis of a pulmonary carcinoid tumor: A case report. Medicine (Baltimore) 2018; 97:e9415. [PMID: 29480829 PMCID: PMC5943869 DOI: 10.1097/md.0000000000009415] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2017] [Revised: 11/29/2017] [Accepted: 11/30/2017] [Indexed: 01/09/2023] Open
Abstract
RATIONALE Carcinoid tumors are derived from neuroendocrine cells and are most frequently found in the gastrointestinal tract and bronchopulmonary system. They are generally characterized by an indolent clinical course but may in some instances spread to regional lymph nodes or to distant sites. Subcutaneous metastases of carcinoid tumors are extremely rare; there are only few cases reported in the literature and the site of the primary tumor was mainly the gastrointestinal tract. Also, the diagnosis of this type of lesions many years after the surgical resection of the pulmonary carcinoid (PC) could be a challenge for clinicians. PATIENT CONCERNS A nonsmoker woman diagnosed with a atypical carcinoid stage IA2 maintained follow-up at our institution. Seven years later she incidentally detected a subcutaneous nodular lesion in the lumbar region. DIAGNOSES A positron emission tomography-computed tomography (PET/CT) was performed and showed pathological uptake of the refered lesion. An excisional biopsy was performed and with the support of immunohistochemistry the diagnosis of a subcutaneous metastasis from a pulmonary atypical carcinoid was made. INTERVENTIONS The patient initiated chemotherapy with carboplatin plus etoposide and complied 4 cycles of treatment. OUTCOMES She maintained tight follow-up at our center and for 12 months there were no signs of relapse. LESSONS This extremely rare case highlights the difficulties in the differential diagnosis and the importance of diagnostic tests as PET/CT and immunohistochemistry in the establishment of a diagnosis. Physicians should be aware of signs of skin metastasis from lung malignancies even if the prognosis is good or many years have passed since the surgical resection.
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Affiliation(s)
| | | | | | - Sara Conde
- Department of Pulmonology
- Multidisciplinary Unit of Thoracic Tumours, Centro Hospitalar Vila Nova de Gaia/Espinho, Vila Nova de Gaia, Portugal
| | - Ana Barroso
- Department of Pulmonology
- Multidisciplinary Unit of Thoracic Tumours, Centro Hospitalar Vila Nova de Gaia/Espinho, Vila Nova de Gaia, Portugal
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Abstract
Pathologists use immunohistochemistry is their day-to-day practices to assist in distinguishing site of origin of metastatic carcinomas. Here, the work-up is discussed neuroendocrine carcinomas, squamous cell carcinomas and adenocarcinomas with particular attention to tumor incident rates and predictive values of the best-performing immunohistochemical markers.
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Affiliation(s)
- Edward B Stelow
- Department of Pathology, University of Virginia, Charlottesville, VA, United States.
| | - Hadi Yaziji
- Vitro Molecular Laboratories, Miami, FL, United States
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40
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Wang HL, Kim CJ, Koo J, Zhou W, Choi EK, Arcega R, Chen ZE, Wang H, Zhang L, Lin F. Practical Immunohistochemistry in Neoplastic Pathology of the Gastrointestinal Tract, Liver, Biliary Tract, and Pancreas. Arch Pathol Lab Med 2017; 141:1155-1180. [PMID: 28854347 DOI: 10.5858/arpa.2016-0489-ra] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
CONTEXT - Immunomarkers with diagnostic, therapeutic, or prognostic values have been increasingly used to maximize the benefits of clinical management of patients with neoplastic diseases of the gastrointestinal tract, liver, biliary tract, and pancreas. OBJECTIVES - To review the characteristics of immunomarkers that are commonly used in surgical pathology practice for neoplasms of the gastrointestinal tract, liver, biliary tract, and pancreas, and to summarize the clinical usefulness of immunomarkers that have been discovered in recent years in these fields. DATA SOURCES - Data sources include literature review, authors' research data, and personal practice experience. CONCLUSIONS - Immunohistochemistry is an indispensable tool for the accurate diagnosis of neoplastic diseases of the gastrointestinal tract, liver, biliary tract, and pancreas. Useful immunomarkers are available to help distinguish malignant neoplasms from benign conditions, determine organ origins, and subclassify neoplasms that are morphologically and biologically heterogeneous. Specific immunomarkers are also available to help guide patient treatment and assess disease aggressiveness, which are keys to the success of personalized medicine. Pathologists will continue to play a critical role in the discovery, validation, and application of new biomarkers, which will ultimately improve patient care.
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41
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Immunohistochemical Characterization of the Origins of Metastatic Well-differentiated Neuroendocrine Tumors to the Liver. Am J Surg Pathol 2017; 41:915-922. [PMID: 28498280 DOI: 10.1097/pas.0000000000000876] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Metastatic neoplasms of unknown primary site pose a major challenge to patient management. As targeted therapies are now being tailored to neuroendocrine tumors (NETs) of different primary sites, identifying the origin of metastatic NETs has become increasingly important. Compared with more extensive efforts on metastatic adenocarcinomas of unknown primary, the literature on metastatic NETs (often to the liver) is relatively sparse and most studies are based on primary tumors. We sought to study metastatic well-differentiated NETs to the liver to identify markers that predict the site of origin. Eighty-five metastatic NETs to the liver were retrieved from the pathology archive. The primary sites were determined based on either pathologic review of the primary tumors (in most cases) or radiologic/clinical findings. Immunohistochemical labeling for TTF1, CDX2, ISL1, NKX2.2, and PDX1 was performed on either tissue microarrays or whole sections. The primary sites of the NETs in the study cohort included: pancreas (35%), small intestine (32%), rectum (8%), stomach (2%), bile duct (1%), lung (9%), and unknown primary (12%). We found predominant expression of TTF1 in lung carcinoid (63%), CDX2 in small intestinal (89%) and ISL1 in pancreatic NETs (77%), respectively. NKX2.2 was mainly expressed in NETs of the digestive organs. PDX1 was detected in a small percentage of pancreatic, small intestinal and the single bile duct NET. There was no statistically significant association between tumor grade (World Health Organization G1 vs. G2) and the expression of any of the above markers. The 3-marker panel (TTF1, CDX2, and ISL1) had sensitivities of 81%, 89%, and 63%, specificities of 100%, 94%, and 100%, positive predictive values of 100%, 89%, and 100%, and negative predictive values of 84%, 94%, and 96% in separating metastatic NETs into 3 major primary sites: pancreas/rectum, small intestine, and lung, respectively, with an overall accuracy of 82%. Furthermore, this panel predicted a primary site for 6 of the 10 NETs of unknown primary, which reduced the NETs of unknown primary from 12% to 5%. Thus, through immunohistochemical study of a large series of metastatic NETs to the liver, we have demonstrated the utility of a 3-marker panel for the identification of one or more potential primary sites of most metastatic NETs, which could provide practical guidance in patient management.
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42
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Iwata R, Maruyama M, Ito T, Nakano Y, Kanemura Y, Koike T, Oe S, Yoshimura K, Nonaka M, Nomura S, Sugimoto T, Yamada H, Asai A. Establishment of a tumor sphere cell line from a metastatic brain neuroendocrine tumor. Med Mol Morphol 2017; 50:211-219. [PMID: 28516286 DOI: 10.1007/s00795-017-0160-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Accepted: 05/09/2017] [Indexed: 02/07/2023]
Abstract
Neuroendocrine tumors are rare, and little is known about the existence of cancer stem cells in this disease. Identification of the tumorigenic population will contribute to the development of effective therapies targeting neuroendocrine tumors. Surgically resected brain metastases from a primary neuroendocrine tumor of unknown origin were dissociated and cultured in serum-free neurosphere medium. Stem cell properties, including self-renewal, differentiation potential, and stem cell marker expression, were examined. Tumor formation was evaluated using intracranial xenograft models. The effect of temozolomide was measured in vitro by cell viability assays. We established the neuroendocrine tumor sphere cell line ANI-27S, which displayed stable exponential growth, virtually unlimited expansion in vitro, and expression of stem-cell markers such as CD133, nestin, Sox2, and aldehyde dehydrogenase. FBS-induced differentiation decreased Sox2 and nestin expression. On the basis of real-time PCR, ANI-27S cells expressed the neuroendocrine markers synaptophysin and chromogranin A. Intracranial xenotransplanted brain tumors recapitulated the original patient tumor and temozolomide exhibited cytotoxic effects on tumor sphere cells. For the first time, we demonstrated the presence of a sphere-forming, stem cell-like population in brain metastases from a primary neuroendocrine tumor. We also demonstrated the potential therapeutic effects of temozolomide for this disease.
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Affiliation(s)
- Ryoichi Iwata
- Department of Neurosurgery, Kansai Medical University, Hirakata, Japan
| | - Masato Maruyama
- Department of Anatomy and Brain Science, Kansai Medical University, Hirakata, Japan
| | - Tomoki Ito
- First Department of Internal Medicine, Kansai Medical University, Hirakata, Japan
| | - Yosuke Nakano
- Department of Anatomy and Brain Science, Kansai Medical University, Hirakata, Japan
| | - Yonehiro Kanemura
- Division of Regenerative Medicine, Institute for Clinical Research, Osaka National Hospital, National Hospital Organization, Osaka, Japan
| | - Taro Koike
- Department of Anatomy and Cell Science, Kansai Medical University, Hirakata, Japan
| | - Souichi Oe
- Department of Anatomy and Cell Science, Kansai Medical University, Hirakata, Japan
| | | | - Masahiro Nonaka
- Department of Neurosurgery, Kansai Medical University, Hirakata, Japan
| | - Shosaku Nomura
- First Department of Internal Medicine, Kansai Medical University, Hirakata, Japan
| | - Tetsuo Sugimoto
- Department of Anatomy and Brain Science, Kansai Medical University, Hirakata, Japan
| | - Hisao Yamada
- Department of Anatomy and Cell Science, Kansai Medical University, Hirakata, Japan
| | - Akio Asai
- Department of Neurosurgery, Kansai Medical University, Hirakata, Japan.
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43
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Hissong E, Rao R. Pneumocytoma (sclerosing hemangioma), a potential pitfall. Diagn Cytopathol 2017; 45:744-749. [PMID: 28398699 DOI: 10.1002/dc.23720] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Revised: 03/15/2017] [Accepted: 03/24/2017] [Indexed: 11/07/2022]
Abstract
Pneumocytoma is an uncommon benign tumor of the lung, derived from primitive respiratory epithelium, with a predilection for middle-aged females. A single, well-circumscribed mass is commonly identified on imaging, necessitating pathologic evaluation for further assessment. Fine-needle aspiration cytology is a minimally invasive and cost-effective method that can be utilized in the diagnosis of these lesions. Yet, distinction of pneumocytoma from other entities such as well-differentiated adenocarcinoma or carcinoid tumor can be quite challenging. Herein, we describe a case initially misdiagnosed as lung adenocarcinoma on FNA that was proven to be pneumocytoma on subsequent resection. This report highlights the importance of recognizing key cytologic features of pneumocytoma, namely the papillary architecture, dual cell population, and the hemorrhagic background with foamy macrophages, among others. An accurate preoperative diagnosis of this entity provides optimal patient management, as conservative surgical excision is curative. Diagn. Cytopathol. 2017;45:744-749. © 2017 Wiley Periodicals, Inc.
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Affiliation(s)
- Erika Hissong
- Department of Pathology & Laboratory Medicine, Papanicolaou Cytology Laboratory, New York-Presbyterian Hospital, Weill Cornell Medical College, New York
| | - Rema Rao
- Department of Pathology & Laboratory Medicine, Papanicolaou Cytology Laboratory, New York-Presbyterian Hospital, Weill Cornell Medical College, New York
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44
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Role of minimal panel immunostaining in accurate diagnosis of lung cancer using small biopsies. EGYPTIAN JOURNAL OF CHEST DISEASES AND TUBERCULOSIS 2017. [DOI: 10.1016/j.ejcdt.2016.10.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
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45
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Chandler CM, Lin X. Cytomorphology of metastatic pituitary carcinoma to the bone. Diagn Cytopathol 2017; 45:645-650. [PMID: 28267302 DOI: 10.1002/dc.23702] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Revised: 01/09/2017] [Accepted: 02/16/2017] [Indexed: 11/10/2022]
Abstract
Metastatic pituitary carcinoma to bone is rare. In this report, we present a case of a 59-year-old female with recurrent pituitary adenoma of the sparsely granulated somatotroph subtype with metastasis to a few bony sites 10 years later. Needle core biopsy (NCB) with touch preparations was performed on a 5 mm lesion in left ilium. Diff-Quik stained NCB touch preparation slides showed a few loosely cohesive epithelial polygonal cells that were arranged in nests or acini, or singly, had scant vacuolated cytoplasm and eccentrically located round nuclei (plasmacytoid) with slight nuclear pleomorphism, fine granular chromatin, conspicuous nucleoli, and smooth nuclear membrane. Trilineage hematopoietic cells of bone marrow were also appreciated in the background. H&E stained core sections showed fragments of bone and bone marrow with nests of bland epithelial cells with similar cytomorphology as seen in NCB touch preparation slides. The tumor cells were immunoreactive for juxtanuclear dot-like staining of pan-cytokeratin (CAM 5.2 and AE1/AE3) (a specific feature), neuroendocrine markers (CD56, synaptophysin, and chromogranin. Additionally, scattered cells were immunoreactive for growth hormone. Molecular test showed that tumor cells were negative for the promoter methylation of O-6-Methylguanine-DNA Methyltransferase (MGMT). Final diagnosis of metastatic pituitary carcinoma was rendered. Morphology of metastatic pituitary carcinoma, its differential, clinical presentation and treatment were discussed. Diagn. Cytopathol. 2017;45:645-650. © 2017 Wiley Periodicals, Inc.
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Affiliation(s)
| | - Xiaoqi Lin
- Department of Pathology, Northwestern University, Chicago, Illinois
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46
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Wang J, Trivedi P, El-Bahrawy M. Positivity rate of TTF-1 on immunohistochemistry in pancreatic neuroendocrine tumors. Pathol Int 2016; 66:708-709. [PMID: 27862649 DOI: 10.1111/pin.12473] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Revised: 08/18/2016] [Accepted: 10/07/2016] [Indexed: 01/04/2023]
Affiliation(s)
- Jayson Wang
- Department of Histopathology, Imperial College London, UK.,Department of Cellular Pathology, St George's Hospital NHS Trust, UK
| | | | - Mona El-Bahrawy
- Department of Histopathology, Imperial College London, UK.,Department of Pathology, Faculty of Medicine, University of Alexandria, Egypt
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47
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Duan K, Mete O. Algorithmic approach to neuroendocrine tumors in targeted biopsies: Practical applications of immunohistochemical markers. Cancer Cytopathol 2016; 124:871-884. [DOI: 10.1002/cncy.21765] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2016] [Accepted: 06/27/2016] [Indexed: 01/19/2023]
Affiliation(s)
- Kai Duan
- Department of Pathology; University Health Network; Toronto Ontario Canada
- Department of Laboratory Medicine and Pathobiology; University of Toronto; Toronto Ontario Canada
| | - Ozgur Mete
- Department of Pathology; University Health Network; Toronto Ontario Canada
- Department of Laboratory Medicine and Pathobiology; University of Toronto; Toronto Ontario Canada
- Endocrine Oncology Site Group, Princess Margaret Cancer Centre; Toronto Ontario Canada
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48
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Pulmonary Neuroendocrine Tumors: Part I. Spectrum and Characteristics of Tumors. J Bronchology Interv Pulmonol 2016; 22:267-73. [PMID: 26165900 DOI: 10.1097/lbr.0000000000000157] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Pulmonary neuroendocrine tumors arise from Kulchitzky cells of the bronchial mucosa and include typical carcinoid, atypical carcinoid, large cell neuroendocrine carcinoma, and small cell lung cancer. These tumors have a variable growth rate that determines their presentation and prognosis. Typical carcinoid has the lowest growth rate and better prognosis; in contrast, small cell lung cancer is an aggressive tumor with a very poor prognosis. Although there are some overlapping histologic features between these tumors, clinical, imaging, and immunohistochemical markers are useful in the differentiation of pulmonary neuroendocrine tumors. The treatment options differ on the basis of histologic characteristics. In this article, we aim to describe the spectrum of neuroendocrine tumors of the lung, except for small cell lung cancer, and their clinical, pathologic, and imaging findings, with a focus on treatment options.
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49
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Pavel M, O'Toole D, Costa F, Capdevila J, Gross D, Kianmanesh R, Krenning E, Knigge U, Salazar R, Pape UF, Öberg K. ENETS Consensus Guidelines Update for the Management of Distant Metastatic Disease of Intestinal, Pancreatic, Bronchial Neuroendocrine Neoplasms (NEN) and NEN of Unknown Primary Site. Neuroendocrinology 2016; 103:172-85. [PMID: 26731013 DOI: 10.1159/000443167] [Citation(s) in RCA: 728] [Impact Index Per Article: 80.9] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- M Pavel
- Charite Virchow Klinikum, Berlin, Germany
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50
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Kandalaft PL, Gown AM. Practical Applications in Immunohistochemistry: Carcinomas of Unknown Primary Site. Arch Pathol Lab Med 2015; 140:508-23. [PMID: 26457625 DOI: 10.5858/arpa.2015-0173-cp] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT -Identification of the site of origin of carcinoma of unknown primary using immunohistochemistry is a frequent requirement of anatomic pathologists. Diagnostic accuracy is crucial, particularly in the current era of targeted therapies and smaller sample sizes. OBJECTIVES -To provide practical guidance and suggestions for classifying carcinoma of unknown primary using both proven and new antibodies, as well as targeting panels based on integration of morphologic and clinical features. DATA SOURCES -Literature review, the authors' practice experience, and authors' research. CONCLUSIONS -With well-performed and interpreted immunohistochemistry panels, anatomic pathologists can successfully identify the site of origin of carcinoma of unknown primary. It is crucial to understand not only the diagnostic uses of the many available antibodies but also the potential limits and pitfalls.
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Affiliation(s)
- Patricia L Kandalaft
- Department of Immunohistochemistry and Anatomic Services, Pacific Pathology Partners, Seattle, Washington (Dr Kandalaft); PhenoPath Laboratories, Seattle (Dr Gown); and Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada (Dr Gown)
| | - Allen M Gown
- Department of Immunohistochemistry and Anatomic Services, Pacific Pathology Partners, Seattle, Washington (Dr Kandalaft); PhenoPath Laboratories, Seattle (Dr Gown); and Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada (Dr Gown)
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