Publications by authors named "Jean Marc Dumollard"

60 Publications

The Immune Microenvironment of Chordomas: An Immunohistochemical Analysis.

Cancers (Basel) 2021 Jul 2;13(13). Epub 2021 Jul 2.

Pathology Department, University Hospital of Saint-Etienne, 42055 Saint-Etienne, France.

Chordomas are rare sarcomas that are usually treated by surgery and/or radiotherapy since these are chemo-resistant tumors, but immunotherapy could be a possible option for chordoma patients. However, few reports investigating the composition of the chordoma immune microenvironment exist. We immunohistochemically studied 81 chordomas regarding their immune microenvironment factors and compared them with clinicopathological data. Macrophages and CD4 cells were the most prominent inflammatory cell populations, followed by CD8 T cells, while CD20 B cells and high endothelial venules (MECA-79+) were less frequently found. PD-L1 (22C3) expression by inflammatory cells was found in 21 (26%) tumors and was associated with a larger tumor size. None of the cases showed the expression of PD-L1 by tumor cells. Survival analysis showed that younger patients had a better overall survival. Considering the immunohistochemical factors studied, higher CD8, the presence of PD-L1+ immune cells, and higher vascular density were adverse prognostic factors, but in multivariate analysis, only PD-L1+ immune cells retained prognostic significance. To conclude, chordoma tumor cells do not express PD-L1, but PD-L1+ immune cells seem to play a negative prognostic role, supporting the need for further studies in this field and the possible beneficial role of immunotherapy in these patients.
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http://dx.doi.org/10.3390/cancers13133335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268246PMC
July 2021

Immunohistochemical analysis of L1 cell adhesion molecule and high endothelial venules in breast cancer brain metastasis.

Pathol Res Pract 2021 Jul 13;223:153484. Epub 2021 May 13.

Pathology Department, University Hospital of Saint-Etienne, France.

Background: The vasculature is a crucial factor in tumor development. Vascular co-option achieved by the L1 cell adhesion molecule (L1CAM) and lymphocyte recruitment inside tumors by high endothelial venules (HEVs) are important prognostic factors in primary breast cancer. Their status in breast cancer brain metastasis is unknown.

Aim Of The Study: To explore the status of L1CAMs and HEVs in this tumor compartment.

Material And Methods: Thirty resected breast cancer brain metastases were immunohistochemically studied for L1CAM and MECA-79, an HEV marker. Clinicopathological factors were recorded.

Results: Age at brain metastasis diagnosis ranged from 37 to 80 years (median 55). The time to brain metastasis development after primary tumor diagnosis ranged from 12 to 187 months (median 57). Median overall survival after brain metastasis diagnosis was 29 months. None of the tumors expressed the factors studied.

Conclusion: L1CAM and high endothelial venules are not found in breast cancer brain metastasis.
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http://dx.doi.org/10.1016/j.prp.2021.153484DOI Listing
July 2021

STAT6: A review of a signaling pathway implicated in various diseases with a special emphasis in its usefulness in pathology.

Pathol Res Pract 2021 Jul 11;223:153477. Epub 2021 May 11.

Pathology Department, University Hospital of Saint-Etienne, France.

Signal Transducer and Activator of Transcription 6 (STAT6), belonging to a family of seven similar members is primarily stimulated by interleukin(IL)-4 and IL-13, and acts as a T helper type 2 (Th2)-inducing factor. Thus, it is implicated in the pathophysiology of various allergic conditions, such as asthma, atopic dermatitis, eosinophilic esophagitis and food allergies, but also in tumor microenvironment regulation. Furthermore, certain forms of lymphomas, notably the Hodgkin lymphoma group, the primary mediastinal and primary central nervous system lymphoma, as well as some follicular and T cell lymphomas are associated with dysregulation of the STAT6 pathway. STAT6 immunohistochemical expression also serves as a surrogate marker in the diagnosis of solitary fibrous tumor, despite not directly responsible for the tumorigenic effect. These pathophysiological implications of the STAT6 pathway, its diagnostic or prognostic role in pathology, as well its immunohistochemical detection with different antibodies will be discussed in this review.
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http://dx.doi.org/10.1016/j.prp.2021.153477DOI Listing
July 2021

Patterns of brachyury expression in chordomas.

Ann Diagn Pathol 2021 Aug 10;53:151760. Epub 2021 May 10.

Pathology Departments, University Hospital of Saint-Etienne, France. Electronic address:

Introduction: Chordomas are rare malignant midline tumors, presumed to arise from notochordal remnants. This was further suggested by the discovery of the brachyury in chordomas pathogenesis. Its immunohistochemical expression has become the principal adjunct in the diagnosis of chordomas. However, studies about brachyury expression in chordomas are not fully comparable, mainly because they use different primary antibodies. Thus, the aim of this study is to investigate the expression of brachyury expression in a series of chordomas in conjunction to clinicopathological characteristics and to review the relevant literature providing all the details needed in the immunohistochemical study of brachyury.

Materials And Methods: This is a retrospective study of 62 chordomas, diagnosed over a 22-year period. No dedifferentiated or poorly differentiated cases were included. A monoclonal primary antibody (clone A-4) was used and brachyury expression was evaluated by the H-score. Clinicopathological parameters studied were age, sex, tumor localization, decalcification status and tissue age. Fetal notochords were used for comparison.

Results: Mean H-score of nuclear brachyury expression was 129.8. The tissue age significantly influenced brachyury expression, the older samples expressing less brachyury. Decalcification demonstrated a trend to weaken brachyury expression. Clinical characteristics were not correlated with the patterns of brachyury expression. Notochords were negative. Literature review reveals several polyclonal antibodies used and a positivity of 75%-100% in chordomas with even more variable results in notochords.

Conclusion: In chordomas, as in other tumor types, an uniformization of studies about brachyury expression is needed, by considering the clone used, and the decalcification and the age of the sample, given the growing importance of brachyury in diagnosis and therapeutic steps.
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http://dx.doi.org/10.1016/j.anndiagpath.2021.151760DOI Listing
August 2021

Proteomic Imaging of Vestibular Schwannomas and Normal Nerves. Histopathologic Correlations.

Otol Neurotol 2021 May 10. Epub 2021 May 10.

Department of Otolaryngology-Head & Neck Surgery, University Medical Center of Saint-Etienne and Jean Monnet University, Saint-Etienne Clinatec Platform of CEA-LETI Laboratory BrainTech Laboratory Inserm U1205 and University Medical Center of Grenoble Department of Pathology, Cytology, and Tumor Banking (CRB42-TTK), University Medical Center of Saint-Etienne and Jean Monnet University, Saint-Etienne Medicalps Laboratory, Grenoble, France.

Objectives: Proteomic analysis of vestibular schwannoma (VS), non-vestibular schwannoma (NVS), and normal nerve (NN) using mass spectrometry and imaging of matrix assisted laser desorption ionization-time of flight (MALDI-TOF).

Methods: Retrospective, qualitative, and descriptive study on VS, NVS, and NN. Samples were provided by our Tumor Bank. They were analyzed histologically then sprayed by acid matrix. The laser beam of MALDI performed desorption-ionization of the sample. A mass spectrogram (MS) was drawn depending on time of flight of ionized peptides, and MALDI-imaging was obtained which is a summation color spectrum depending on sample's peptide content. The slice was reexamined histologically and results compared with MALDI-imaging.

Results: Fifty schwannomas were sampled, of which 27 exploitable: 22 VS (17 Antoni type A and five type B) and five NVS (all Antoni type B). Eleven NN were analyzed. Among the 22 VS, near-total correlation between MALDI-imaging and pathology was found in two cases (9.1%), partial correlation in four (18.2%), and no correlation in 16 (72.7%); correlations were more frequent in VS of the Antoni type B. MS showed a peptide spike at 2,000 m/z in 7 (31.8%) and 5,000 m/z in 21 (95.5%). Among the five NVS, near-total correlation was found in three cases (60%), partial correlation in one (20%), and no correlation in one (20%). MS showed a peptide spike at 2,000 m/z in two (40%) and 5,000 m/z in all (100%). Among the 11 NN, near-total correlation was found in nine cases (81.8%), partial correlation in one (9.1%), and no correlation in one (9.1%). MS showed no peptide spike at 2,000 or 5,000 m/z. Behind homogeneous areas on histology, there was great heterogeneity on MALDI-imaging and MS, regarding VS and NVS, but not NN.

Conclusions: There was a lack of correlation between MALDI-imaging and pathology in VS (except Antoni type B) as compared with NVS and NN. The lack of correlation in VS of the type A as compared with type B VS and NVS could be attributed to the overexpression of degeneration-associated proteins/peptides in VS of the type B as well as NVS that are better correlated with histologic findings. The two peptide spikes detected in schwannoma and not in NN opens up the prospect of tumor biomarkers identifiable by sequencing. The proteomic polymorphism found in VS and NVS was absent on histology which is a new morphologic characteristic of schwannoma. Further studies should be performed in the future to confirm the benefit and usefulness of the MALDI in the analysis of VS and NVS.
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http://dx.doi.org/10.1097/MAO.0000000000003179DOI Listing
May 2021

Autophagic Markers in Chordomas: Immunohistochemical Analysis and Comparison with the Immune Microenvironment of Chordoma Tissues.

Cancers (Basel) 2021 Apr 30;13(9). Epub 2021 Apr 30.

Pathology Department, University Hospital of Saint-Etienne, 42055 Saint-Etienne, France.

Chordomas are notably resistant to chemotherapy. One of the cytoprotective mechanisms implicated in chemoresistance is autophagy. There are indirect data that autophagy could be implicated in chordomas, but its presence has not been studied in chordoma tissues. Sixty-one (61) chordomas were immunohistochemically studied for autophagic markers and their expression was compared with the expression in notochords, clinicopathological data, as well as the tumor immune microenvironment. All chordomas strongly and diffusely expressed cytoplasmic p62 (sequestosome 1, SQSTM1/p62), whereas 16 (26.2%) tumors also showed nuclear p62 expression. LC3B (Microtubule-associated protein 1A/1B-light chain 3B) tumor cell expression was found in 44 (72.1%) tumors. Autophagy-related 16‑like 1 (ATG16L1) was also expressed by most tumors. All tumors expressed mannose-6-phosphate/insulin-like growth factor 2 receptor (M6PR/IGF2R). LC3B tumor cell expression was negatively associated with tumor size, while no other parameters, such as age, sex, localization, or survival, were associated with the immunohistochemical factors studied. LC3B immune cell expression showed a significant positive association with programmed death-ligand 1 (PD-L1)+ immune cells and with a higher vascular density. ATG16L1 expression was also positively associated with higher vascular density. Notochords ( = 5) showed different immunostaining with a very weak LC3B and M6PR expression, and no p62 expression. In contrast to normal notochords, autophagic factors such as LC3B and ATG16L1 are often present in chordomas, associated with a strong and diffuse expression of p62, suggesting a blocked autophagic flow. Furthermore, PD-L1+ immune cells also express LC3B, suggesting the need for further investigations between autophagy and the immune microenvironment.
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http://dx.doi.org/10.3390/cancers13092169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124629PMC
April 2021

Senescence, immune microenvironment, and vascularization in cardiac myxomas.

Cardiovasc Pathol 2021 May-Jun;52:107335. Epub 2021 Mar 21.

Pathology Department, University Hospital of Saint-Etienne, Saint-Priest-en-Jarez, France.

Aims: Cardiac myxomas are rare tumors of incompletely elucidated pathogenesis. The aim of this study is to explore the possible presence of a senescence phenotype in cardiac myxomas, associated with an inflammatory and vasculogenic tumor microenvironment.

Methods And Results: This is a retrospective study of 29 cardiac myxomas with immunohistochemical detection of various inflammatory, vascular, and senescence markers. We show that all myxomas contain tumor cells in senescence overexpressing p16, and a fraction of senescent endothelial cells. Macrophages are the principal inflammatory cell population, followed by cytotoxic T cells, with fewer plasma cells, mastocytes, and B lymphocytes. These populations are found in different intratumoral localizations. Larger tumor volume is associated with a lower percentage of myxoid matrix, higher cellularity, higher macrophage, and lower number of mast cells as well as higher PD-L1 expression by inflammatory cells. Higher vascular density is associated with higher percentage of B cells, a lower number of macrophages and higher number of mastocytes, and lower PD-L1 expression by inflammatory cells. Tumors with higher vascular density and higher cellularity show higher amounts of p16 senescent endothelial cells.

Conclusions: Myxoma tumor cells are in senescence and reside inside a tumor microenvironment with a distinct inflammatory profile rich in macrophages and cytotoxic T cells, and a rich vasculature, probably attributed to a senescence-associated secretory phenotype.
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http://dx.doi.org/10.1016/j.carpath.2021.107335DOI Listing
March 2021

High endothelial venules are present in pharyngeal and laryngeal carcinomas and they are associated with better prognosis.

Pathol Res Pract 2021 Apr 18;220:153392. Epub 2021 Feb 18.

Departments of Pathology, North Hospital, University Hospital of St-Etienne, France.

Background: Tumors lymphocytic infiltration has prognostic and predictive value. However, the mechanisms involved in lymphocyte recruitment remain poorly characterized. High endothelial venules (HEV) are blood vessels specialized in lymphocyte recruitment, recently showing prognostic significance in some types of cancer. Their implications in laryngeal or pharyngeal cancer is largely unknown.

Aim Of The Study: To investigate the possible presence of HEVs in head and neck cancer.

Material And Methods: Oropharyngeal (n = 61), hypopharyngeal (n = 53) and laryngeal (n = 21) squamous cell carcinomas were immunohistochemically studied with the MECA-79 antibody, which specifically recognizes HEVs. Histological and clinical factors were correlated with HEVs' presence.

Results: HEVs were present in 34% of tumors, showing significant correlations with oropharyngeal localization, higher lymphocytic response, lower tumor budding, lower T status, absence of distant metastases and better overall and progression-free survival.

Conclusion: HEVs represent an important prognostic factor in head and neck cancer.
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http://dx.doi.org/10.1016/j.prp.2021.153392DOI Listing
April 2021

INSM1 Expression in Chordomas.

Am J Clin Pathol 2021 Feb 25. Epub 2021 Feb 25.

Pathology Department, University Hospital of Saint-Etienne, Saint-Etienne, France.

Objectives: Chordomas are rare malignant tumors with a broad differential diagnosis, including chondrosarcomas and metastatic carcinomas. Recently, insulinoma-associated protein 1 (INSM1) has gained great interest regarding the diagnosis of neuroendocrine tumors but also extraskeletal myxoid chondrosarcomas. However, its expression in chordomas remains largely unknown.

Methods: We retrospectively examined 57 chordomas for INSM1 expression.

Results: INSM1 expression was found in only 5% of tumors.

Conclusions: This marker is rarely expressed in this type of tumor, raising questions about neuroendocrine differentiation.
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http://dx.doi.org/10.1093/ajcp/aqaa250DOI Listing
February 2021

Meningioma sampling: how much is enough for the accurate grading of atypical meningiomas?

Pathology 2021 Aug 20;53(5):602-607. Epub 2021 Feb 20.

University Hospital of Saint Etienne, North Hospital, Department of Pathology, Saint Etienne, France; Corneal Graft Biology, Engineering, and Imaging Laboratory, BiiGC, EA2521, Federative Institute of Research in Sciences and Health Engineering, Faculty of Medicine, Jean Monnet University, Saint-Etienne, France. Electronic address:

Meningioma grading relies on several pathological criteria (brain invasion, mitotic count, sheeting, small cell foci, necrosis, macronucleoli and hypercellularity) and histopathological subtypes. Regardless of histopathological subtype, the presence of these pathological parameters can be focally present and not present on each slide of a meningioma. We performed (1) a retrospective work comparing the frequency of parameters used for meningioma grading between two periods with different sampling techniques, and (2) we calculated the probability of presence of each criterion on resected meningiomas entirely processed included and examined. First, we compared two time periods: between 2002-2008 where meningiomas were not all entirely sampled, and between 2012-2018 where all meningiomas were entirely sampled. The frequency of tumour grades was not significantly different between the two periods (p=0.17). Mitosis ≥4/1.6mm, small cell foci, macronucleoli and hypercellularity were more frequently found when meningiomas were entirely sampled (p<0.05). Second, we focused on 59 grade 2 meningiomas entirely sampled to highlight the distribution of histopathological parameters used for meningioma grading. We have shown that a correct grading of more than 95% of meningiomas can be achieved when at least six slides are examined. Our work suggests that meningioma sampling might be an issue and the sampling system must be specified in research works on grading.
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http://dx.doi.org/10.1016/j.pathol.2020.10.024DOI Listing
August 2021

The transcriptional factors CDX2 and FOXA1 in chordomas.

Pathol Res Pract 2020 Nov 12;216(11):153160. Epub 2020 Aug 12.

Pathology Department, University Hospital of Saint-Etienne, France. Electronic address:

Chordomas are rare osseous tumors believed to originate from notochordal remnants through brachyury activation. CDX2 and FOXA1 are both induced by brachyury, but their expression has not been studied in chordomas. We retrospectively studied the immunohistochemical expression of these two factors in 57 chordomas, finding that CDX2 is not expressed in these tumors. FOXA1 expression was found in 7 (12.3%) tumors. No association of FOXA1 expression with clinical factors was found. Thus, CDX2 expression is not a feature of chordomas, while a limited expression of FOXA1 is seen.
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http://dx.doi.org/10.1016/j.prp.2020.153160DOI Listing
November 2020

Maxillary Ameloblastoma: A Review With Clinical, Histological and Prognostic Data of a Rare Tumor.

In Vivo 2020 Sep-Oct;34(5):2249-2258

Department of Pathology and Otorhinolaryngology, University Hospital of Ioannina, Ioannina, Greece

Diagnosis of odontogenic tumors can be challenging due to their rarity and diverse morphology, but when arising near the tooth, the diagnosis could be suspected. When their location is not typical, like inside the paranasal sinuses, the diagnosis is less easy. Maxillary ameloblastomas are exceedingly rare with only sparse information on their epidemiological, histological and genetic characteristics. The aim of this report is to thoroughly review the available literature in order to present the characteristics of this tumor. According to available data, maxillary ameloblastomas can occur in all ages but later than mandible ones, and everywhere within the maxillary region without necessarily having direct contact with the teeth. No sex preference has been shown. The most common histological patterns seen in this location are the follicular and plexiform ones. Maxillary ameloblastomas are locally aggressive neoplasms, thus therapy aims for excision including normal bone beyond the lesion. In contrast to mandible ameloblastomas, maxillary ones most commonly show mutations of the SMO gene. Furthermore, differential tumor diagnosis is thoroughly discussed in the present review.
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http://dx.doi.org/10.21873/invivo.12035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652510PMC
June 2021

Brain metastasis PD-L1 and CD8 expression is dependent on primary tumor type and its PD-L1 and CD8 status.

J Immunother Cancer 2020 08;8(2)

Pathology, University Hospital of Saint-Etienne, Saint-Etienne, France.

Background: Brain metastases (Bmets) are frequent; however, limited data exist on the efficacy of immunotherapy in these lesions. The aims of the study were to analyze the immunohistochemical expressions of programmed death ligand 1 (PD-L1) and CD8 in Bmets and to compare them with their expressions in paired primary tumors, as well as correlate the results with clinicopathological features.

Methods: This is a retrospective study of 233 patients with Bmets and 111 paired primaries. Clinical, histological, and molecular data were recorded and compared with the immunohistochemical results of PD-L1 and CD8 expressions. The statistical analysis included χ test, Cramer's V test, factorial analyses of variance, simple regression analysis, and Kaplan-Meier analysis with log-rank product limit estimation.

Results: PD-L1 expression was found in 23.6% of Bmets and in 29.0% of primary tumors with concordant expression between them in 75.5% of cases. Bmets PD-L1 expression was associated with primary tumor PD-L1 expression and the primary tumor type. Significant CD8 peritumoral expression was found in 68.6% of Bmets and in 87.7% of primary tumors. CD8 expression was concordant between primary and metastatic tumors in 73.3% of cases. Bmets CD8 expression was associated with primary tumor CD8 expression and primary tumor type. PD-L1 expression was associated with CD8 expression in both primary and metastatic tumors. The concordance between primary and metastatic tumor PD-L1 expression was independent of all factors studied. The concordance between primary and metastatic CD8 expressions was marginally associated to the time of Bmets development. No prognostic role for PD-L1 and CD8 expression in Bmets was found.

Conclusion: PD-L1 and CD8 Bmets expressions are associated with the primary tumor type and its PD-L1 and CD8 expressions. No factor predicts the discordance for PD-L1 expression, while time to Bmets development is associated with CD8 expression discordance.
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http://dx.doi.org/10.1136/jitc-2020-000597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454240PMC
August 2020

Chordomas: A review with emphasis on their pathophysiology, pathology, molecular biology, and genetics.

Pathol Res Pract 2020 Sep 29;216(9):153089. Epub 2020 Jun 29.

Pathology Department, University Hospital of Saint-Etienne, France.

Chordomas are uncommon, bone, axial, or (rarely) extra-axial tumors that are malignant and frequently recur but less commonly metastasize. They usually affect adults, with a very small proportion being pediatric tumors. For children, such tumors present a different biology, since they are more common as scull rather than sacral tumors, with aggressive histological features, including a loss of SMARCB1/INI1 and a dismal prognosis. Histologically, chordomas, believed to derive from notochordal tissue, characteristically show physaliphorous cells in a myxoid or chondroid matrix. Dedifferentiated and poorly differentiated forms can be observed. Moreover, a grading scale for chordomas has been proposed. Cytokeratin, EMA, S100, and brachyury are expressed by most chordomas. These are chemo-resistant tumors, for which surgical resection and/or radiotherapy are the treatments of choice. In this review, the histological, immunohistochemical, molecular, and clinical data of chordomas are discussed.
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http://dx.doi.org/10.1016/j.prp.2020.153089DOI Listing
September 2020

Histologic Findings of Uterine Niches.

Am J Clin Pathol 2020 10;154(5):645-655

Pathology Department, France.

Objectives: The disruption or defect of the myometrium in the uterine scar of a cesarean section (CS) has been known by various names, such as uterine niche, isthmocele, deficient uterine scar, scar pouch, or diverticulum. Symptomatology, risk factors for niche development, and available treatment modalities have been recently studied. However, the histologic features of this disease remain unknown.

Methods: The histologic features of eight uterine niches are thoroughly described and a summary of the most important aspects of the uterine niche literature is provided. Five cases of CS scars without niche formation are comparatively examined.

Results: Most uterine niches harbor endocervical mucosa, often cystically dilated and/or an atrophic or disorganized endometrial mucosa of lower uterine segment origin. Regenerative epithelial atypia and fibroblastic stromal reaction are frequent features. No granulomatous reaction, important inflammation, or hemorrhage is seen. CS scars without niche formation do not harbor endocervical mucosa or inclusion cysts, fibroblastic stroma, or regenerative atypia.

Conclusions: As more prospective studies of uterine niche development and treatment will be conducted, a detailed pathologic report with the criteria proposed herein can be designed.
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http://dx.doi.org/10.1093/ajcp/aqaa080DOI Listing
October 2020

Granular cell tumor a study of 42 cases and systemic review of the literature.

Pathol Res Pract 2020 Apr 12;216(4):152865. Epub 2020 Feb 12.

Department of Pathology, North Hospital, University Hospital of St-Etienne, France.

Background: Granular cell tumor (GCT) remains a diagnostic clinicopathologic problem because the exact frequency of its detailed morphological and clinical characteristics is unknown as most observations are collected from small series or isolated cases. Herein, our aim is to highlight the frequency of all clinicopathological characteristics of this rare tumor based in our series and the available medical (PubMed) literature.

Material And Methods: 42 cases were evaluated for: tissue layers involved by the tumor (in skin and mucosae), growth pattern, nuclear pleomorphism, mitotic index, necrosis, spindling, calcification, hyalinization, and pustule-ovoid bodies of Milian, as well as perineural and vascular invasion, and the presence of adjacent epithelium changes, and lymphocytes and eosinophils infiltration., Follow-up was analyzed. The tumors were subclassified into benign, atypical and malignant according to Fanburg-Smith criteria and into benign or GCT of uncertain malignant potential according to Nasser criteria. The same characteristics were analyzed for 1499 cases reviewed according to PRISMA guidelines.

Results: In the current series, the mean age at diagnosis was 45.8 years (range 6-69 years). Most patients were females (60 %) and the involved organs were by descending frequency: skin and subcutaneous tissue, bronchus, esophagus, breast, tongue, larynx, pharynx, gingiva, trachea, right colon, vulva, and hypopharynx. No recurrence or progression was seen, despite 32 cases were incompletely excised, with the exception of one malignant tumor. The growth pattern was either infiltrative (85.71 %) or well limited (7.14 %). Sixteen tumors had vesicular nuclei. Mitotic activity was found in two tumors. Lymphocytic infiltration was found in 14 tumors. Eosinophils were present in 6 cases. One GCT of the right colon showed extensive calcification and hyalinization. Perineural invasion was noted in 6 lesions. No vascular invasion was found. One tumor was clinically malignant and the patient died 2 years after diagnosis. Medical literature review showed similar results in terms of frequency of the reported clinical and morphological features. Among cases with available follow up, almost 20 % showed positive margins and of those 20 % developed local recurrence. According to the Fanburg-Smith criteria, 72 % would be benign, 17 % atypical and 11 % malignant tumors, while according to those of Nasser, 93 % would be benign and 7% of uncertain malignant potential. However, true malignancy, as affirmed by metastasis of GCT is found in almost 2.5 % of the cases.

Conclusion: GCT is a usually benign tumor, affecting any anatomic location. Necrosis and mitotic activity seem to be the most effective histologic criteria for detecting aggressive tumors, but the presence of metastasis (2.5 % of the cases) remains the most accepted definitive criterion for diagnosis of malignant GCT.
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http://dx.doi.org/10.1016/j.prp.2020.152865DOI Listing
April 2020

Cytoplasmic p16 Is Expressed in Normal Brown Fat and Hibernomas.

Int J Surg Pathol 2020 Aug 5;28(5):496-501. Epub 2020 Feb 5.

University Hospital of Ioannina, Ioannina, Greece.

White adipose tissue browning has emerged as a putative therapy of obesity, and studies in mice have shown that is implicated in white-to-brown transition. However, the role of product p16 has been never studied in human brown fat tissue. The aim of the study is to investigate the expression of p16 in normal brown fat and in hibernoma, a lipoma containing brown fat-like adipocytes. Ten normal brown fat tissues and 5 hibernomas were immunohistochemically studied for p16 expression. Nearby white adipose tissue was used for comparison. All brown fat and hibernomas specimens express p16 in a cytoplasmic manner. Neighboring white adipose tissue is negative for p16 expression. Thus, cytoplasmic p16 may be associated with fat tissue browning.
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http://dx.doi.org/10.1177/1066896920904423DOI Listing
August 2020

Laryngeal Tumor Microenvironment.

Adv Exp Med Biol 2020 ;1296:79-101

Pathology Department, North Hospital, University Hospital of Saint-Etienne, Saint-Priest-en-Jarez, France.

Tumor microenvironment has been extensively studied in various forms of cancer, like head and neck squamous cell carcinoma. Progress in the field revealed the prognostic significance of the various components of the tumor's ecosystem and led to changes in treatment strategies, like including immunotherapy as an important tool. In this chapter, the microenvironment of tumors with a special interest in laryngeal cancer will be described. The issues assessed include innate immune response factors, like neutrophils, neutrophil extracellular traps (NET), platelets, macrophages M1 or M2, dendritic cells, natural killer cells, as well as adaptive immunity aspects, like cytotoxic, exhausted and regulatory T cells, and immune checkpoints (PD-1/PD-L1, CTLA4). Also, stroma-associated factors, like fibroblasts, fibrosis, extracellular matrix, vessels and perineural invasion, hypoxia and cancer metabolism aspects, as well as the pre-metastatic niche, exosomes and cGAS-STING, are reviewed.
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http://dx.doi.org/10.1007/978-3-030-59038-3_5DOI Listing
July 2021

Correlation Between Semiquantitative Metabolic Parameters After PET/CT and Histologic Prognostic Factors in Laryngeal and Pharyngeal Carcinoma.

Head Neck Pathol 2020 Sep 23;14(3):724-732. Epub 2019 Dec 23.

Department of Pathology, University Hospital of Saint-Etienne, 42055, CEDEX2 Saint-Étienne, France.

Positron emission tomography/computed tomography (PET/CT) has shown prognostic significance in head and neck cancer patients. The underlying pathologic features that could explain the mechanisms associated with this observation are not clear. To analyze the correlation between 18-F-fluoro-2-deoxy-D-glucose (18F-FDG) uptake assessed by PET/CT in head and neck cancer and histopathologic prognostic factors. Ninety-nine patients with laryngeal and pharyngeal squamous cell carcinoma were retrospectively reviewed for pretreatment PET/CT measurements, namely standardized uptake value (SUV), metabolic tumor volume (MTV), and total lesion glycolysis (TLG). The corresponding histologic material was evaluated for tumor stroma-related prognostic factors such as the amount and type of stroma, lymphocytic response, tumor budding activity, and size of tumor cell nests in the tumor core area and tumor front. TLG and MTV were associated with tumor localization, as they were higher in oropharyngeal tumors. These values were also associated with tumor cell nest size in the tumor core with higher values corresponding to tumors with smaller nests. MTV40% was marginally associated with fibroblastic stroma type and higher budding activity. SUVmax was not associated with the histological factors in the whole sample, but higher values trended with higher tumor budding activity and stroma-rich tumors of the oropharynx. 18F-FDG PET measurements in head and neck squamous cell carcinomas are associated with prognostic histopathologic factors and suggest a possible correlation of glucose metabolism to epithelial-to-mesenchymal transition.
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http://dx.doi.org/10.1007/s12105-019-01116-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413956PMC
September 2020

Gene Expression Comparison Between the Primary Tumor and its Lymph Node Metastasis in Head and Neck Squamous Cell Carcinoma: A Pilot Study.

Cancer Genomics Proteomics 2019 May-Jun;16(3):155-161

Department of Pathology, North Hospital, University Hospital of St-Etienne, Saint-Étienne, France.

Background/aim: In metastatic head and neck squamous cell carcinoma (HNSCC) the metastatic tumor does not always keep the same gene expression profile as the parental tumor, which may influence the course of the disease. The aim of this study was to compare the expression of genes implicated in HNSCC carcinogenesis between the primary tumor and the corresponding lymph node metastasis.

Materials And Methods: Eighteen HNSCC, their corresponding node metastases and non-neoplastic tissues were studied by RT-qPCR for the expression of EGFR, VEGF, claudin7, maspin, survivin and SCCA. The levels of expression were correlated with histological characteristics and patients' prognosis.

Results: All genes except for survivin displayed different expression in node metastasis compared to the primary tumor. The expression of EGFR, survivin, maspin, and claudin7 in node metastasis and SSCA in the primary tumor affected the prognosis. SCCA expression is associated with the expression of claudin7 and maspin. P16-positive tumors expressed low levels of VEGF and SCCA, while keratinizing tumors over-expressed VEGF.

Conclusion: Differential gene expression levels in node metastases compared to the primary tumor is linked to the prognosis of HNSCC patients. The histological/immunohisto-chemical characteristics of the tumor are associated with these genes expression changes.
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http://dx.doi.org/10.21873/cgp.20121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6542642PMC
September 2019

Prognostic significance of tumor budding, tumor-stroma ratio, cell nests size, and stroma type in laryngeal and pharyngeal squamous cell carcinomas.

Head Neck 2019 06 8;41(6):1918-1927. Epub 2019 Jan 8.

Department of Pathology, North Hospital, University Hospital of Saint-Etienne, Saint-Etienne, France.

Background: Despite immune microenvironment of head and neck squamous cell carcinoma (HNSCC) has been studied, there are no sufficient data on the role of tumor stroma factors. The aim of the study was to explore the prognostic and predictive role of these factors in a large series of HNSCC.

Methods: This is a retrospective study of 266 patients with laryngeal and pharyngeal SCC. Clinical data were correlated with the following histological parameters: tumor-stroma ratio (TSR), tumor budding activity (BA), cell nests size (CNS), and stroma type.

Results: Stroma-rich tumors, tumor budding, smaller CNS at core and front area, and fibroblastic stroma type, were all adverse prognostic factors (P < 0.0001, 0.001, 0.003, 0.001, 0.007, respectively). Stroma-poor tumors and with larger CNS showed good response to induction chemotherapy (P = 0.009 and 0.02, respectively).

Conclusions: TSR, tumor budding, CNS, and stroma type are important prognostic and predictive factors in laryngeal and pharyngeal SCC.
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http://dx.doi.org/10.1002/hed.25629DOI Listing
June 2019

Impact of thyroid surgery volume and pathologic detection on risk of thyroid cancer: A geographical analysis in the Rhône-Alpes region of France.

Clin Endocrinol (Oxf) 2018 12 11;89(6):824-833. Epub 2018 Sep 11.

Hospices Civils de Lyon, Registre Rhône Alpin des Cancers Thyroïdiens - Centre de Médecine Nucléaire et Fédération d'Endocrinologie, Groupement Hospitalier Est, Lyon, France.

Objective: To investigate the impact of the volume of thyroid surgery and pathologic detection on the risk of thyroid cancer.

Methods: We investigated the influence of the volume of thyroid surgery in a first study that included 23 384 thyroid surgeries and 5302 thyroid cancers collected between 2008 and 2013. Standardized incidence ratios (SIRs) and thyroid intervention rates (STIRs) were used as indicators of cancer risk and surgery volume, respectively. The influence of pathologic detection, using the number of cuts per gram of tissue as the indicator, was studied in a second study that included 1257 thyroid specimens, collected in 2014.

Results: We found departmental variations in SIRs and a significant effect of the STIR on the SIR (men, P = 0.0008; women, P < 0.0001). A 1/100 000 increase in the STIR resulted in a 3% and 1.3% increase in the SIR in men and women, respectively. This effect was greatest for microcancers and absent for tumours >4 cm. The risk of cancer diagnosis was significantly associated with the number of cuts per gram of tissue (OR 6.1, P < 0.001), and was greater for total thyroidectomy than for lobectomy (P = 0.014) and when FNA cytology had been preoperatively performed (P < 0.001). The prevalence of incidental microcancers was highest in the centres performing the highest number of cuts per gram.

Conclusions: The risk of thyroid cancer, particularly microcancer, is related to the volume of surgery and to the level of pathologist scrutiny. Both factors contribute to the increase in overdiagnosis. This further advocates for appropriate selection of patients for thyroid surgery.
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http://dx.doi.org/10.1111/cen.13833DOI Listing
December 2018

Storage of Porcine Cornea in an Innovative Bioreactor.

Invest Ophthalmol Vis Sci 2017 11;58(13):5907-5917

Corneal Graft Biology, Engineering and Imaging Laboratory, BiiGC, EA2521, Faculty of Medicine, Jean Monnet University, Saint-Etienne, France.

Purpose: To quantify cell survival and tissue structure preservation of porcine cornea stored in a bioreactor (BR) that recreates a transcorneal pressure gradient equivalent to intraocular pressure (IOP) and renews the medium.

Methods: A BR comprising endothelial and epithelial chambers was machined in a biocompatible material. The porcine cornea, securely held, separated the chambers. Medium flow and pressure inside the endothelial chamber were maintained by a peristaltic pump. In the epithelial chamber, the corneal surface was alternatively exposed to air and a specific medium. Two transparent windows allowed thickness measurement by optical coherence tomography without opening the BR. Porcine corneas stored in the BR-on (pressure 20 mm Hg, flow 5 μL/min, temperature 31°C) were compared with (1) BR-off (no pressure or flow); (2) organ culture; and (3) Petri dish with agar on the endothelial side. Epithelial and limbal structure and differentiation, corneal transparency and thickness, and endothelial viability were compared after 7 days of storage and with fresh corneas.

Results: Corneas stored in the BR-on were thinner and more transparent than those stored with the other methods. The BR-on preserved a stratified and differentiated (K3/K12+) corneal epithelium and undifferentiated basal limbal cells with stemness markers (K3/K12-; ABCB5, K14, p75+), as well as endothelial integrity.

Conclusions: By recreating equivalent IOP and medium renewal, the BR obtained unprecedented storage quality of porcine corneas and preserved their main epithelial, limbal, and endothelial characteristics.
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http://dx.doi.org/10.1167/iovs.17-22218DOI Listing
November 2017

FOXA1 in HPV associated carcinomas: Its expression in carcinomas of the head and neck and of the uterine cervix.

Exp Mol Pathol 2017 04 14;102(2):230-236. Epub 2017 Feb 14.

Department of Pathology, North Hospital, University Hospital of St-Etienne, France.

Background: FOXA1 is a major transcription factor involved in the action of human papilloma virus (HPV). However, it has been never studied in HPV-associated tumors.

Aim Of The Study: To investigate its expression in cervical and head and neck tumors.

Material And Methods: 63 cervical carcinomas/dysplasias and 152 head and neck squamous cell carcinomas (HNSCC) were immunohistochemically studied for the expression of FOXA1.

Results: 63.1% of cervical SCC and 40.7% of endocervical adenocarcinomas strongly expressed FOXA1. Most (90%) pre-invasive lesions (CIN3 and in situ adenocarcinomas) strongly expressed FOXA1 and this difference from invasive lesions was statistically significant (p=0.005). No association with clinicopathological factors was found. 51.3% of HNSCC expressed FOXA1. In these tumors, FOXA1 expression was associated with the non-keratinizing morphology but not with the HPV/p16 status neither other clinicopathological features. Of normal structures, salivary glands, endocervical glands and basal/parabasal cell layer of squamous epithelium of both uterine cervix and head and neck mucosa, all strongly expressed FOXA1.

Conclusion: FOXA1 is expressed by basal cells of squamous epithelium, pre-invasion lesions of the uterine cervix and the head/neck and almost half invasive cervical and head/neck carcinomas, supporting its possible implication in HPV pathogenesis.
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http://dx.doi.org/10.1016/j.yexmp.2017.02.010DOI Listing
April 2017

Prognostic impact of immune microenvironment in laryngeal and pharyngeal squamous cell carcinoma: Immune cell subtypes, immuno-suppressive pathways and clinicopathologic characteristics.

Oncotarget 2017 Mar;8(12):19310-19322

Department of Pathology, North Hospital, University Hospital of St-Etienne, St-Etienne, France.

Background: Immune system affects prognosis of various malignancies. Anti-immune pathways like PD-L1 and CTLA4 are used by the tumor to overcome immune system and they serve as immunotherapy targets. The immune microenvironment of head-and-neck squamous cell carcinoma (SCCHN) has not been sufficiently studied.

Patients And Methods: 152 SCCHN were immunohistochemically studied for the expression of CD3, CD8, CD57, CD4, granzyme b, CD20, CD163, S100, PD-L1, CTLA4 and CXCR4.

Results: CD3, CD8, CD57 and stromal S100 higher density is a good prognostic factor (p=0.02, 0.01, 0.02, 0.03 respectively). CTLA4 tumor expression is a poor prognostic factor (p=0.05). The rest immune cells do not affect prognosis. CD3 and CD8 density does not correlate with clinicopathological factors or p16/p53 expression, while CD57 and CD4 higher density is associated with the absence of distant metastases (p=0.03 and 0.07, respectively). Higher CD20 and S100 density is associated with lower T stage (p=0.04 and 0.03, respectively). PD-L1 expression is higher in CD3, CD8, and CD163 infiltrated tumors and in histologically more aggressive tumors. Response to neoadjuvant chemotherapy is better in highly CD3 infiltrated tumors and in tumors with less intraepithelial macrophages.

Conclusion: Rich T-lympocytic and dendritic cell response is a good prognostic factor in SCCHN, whereas tumors expressing CTLA4 show poor prognosis. PDL1 expression does not affect prognosis, but it is expressed in histologically more aggressive tumors and in T-cells rich tumors. Response to induction chemotherapy is better in tumors less infiltrated by macrophages and mostly infiltrated by T cells.
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http://dx.doi.org/10.18632/oncotarget.14242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386686PMC
March 2017

Clinical and Histologic Predictive Factors of Response to Induction Chemotherapy in Head and Neck Squamous Cell Carcinoma.

Am J Clin Pathol 2016 Nov;146(5):546-553

From the Department of Pathology.

Objectives: Induction chemotherapy (IC) is occasionally used in head and neck cancer, leading to less extensive surgery and reduced need for irradiation. Factors predicting the response to IC have not been determined. In this study, we investigated the clinical and histopathologic factors that predict the response to IC.

Methods: Head and neck squamous cell carcinomas from 81 patients were analyzed; clinical factors, histologic parameters, and expression of p16 and p53 were correlated with response to chemotherapy and prognosis.

Results: Factors predicting a good response to IC were the nonoropharyngeal localization, a rich lymphocytic tissue response, and a low platelet-to-lymphocyte blood ratio before treatment. Response to IC did not correlate with prognosis, whereas a low neutrophil-to-lymphocyte ratio (NLR), the absence of a desmoplastic reaction, a rich lymphocytic tissue response, and the overexpression of p53 were associated with better prognosis.

Conclusions: Lymphocytic tissue response, NLR, and nonoropharyngeal localization are factors predictive of response to IC.
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http://dx.doi.org/10.1093/ajcp/aqw145DOI Listing
November 2016

Intraoperative monitoring of the recurrent laryngeal nerve by vagal nerve stimulation in thyroid surgery.

Eur Arch Otorhinolaryngol 2017 Jan 15;274(1):421-426. Epub 2016 Jul 15.

Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital St Etienne, St Etienne, France.

The aim of the present study was to evaluate the thyroarytenoid muscle response during bilateral thyroid surgery using vagal nerve stimulation. 195 patients (390 nerves at risk) underwent a total thyroidectomy. The recurrent laryngeal nerve's function was checked by analyzing the amplitude and the latency of the thyroarytenoid muscle's responses after a vagal nerve's stimulation (0.5 and 1 mA) using the NIM3 Medtronic system. All patients were submitted to preoperative and postoperative laryngoscopy. 20 patients get no thyroarytenoid muscle response to the vagal nerve stimulation, and 14 postoperative recurrent laryngeal nerve palsies were confirmed (3.8 %). Two palsies were present after 6 months (0.51 %). All the patients with muscle's response have normal mobility vocal fold. The test sensitivity was 100 % and the test specificity was 98 %. Physiologically, the mean latencies of the muscular potentials for the right RLN were, respectively, 3.89 and 3.83 ms (p > 0.05) for the stimulation at 0.5 and 1 mA. The mean latencies for the left RLN were, respectively, 6.25 and 6.22 ms for the stimulation at 0.5 and 1 mA (p > 0.05). The difference of the latencies between the right and the left nerve was 2.30 ms (1.75-3.25 ms) with a stimulation of 0.5 or 1 mA (p < 0.05). Thyroarytenoid muscle's response via a vagal nerve stimulation showed a functional asymmetry of the laryngeal adduction with a faster right response. Surgically, this method can predict accurately an immediate postoperative vocal folds function in patients undergoing a bilateral thyroid surgery.
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http://dx.doi.org/10.1007/s00405-016-4191-2DOI Listing
January 2017

p16 and p53 expression status in head and neck squamous cell carcinoma: a correlation with histological, histoprognostic and clinical parameters.

Pathology 2016 Jun 23;48(4):341-8. Epub 2016 Apr 23.

Department of Pathology, North Hospital, University Hospital of St-Etienne, France.

Different histopathology and prognosis characterise the human papillomavirus (HPV)-related oropharyngeal tumours, but squamous cell carcinomas (SCC) of other localisations have not been exhaustively studied. Tissues from 120 patients with a head and neck SCC were studied for the expression of p16 and p53, and the Brandwein-Gensler (BG) histological risk assessment model. p16 positivity and p53 normal expression were significantly correlated with non-smoking, an earlier T stage and a non-keratinising morphology. The BG risk score was not associated with p16 or p53 expression; p16 expression was associated with a lymphocytic T-cytotoxic response. BG risk score was significantly correlated with overall survival and progression-free survival, while neither p16 nor p53 expression were associated with prognosis. p16 and p53 expression are associated with the histological subtype and the T stage even in non-oropharyngeal-restricted tumours. The BG risk score is not correlated with p16 or p53 and retains its power in non-site-specific SCCs.
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http://dx.doi.org/10.1016/j.pathol.2016.01.005DOI Listing
June 2016

Optimization of immunostaining on flat-mounted human corneas.

Mol Vis 2015 30;21:1345-56. Epub 2015 Dec 30.

"Corneal Graft Biology, Engineering and Imaging" Laboratory, EA2521, SFR 143, Faculty of Medicine, Jean Monnet University, Saint-Etienne, France.

Purpose: In the literature, immunohistochemistry on cross sections is the main technique used to study protein expression in corneal endothelial cells (ECs), even though this method allows visualization of few ECs, without clear subcellular localization, and is subject to the staining artifacts frequently encountered at tissue borders. We previously proposed several protocols, using fixation in 0.5% paraformaldehyde (PFA) or in methanol, allowing immunostaining on flatmounted corneas for proteins of different cell compartments. In the present study, we further refined the technique by systematically assessing the effect of fixative temperature. Last, we used optimized protocols to further demonstrate the considerable advantages of immunostaining on flatmounted intact corneas: detection of rare cells in large fields of thousands of ECs and epithelial cells, and accurate subcellular localization of given proteins.

Methods: The staining of four ubiquitous proteins, ZO-1, hnRNP L, actin, and histone H3, with clearly different subcellular localizations, was analyzed in ECs of organ-cultured corneas. Whole intact human corneas were fixed for 30 min in 0.5% paraformaldehyde or pure methanol at four temperatures (4 °C for PFA, -20 °C for methanol, and 23, 37, and 50 °C for both). Experiments were performed in duplicate and repeated on three corneas. Standardized pictures were analyzed independently by two experts. Second, optimized immunostaining protocols were applied to fresh corneas for three applications: identification of rare cells that express KI67 in the endothelium of specimens with Fuch's endothelial corneal dystrophy (FECD), the precise localization of neural cell adhesion molecules (NCAMs) in normal ECs and of the cytokeratin pair K3/12 and CD44 in normal epithelial cells, and the identification of cells that express S100b in the normal epithelium.

Results: Temperature strongly influenced immunostaining quality. There was no ubiquitous protocol, but nevertheless, room temperature may be recommended as first-line temperature during fixation, instead of the conventional -20 °C for methanol and 4 °C for PFA. Further optimization may be required for certain target proteins. Optimized protocols allowed description of two previously unknown findings: the presence of a few proliferating ECs in FECD specimens, suggesting ineffective compensatory mechanisms against premature EC death, and the localization of NCAMs exclusively in the lateral membranes of ECs, showing hexagonal organization at the apical pole and an irregular shape with increasing complexity toward the basal pole. Optimized protocols were also effective for the epithelium, allowing clear localization of cytokeratin 3/12 and CD44 in superficial and basal epithelial cells, respectively. Finally, S100b allowed identification of clusters of epithelial Langerhans cells near the limbus and more centrally.

Conclusions: Fixative temperature is a crucial parameter in optimizing immunostaining on flatmounted intact corneas. Whole-tissue overview and precise subcellular staining are significant advantages over conventional immunohistochemistry (IHC) on cross sections. This technique, initially developed for the corneal endothelium, proved equally suitable for the corneal epithelium and could be used for other superficial mono- and multilayered epithelia.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4704774PMC
September 2016
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