Clinical features, diagnosis, treatment, and course of ocular sarcoidosis with or without uveitis: A retrospective, comparative study.

OBJECTIVE: To evaluate and compare characteristics, diagnosis, treatment, visual prognosis, and course between ocular sarcoidosis with or without uveitis in a population in Southern France. METHODS: We retrospectively analyzed data from patients with ocular sarcoidosis in a tertiary eye care center in Nice from January 2003 to December 2021. The inclusion criterion was biopsy-proven ocular sarcoidosis according to IWOS criteria as the first clinical manifestation of sarcoidosis. RESULTS: A total of 25 patients were included. Twenty patients had uveitis (70% panuveitis, 20% intermediate uveitis, and 10% anterior uveitis) and five patients had non-uveitic ocular sarcoidosis (one patient with dacryoadenitis, one patient with orbital granuloma, two patients with palpebral granuloma, and one patient with episcleritis). Only the cases with uveitis had bilateral involvement (85% of cases). There was no significant difference in ethnicity, biopsy diagnosis, systemic manifestations, or treatment between the two groups. Final visual outcomes remained good for both groups, with 96% of patients with BCVA>20/50, with no significant difference. Patients with non-uveitic sarcoidosis experienced less recurrence on treatment (P=0.042) and more remission (P=0.038) than patients with uveitis. Eighty percent of patients with uveitis had at least three suggestive clinical intraocular signs meeting IWOS criteria. CONCLUSION: In this population in Southern France, uveitis was the most common presentation of ocular sarcoidosis. The type of ocular sarcoidosis does not appear to be correlated with the type of systemic manifestations, use of systemic therapy, or visual prognosis, but patients with non-uveitic ocular sarcoidosis appear to have a better course with fewer recurrences on treatment and more remission than patients with uveitic ocular sarcoidosis.

Can 18F-FDG PET/CT findings be used to predict orbital tumor histology?

PURPOSE: To investigate whether 18F-FDG PET/CT might be useful to predict the histology of various orbital tumors based on the maximum standard uptake value (SUVmax) and the OMSUV (orbital max SUV)/MLSUV (mean liver SUV) ratio. PATIENTS AND METHODS: A retrospective single-center study was conducted between May 2019 and December 2020. Patients with an orbital mass who underwent preoperative 18F-FDG PET/CT followed by an orbital biopsy were included. Tumor histology was classified as follows: orbital inflammation, solid tumor, low-grade lymphoid tumor, and high-grade lymphoid tumor. Orbital tumors were also classified as indolent or aggressive. Data recorded included the orbital SUVmax, OMSUV/MLSUV ratio and additional extra-orbital SUV sites. RESULTS: Forty-five patients (24 men) were included. There were 15 (33.3%), 14 (31.1%), 9 (20%), and 7 (15.5%) cases of orbital inflammation, solid tumor, low-grade lymphoid tumor, and high-grade lymphoid tumor, respectively. No correlation was found between the OMSUV/MLSUV ratio and orbital SUVmax and tumor histology (Z = -0.77, Z = -0.6, Z = -1.6, and Z = 0.94, all P > 0.05, respectively). No correlation was found between the OMSUV/MLSUV ratio (Z = -1.42, P > 0.05) and orbital SUVmax (Z = -0.82, P > 0.05) and tumor aggressiveness (indolent versus aggressive). Subgroup analyses showed that SUVmax was predictive of lymphoma aggressiveness (P = 0.05) and was able to distinguish orbital cancers (all lymphomas+solid tumors) from benign tumors (P = 0.02). CONCLUSION: 18F-FDG PET/CT could not be used to predict the underlying orbital tumor histology. However, more aggressive tumors, especially high-grade lymphomas and cancers, tended to have a higher orbital SUVmax compared to indolent lesions.

Clinical and molecular practice of European thoracic pathology laboratories during the COVID-19 pandemic. The past and the near future.

BACKGROUND: This study evaluated the consequences in Europe of the COVID-19 outbreak on pathology laboratories orientated toward the diagnosis of thoracic diseases. MATERIALS AND METHODS: A survey was sent to 71 pathology laboratories from 21 European countries. The questionnaire requested information concerning the organization of biosafety, the clinical and molecular pathology, the biobanking, the workload, the associated research into COVID-19, and the organization of education and training during the COVID-19 crisis, from 15 March to 31 May 2020, compared with the same period in 2019. RESULTS: Questionnaires were returned from 53/71 (75%) laboratories from 18 European countries. The biosafety procedures were heterogeneous. The workload in clinical and molecular pathology decreased dramatically by 31% (range, 3%-55%) and 26% (range, 7%-62%), respectively. According to the professional category, between 28% and 41% of the staff members were not present in the laboratories but did teleworking. A total of 70% of the laboratories developed virtual meetings for the training of residents and junior pathologists. During the period of study, none of the staff members with confirmed COVID-19 became infected as a result of handling samples. CONCLUSIONS: The COVID-19 pandemic has had a strong impact on most of the European pathology laboratories included in this study. Urgent implementation of several changes to the organization of most of these laboratories, notably to better harmonize biosafety procedures, was noted at the onset of the pandemic and maintained in the event of a new wave of infection occurring in Europe.

Incidence of Orbital Exenteration: A Nationwide Study in France over the 2006-2017 Period.

PURPOSE: Orbital exenteration is a radical and disfiguring surgery mainly performed for treating orbital malignancies. Recently, several studies found favorable results in terms of overall survival with eye-sparing surgeries combined with targeted therapies and/or radiotherapy. The aim of this study was to assess the incidence of orbital exenteration and its evolution in France between 2006 and 2017. METHODS: A national observational cohort study was conducted in France between January 2006 and December 2017. Data were collected from the national PMSI (Programme de Médicalisation des Systèmes d'Information) database provided by the CNAM (Caisse Nationale de l'Assurance Maladie). All patients undergoing orbital exenteration over the study period in France were included. RESULTS: One thousand and fifty-seven patients were included. The mean annual number of orbital exenterations was 88.1 (63-117), corresponding to a mean incidence of 0.1/100,000 inhabitants/year. A male predominance was noted (n = 626, 59.2%). Exenteration was mainly performed between 75 and 79 years. The underlying etiology was available for 821 patients (77.7%): malignancies were the most common (n = 755; 92.0%) followed by infectious diseases (n = 16; 1.9%). Over the study period, no statistical difference in the mean incidence of orbital exenteration was found (p = .132). CONCLUSION: The mean annual incidence of orbital exenteration was 0.1/100,000 inhabitants in France and was not significantly modified during the study period.

Association of combined PD-L1 expression and tumour-infiltrating lymphocyte features with survival and treatment outcomes in patients with metastatic melanoma.

BACKGROUND: Recent advances obtained with immune checkpoint inhibitors (ICIs) targeting the programmed cell death-1 (PD-1) protein have significantly improved the outcome of patients with metastatic melanoma. The PD-L1 expression in tumour cells as detected by immunohistochemistry is a predictive biomarker in some solid tumours, but appears insufficient as prognostic or predictive factor of response to ICIs in metastatic melanomas. OBJECTIVES: We investigated whether the presence and the features of pretreatment CD8+ tumour-infiltrating T lymphocytes (TILs) could be a complementary prognostic or predictive biomarker in patients with metastatic melanoma. METHODS: In this retrospective study, we evaluated the association of PD-L1 expression ≥5% of tumour cells combined with TIL features (CD8, CD28, Ki67) with the overall survival (OS) among 51 patients treated with ICIs and 54 patients treated with other treatment options (non-ICIs). RESULTS: PD-L1 positivity was observed in 33% and 39% of primary melanomas and matched metastases, respectively, with, however, poor concordance between the primary and the matched metastatic site (κ = 0.283). No significant association was noted between PD-L1 expression and CD8+ TIL profile analysed as single markers and OS or response to immunotherapy. Instead, their combined analysis in primary melanoma samples showed that the PD-L1-/CD8+ status was significantly associated with prolonged OS in the whole population (P = 0.04) and in the subgroup treated with non-ICIs (P = 0.009). Conversely, the PD-L1+/CD8+ status was a good prognostic factor in patients treated with ICIs (P = 0.022), whereas was significantly associated with poor prognosis in patients treated with non-ICIs (P = 0.014). While the expression of CD28 was not related to outcome, the Ki67 expression was significantly associated with poor OS in the subgroup CD8+ TIL+/PD-L1- (P = 0.02). CONCLUSIONS: The pretreatment combination of PD-L1 expression with the level of CD8+ TILs could better assess OS and predict therapeutic response of patients with metastatic melanoma treated by either immunotherapy or other treatment regimens.

[Local, regional and systemic dissemination of choroidal melanoma : Clinical and pathological correlation from 2 cases]. / Dissémination locorégionale et systémique du mélanome choroïdien : corrélation anatomoclinique à partir de 2 cas.

PURPOSE: To describe didactically the local, regional and systemic spread of choroidal melanoma. PATIENTS AND METHODS: Two patients who had undergone primary enucleation for the management of choroidal melanoma in 2018 at the University Hospital of Nice were included. Extrascleral extension and invasion of the vortex veins were evaluated, as well as synchronous and metachronous metastases, based on our database. RESULTS: Patient 1 was diagnosed with large choroidal melanoma with partial scleral invasion and vortex vein involvement. Cytogenetic analysis demonstrated a loss of chromosome 3, and a gain of chromosome 8q. Systemic work-up was unremarkable. Patient 2 was diagnosed with a large choroidal melanoma with extrascleral extension and vortex vein involvement. Cytogenetic analysis demonstrated a loss of chromosome 3 and a gain of chromosome 8q. Systemic work-up revealed several liver metastases. A total of 1762 patients were included in our database. Eighty-five patients (4.8 %) and 46 patients (2.6 %) experienced vortex vein invasion and extrascleral extension respectively. Patients with vortex vein invasion were diagnosed with synchronous and metachronous liver metastases in 1.2 % and 18.8 % respectively. Patients with extrascleral extension had synchronous and metachronous liver metastases in 6.5 % and 30.4 % respectively. The mean follow-up was 49.4 months (1-180). CONCLUSION: Extrascleral extension and vortex vein invasion illustrate the local, regional and systemic spread of choroidal melanoma. The latter are often associated with genetically aggressive tumours associated with high metastatic risk.

Immunotherapy in Non-Small Cell Lung Cancer: Biological Principles and Future Opportunities.

Immunotherapy aims to amplify the anticancer immune response through reactivation of the lymphocytic response raised against several tumor neo-antigens. To obtain an effective immune response, this therapeutic approach requires that a number of immunological checkpoints be passed, such as the activation of excitatory costimulatory signals or the avoidance of coinhibitory molecules. Among the immune checkpoints, the interaction of the membrane-bound ligand PD-1 and its receptor PD-L1 has received much attention because of remarkable efficacy in numerous clinical trials for various cancer types, including non-small cell lung cancer (NSCLC). However, several limitations exist with these therapeutic agents when used as monotherapy, with objective responses observed in only 30-40% of patients, with the majority of patients demonstrating innate resistance, and approximately 25% of responders later demonstrating disease progression. Recent developments in the understanding of cancer immunology have the potential to identify mechanisms of innate and acquired resistance to immune checkpoint inhibitors through translational research in human samples. This review focuses on the biological basic principles for immunological checkpoint blockade, and highlights the current status and the perspectives of this therapeutic approach in NSCLC patients.

Comparative study of the PD-L1 status between surgically resected specimens and matched biopsies of NSCLC patients reveal major discordances: a potential issue for anti-PD-L1 therapeutic strategies.

BACKGROUND: High expression of programmed death ligand-1 (PD-L1) on tumor cells (TC) and/or on tumor-infiltrating immune cells (IC) is associated with a high response rate in patients with advanced nonsmall-cell lung cancer (NSCLC) treated with PD-L1 inhibitors. The use of a PD-L1 immunohistochemical (IHC) test in determining the responsiveness to immunotherapy has raised the question of the reliability and reproducibility of its evaluation in lung biopsies compared with corresponding resected surgical specimens. PATIENTS AND METHODS: PD-L1 expression in TC and IC was assessed in 160 patients with operable NSCLC on both whole surgical tissue sections and matched lung biopsies, by using a highly sensitive SP142 IHC assay. The specimens were scored as TC 0-3 and IC 0-3 based on increasing PD-L1 expression. RESULTS: PD-L1 expression was frequently discordant between surgical resected and matched biopsy specimens (the overall discordance rate = 48%; 95% confidence interval 4.64-13.24) and κ value was equal to 0.218 (poor agreement). In all cases, the biopsy specimens underestimated the PD-L1 status observed on the whole tissue sample. PD-L1-positive IC tumors were more common than PD-L1-positive TC tumors on resected specimens. The discrepancies were mainly related to the lack of a PD-L1-positive IC component in matched biopsies. CONCLUSIONS: Our results indicate relatively poor association of the PD-L1 expression in TC and IC between lung biopsies and corresponding resected tumors. Although these results need to be further validated in larger cohorts, they indicate that the daily routine evaluation of the PD-L1 expression in diagnostic biopsies can be misleading in defining the sensitivity to treatment with PD-L1 targeted therapy.

Why and how immunohistochemistry should now be used to screen for the BRAFV600E status in metastatic melanoma? The experience of a single institution (LCEP, Nice, France).

BACKGROUND: Knowledge of the BRAFV600E status is mandatory in metastatic melanoma patients (MMP). Molecular biology is currently the gold standard method for status assessment. OBJECTIVES: We assessed and compared the specificity, sensibility, cost-effectiveness and turnaround time (TAT) of immunohistochemistry (IHC) and molecular biology for detection of the BRAFV600E mutation in 188 MMP. METHODS: IHC, with the VE1 antibody, and pyrosequencing analysis were performed with formalin fixed paraffin embedded tumour samples. RESULTS: The BRAFV600E mutation was detected by pyrosequencing in 91/188 (48%) patients. IHC was strongly positive (3+) in all of these 91 cases. IHC was strongly positive in 9/188 (5%) cases in which the molecular testing failed due to non-amplifiable DNA. Weak or moderate staining was noted in 10/188 (5%) cases in which the molecular biology identified BRAF wild-type tumours. The ratio of the global cost for IHC/molecular biology testing was 1 : 2.2. The average TAT was 48 h vs. 96 h, for IHC vs. molecular biology testing, respectively. CONCLUSIONS: This study showed that VE1 IHC should be a substitute for molecular biology in the initial assessment of the BRAFV600E status in MPP. This methodology needs to be set up in pathology laboratories in accordance with quality control/quality assurance accreditation procedures. Under these strict conditions the question is to know if BRAFV600E-IHC can serve not only as a prescreening tool, but also as a stand-alone test (at least in cases displaying an unequivocally staining pattern) as well as an alternative predictive test for samples for which the molecular biology failed.

Role of frozen section analysis in nodular thyroid pathology.

INTRODUCTION: Frozen section (FS) analysis used to be the principal examination guiding surgical strategy. The development and recent standardization of fine-needle aspiration cytology (FNAC) challenges it as a systematic attitude. The present study assessed the current contribution of FS, comparing it with FNAC as a diagnostic tool guiding surgery. MATERIAL AND METHODS: A retrospective diagnostic study analyzed 1515 thyroid samples over a 6-year period. Two hundred and fifty-two of the patients had undergone both FNAC (analyzed in our unit) and FS, revealing 69 cancers. RESULTS: The sensitivity and specificity of FS and FNAC were 75.36% and 100% versus 31.88% and 100%, respectively. In case of malignancy on FNAC (22 patients), FS did not influence indications for surgery. In case of non-malignant FNAC findings, FS diagnosed cancer in 13% of cases (30/230). In the subgroup of follicular lesions (Bethesda 3 and 4), FS modified surgical strategy in only 6.2% of cases (6/97), but diagnosed 13 of the 16 cancers (81.25%) in case of Bethesda 5 on FNAC (21 cases) and in 9 of the 13 cancers (69%) associated with non-diagnostic FNAC results (Bethesda 1: 70 cases). CONCLUSION: Although its contribution is small, FS optimizes surgery in certain cases. Systematic implementation may be economically justified, especially in follicular lesions diagnosed on FNAC, improving interpretation of a difficult and operator-dependent test, as is essential in certain FNAC results.

Usefulness of ancillary methods for diagnosis, prognosis and targeted therapy in thyroid pathology.

The development of molecular analyses for thyroid pathologies is on going. These analyses provide new diagnostic tools with the aim of accurately distinguishing malignant and benign thyroid tumors. They are particularly useful as most of them can be done preoperatively on thyroid fine-needle aspiration biopsy samples. Furthermore, molecular biomarkers may play a promising role since they are able to predict the prognosis of patients with thyroid tumors. Moreover, identification of molecular markers as well as a better understanding of thyroid carcinogenesis will help develop innovative targeted therapies, particularly in patients with metastatic iodo-resistant thyroid carcinoma. To date, four types of somatic genetic alterations are known to hold potential interest for the diagnosis and/or prognosis of follicular cell-derived thyroid carcinomas: BRAF and RAS mutations, and RET/PTC and PAX8/PPARγ rearrangements. Other recent molecular biomarkers have been investigated in thyroid oncology, in particular different microRNA signatures. This review describes the different aspects of ancillary methods, including those bassed on molecular biology, that are of current interest for the diagnosis, prognosis and treatment of follicular cell-derived thyroid carcinomas.

Indications of external beam radiation therapy in non-anaplastic thyroid cancer and impact of innovative radiation techniques.

BACKGROUND: The mainstay of treatment for differentiated thyroid carcinomas is surgery. There is hardly any room for radiation therapy in differentiated thyroid carcinomas. We aimed to update recommendations for RT in the context of histological variants, increased use of radioiodine and new irradiations techniques. MATERIALS AND METHODS: A search of the French and English literature was performed using thyroid carcinoma, radiation therapy, surgery, variants and radioiodine. RESULTS: Papillary, follicular, Hürthle and medullary carcinomas represent about 80%, 11%, 3% and 4% of all thyroid carcinomas, respectively. Ten-year survival rates for patients with papillary, follicular and Hürthle cell carcinomas are 93%, 85%, and 76%, respectively. The occurrence of criteria such as older age (45 or 60 years-old), massive primary disease, extensive extracapsular spread and macroscopic iodine-negative components inconsistently indicate external beam irradiation (EBRT). The impact of EBRT on poorer-prognosis histological variants is an emerging issue. Noteworthy, the incidence of laryngeal and wound healing complications has been an important limitation to EBRT. However, intensity modulated radiation therapy (IMRT) offers clear dosimetric advantages on tumor coverage and organ sparing such as the larynx, thus reducing late toxicities to less than 5%. Iodine contrast agents should be avoided during 4-6 weeks before radioiodine. PET CT is increasingly used in iodine-negative tumors. CONCLUSION: There are elective indications for EBRT and IMRT has the potential to improve local control.

Ectopic pyriform sinus parathyroid adenoma.

OBJECTIVE: To describe the diagnosis and treatment of ectopic pyriform sinus parathyroid adenoma. MATERIAL AND METHODS: A 44-year-old woman presented with persistent primary hyperparathyroidism after previous failed cervical exploratory surgery. RESULTS: Diagnosis of ectopic pyriform sinus parathyroid adenoma was suggested by computed tomography and technetium-99m sestamibi scintigraphy (99mTc-MIBI SPECT/CT). A submucosal tumor was identified under laryngoscopy and resected by endoscopic CO2 laser. Histopathology confirmed the diagnosis of parathyroid adenoma. CONCLUSIONS: Ectopic pyriform sinus locations are rare in parathyroid adenoma. 99mTc-MIBI SPECT/CT facilitates diagnosis, especially in case of previous failed neck exploration. Endoscopic CO2 laser resection is the treatment of choice.

Chemoradiation in anaplastic thyroid carcinomas.

BACKGROUND: ATC represents 1-2% of all thyroid carcinomas. Median survival is poor (3-10 months). Our goal is to update recommendations for RT in the context of new irradiation techniques. MATERIALS AND METHODS: A search of the French and English literature was performed with terms: thyroid carcinoma, anaplastic, chemoradiation, radiation therapy and surgery. Level-based evidence remains limited in the absence of prospective studies and the small size of retrospective series of this rare tumor. RESULTS: Surgery when possible should be as complete as possible but without mutilation given the 8-month median survival of ATC. It should be followed by systematic chemoradiation in ATC. Initiation of treatment is an emergency given fast tumor doubling time. The most promising results of chemoradiation to date have been shown in series of radiation therapy (+/- acceleration) combined with doxorubicin +/- taxanes or cisplatin. Adjuvant chemotherapy (doxorubicin, cisplatine and/or taxane-based) may also be recommended given the metastatic potential of ATC and warrants further investigations. Data on neoadjuvant chemotherapy are missing. Intensity modulated radiation therapy offers clear dosimetric advantages and has the potential to improve tumor and nodal (posterior neck, mediastinum) coverage, i.e., locoregional control while optimally sparing the spinal cord, larynx, parotids, trachea and esophagus. PET-CT and MRI may be used for RT planning. CONCLUSION: Chemoradiation with debulking surgery whenever possible is the mainstay of treatment of anaplastic thyroid carcinomas (ATC). EBRT using IMRT has the potential to improve local control. Taxane-doxorubicin concomitant chemoradiotherapy is worth further investigation.

The thyroid gland: a crossroad in inflammation-induced carcinoma? An ongoing debate with new therapeutic potential.

Chronic infection and inflammation contribute to around 25% of cancer cases worldwide. While a direct link between several types of human malignancies and inflammation has now been established, in particular at the gastrointestinal level, the relationship between inflammation and thyroid cancer and the pathophysiology of chronic inflammation that induces papillary thyroid carcinoma (PTC) are still subjects of debate. However, several epidemiological and morphological studies have strongly suggested an increased risk of PTC in patients with Hashimoto's thyroiditis (HT). As in HT, an intense immune infiltrate is associated with certain PTC and might play a critical role in the regulation of carcinogenesis and in carcinoma progression. Proinflammatory molecules, such as cytokines and chemokines, which are produced by immune infiltrate in the tumor microenvironment, contribute to the regulation of key cellular processes for cancer onset and progression, in particular for tumor cell proliferation, apoptosis, autophagy, angiogenesis and metastasis. Molecular studies have identified activation of the RET/PTC rearrangement-induced MAPK signaling pathway as the driving force in the development of PTC in the context of HT. These genetic alterations may be favored by chronic inflammation. In this regard, the RET oncoprotein and its downstream effectors, such as those implicated in the activation of the MAPK pathway, as well as inflammatory molecules of the tumor microenvironment could be promising molecular targets for new therapeutic strategies for thyroid cancer. This review focuses on the complex link between thyroid cancer and chronic inflammation and highlights the different current hypotheses regarding the role of the immune cell microenvironment in the initiation and progression of PTC.