Real-world EGFR testing practices for non-small-cell lung cancer by thoracic pathology laboratories across Europe.

BACKGROUND: Testing for epidermal growth factor receptor (EGFR) mutations is an essential recommendation in guidelines for metastatic non-squamous non-small-cell lung cancer, and is considered mandatory in European countries. However, in practice, challenges are often faced when carrying out routine biomarker testing, including access to testing, inadequate tissue samples and long turnaround times (TATs). MATERIALS AND METHODS: To evaluate the real-world EGFR testing practices of European pathology laboratories, an online survey was set up and validated by the Pulmonary Pathology Working Group of the European Society of Pathology and distributed to 64 expert testing laboratories. The retrospective survey focussed on laboratory organisation and daily EGFR testing practice of pathologists and molecular biologists between 2018 and 2021. RESULTS: TATs varied greatly both between and within countries. These discrepancies may be partly due to reflex testing practices, as 20.8% of laboratories carried out EGFR testing only at the request of the clinician. Many laboratories across Europe still favour single-test sequencing as a primary method of EGFR mutation identification; 32.7% indicated that they only used targeted techniques and 45.1% used single-gene testing followed by next-generation sequencing (NGS), depending on the case. Reported testing rates were consistent over time with no significant decrease in the number of EGFR tests carried out in 2020, despite the increased pressure faced by testing facilities during the COVID-19 pandemic. ISO 15189 accreditation was reported by 42.0% of molecular biology laboratories for single-test sequencing, and by 42.3% for NGS. 92.5% of laboratories indicated they regularly participate in an external quality assessment scheme. CONCLUSIONS: These results highlight the strong heterogeneity of EGFR testing that still occurs within thoracic pathology and molecular biology laboratories across Europe. Even among expert testing facilities there is variability in testing capabilities, TAT, reflex testing practice and laboratory accreditation, stressing the need to harmonise reimbursement technologies and decision-making algorithms in Europe.

Molecular and clinical diversity in primary central nervous system lymphoma.

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a rare and distinct entity within diffuse large B-cell lymphoma presenting with variable response rates probably to underlying molecular heterogeneity. PATIENTS AND METHODS: To identify and characterize PCNSL heterogeneity and facilitate clinical translation, we carried out a comprehensive multi-omic analysis [whole-exome sequencing, RNA sequencing (RNA-seq), methylation sequencing, and clinical features] in a discovery cohort of 147 fresh-frozen (FF) immunocompetent PCNSLs and a validation cohort of formalin-fixed, paraffin-embedded (FFPE) 93 PCNSLs with RNA-seq and clinico-radiological data. RESULTS: Consensus clustering of multi-omic data uncovered concordant classification of four robust, non-overlapping, prognostically significant clusters (CS). The CS1 and CS2 groups presented an immune-cold hypermethylated profile but a distinct clinical behavior. The 'immune-hot' CS4 group, enriched with mutations increasing the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and nuclear factor-κB activity, had the most favorable clinical outcome, while the heterogeneous-immune CS3 group had the worse prognosis probably due to its association with meningeal infiltration and enriched HIST1H1E mutations. CS1 was characterized by high Polycomb repressive complex 2 activity and CDKN2A/B loss leading to higher proliferation activity. Integrated analysis on proposed targets suggests potential use of immune checkpoint inhibitors/JAK1 inhibitors for CS4, cyclin D-Cdk4,6 plus phosphoinositide 3-kinase (PI3K) inhibitors for CS1, lenalidomide/demethylating drugs for CS2, and enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) inhibitors for CS3. We developed an algorithm to identify the PCNSL subtypes using RNA-seq data from either FFPE or FF tissue. CONCLUSIONS: The integration of genome-wide data from multi-omic data revealed four molecular patterns in PCNSL with a distinctive prognostic impact that provides a basis for future clinical stratification and subtype-based targeted interventions.

Characteristics of IDH-mutant gliomas with non-canonical IDH mutation.

BACKGROUND: Approximately 10% of IDH-mutant gliomas harbour non-canonical IDH mutations (non-p.R132H IDH1 and IDH2 mutations). OBJECTIVE: The aim of this study was to analyse the characteristics of non-canonical IDH-mutant gliomas. MATERIALS AND METHODS: We retrospectively analysed the characteristics of 166 patients with non-canonical IDH mutant gliomas and compared them to those of 155 consecutive patients with IDH1 p.R132H mutant gliomas. RESULTS: The median age at diagnosis was 38 years in patients with non-canonical IDH mutant gliomas and 43 years in glioma patients with IDH1 p.R132H-mutant tumours. Family history of cancer was more frequent among glioma patients harbouring non-canonical IDH mutations than in patients with IDH1 p.R132H mutations (22.2% vs 5.1%; P < 0.05). Tumours were predominantly localised in the frontal lobe regardless of the type of IDH mutation. Compared to IDH1 p.R132H-mutant gliomas, tumours with non-canonical IDH mutations were more frequently found in the infratentorial region (5.5% vs 0%; P < 0.05) and were often multicentric (4.8% vs 0.9%; P < 0.05). Compared to IDH1 P.R132H-mutant gliomas, tumours with non-canonical IDH1 mutations were more frequently astrocytomas (65.6% vs 43%, P < 0.05), while those with IDH2 mutations were more frequently oligodendrogliomas (85% vs 48.3%; P < 0.05). The median overall survival was similar in patients with IDH1 p.R132H-mutant gliomas and patients with non-canonical IDH-mutant gliomas. CONCLUSION: Gliomas with non-canonical IDH mutations have distinct radiological and histological characteristics. The presence of such tumours seems to be associated with genetic predisposition to cancer development.

Zosteriform configuration of multiple eccrine spiradenomas of the scalp.

BACKGROUND: Eccrine spiradenoma (ES) is a benign adnexal tumor predominantly located in the head and neck regions. Multiple neoplasms located on the scalp have been reported but never with a zosteriform configuration on the first trigeminal area. CASE REPORT: We describe an original case report of a 75-year-old Caucasian man presenting multiple subcutaneous blue and purple nodules disseminated on the first left trigeminal dermatome. All the nodules appeared gradually on a one-year period. Biopsy revealed a nodular adnexal tumor in the dermis without malignant eccrine spiradenoma (MES) transformation. The surgical procedure was performed in a manner to protect the galea aponeurotica in the upper half on the first left trigeminal area. The frontalis muscle was raised with the surgical specimen in the lower half of the first trigeminal area. A split-thickness skin graft was applied on the surgical defect. Histological examination revealed multilobular well-defined tumors located in the dermis. CONCLUSION: The presence of multiple subcutaneous nodules in a trigeminal pattern should suggest a multiple localized zosteriform ES. The diagnosis is focused on clinical findings and the treatment is based on a large surgical excision. The histological examination is essential for not to fail a MES transformation.

[X-ray pelvimetry practice survey in Northeast French maternities]. / Enquête sur la pratique de la radiopelvimétrie dans les maternités de l'inter-région Nord-Est.

OBJECTIVE: To describe and compare the indications and modalities of X-ray pelvimetry in obstetrical practice in the Northeast French maternities. MATERIALS AND METHODS: An anonymous questionnaire was sent to the heads of obstetric departments in the Northeast French maternities. The questionnaire was built around four issues: description of the hospital characteristics, assessment of the obstetrical prognosis (modalities of delivery), indications and modalities of X-ray pelvimetry. RESULTS: The response rate was 47%. The evaluation of the obstetrical prognosis was performed in 77% of maternities. Indications were: breech presentation (86%), suspicion of fetal-pelvic disproportion (78%), mother size lesser than 150cm (64%) and previous caesarean section (42%). Pelvic computed tomography was performed in the majority of the maternities (94%), between 35 and 37 weeks of amenorrhea (47%). Level III maternities and maternities with more than 2000 deliveries per year seemed to observe fewer indications than other maternities, but these indications were still globally excessive, comparing with the Collège national des gynécologues et obstétriciens français' recommendations. CONCLUSION: These results should lead professionals to develop an assessment of their practices about the indications of X-ray pelvimetry.

Pilomatrix Carcinoma of the scalp. A case report and review of the literature.

INTRODUCTION: Pilomatrix Carcinoma (PC) is a rare and malignant dermo-hypodermic tumor. Only 11 cases were reported in patients younger than 18 years old and only 13 cases were reported on the scalp. CASE REPORT: We report the case of a 15-year-old woman who underwent cyst excision on the vertex. Anatomopathology shed light trichilemmal cyst. Five months later, she presented a first local recurrence. The tumor was removed with wide margin. Anatomopathology shed light PC. No adjuvant therapy was performed. The patient presented a second recurrence 3 months later with a parietal bone and superior sagittal sinus invasion and a lung metastasis. She underwent a craniotomy and radiochemotherapy. A third local recurrence was detected 4 months later. Three more lines of chemotherapy were performed without success. DISCUSSION: PC is a locally aggressive tumour, with a high rate of local recurrences and metastases. PC arises de novo or through malignant transformation of a pilomatrixoma. PC were observed frequently in the white male over 50 years old. The histological diagnosis is difficult to prove. Treatment consists of a wide surgical excision. Peritumoral margins are not codified. Because of most cases are on the face and neck, Mohs Micrographic Surgery seems to be a good modality to limit margins. Radiation therapy is an adjuvant treatment. Chemotherapy can be used in metastasis case. CONCLUSION: PC is a rare malignant tumor with high rate of disease relapse. Histological diagnosis is difficult and treatment is not standardized. Surgical procedure with wide margins is recommended to avoid the large recurrence when the staging shows no metastasis.

Decreased vitamin B12 availability induces ER stress through impaired SIRT1-deacetylation of HSF1.

Vitamin B12 (cobalamin) is a key determinant of S-adenosyl methionine (SAM)-dependent epigenomic cellular regulations related to methylation/acetylation and its deficiency produces neurodegenerative disorders by elusive mechanisms. Sirtuin 1 deacetylase (SIRT1) triggers cell response to nutritional stress through endoplasmic reticulum (ER) stress. Recently, we have established a N1E115 dopaminergic cell model by stable expression of a transcobalamin-oleosin chimera (TO), which impairs cellular availability of vitamin B12, decreases methionine synthase activity and SAM level, and reduces cell proliferation. In contrast, oleosin-transcobalamin chimera (OT) does not modify the phenotype of transfected cells. Presently, the impaired cellular availability of vitamin B12 in TO cells activated irreversible ER stress pathways, with increased P-eIF-2α, P-PERK, P-IRE1α, ATF6, ATF4, decreased chaperon proteins and increased pro-apoptotic markers, CHOP and cleaved caspase 3, through reduced SIRT1 expression and consequently greater acetylation of heat-shock factor protein 1 (HSF1). Adding either B12, SIRT1, or HSF1 activators as well as overexpressing SIRT1 or HSF1 dramatically reduced the activation of ER stress pathways in TO cells. Conversely, impairing SIRT1 and HSF1 by siRNA, expressing a dominant negative form of HSF1, or adding a SIRT1 inhibitor led to B12-dependent ER stress in OT cells. Addition of B12 abolished the activation of stress transducers and apoptosis, and increased the expression of protein chaperons in OT cells subjected to thapsigargin, a strong ER stress stimulator. AdoX, an inhibitor of methyltransferase activities, produced similar effects than decreased B12 availability on SIRT1 and ER stress by a mechanism related to increased expression of hypermethylated in cancer 1 (HIC1). Taken together, these data show that cellular vitamin B12 has a strong modulating influence on ER stress in N1E115 dopaminergic cells. The impaired cellular availability in vitamin B12 induces irreversible ER stress by greater acetylation of HSF1 through decreased SIRT1 expression, whereas adding vitamin B12 produces protective effects in cells subjected to ER stress stimulation.

Composite renal cell carcinoma with clear cell renal cell carcinomatous and carcinoid tumoral elements: a first case report.

Renal endocrine tumours are extremely rare, and carcinoid tumoral elements in renal cell carcinoma have never been reported. This is the first report of a composite renal cell carcinoma containing a clear cell renal cell carcinoma associated with carcinoid tumoral elements, in a patient with synchronous metastatic disease. In the absence of specific radiological and clinical manifestations, typical morphological features as well as an immunostaining profile of neuroendocrine differentiation were identified by microscopy. Secondary nodal and liver localisations were characterised by carcinoid elements only. Despite antiangiogenic therapy, liver metastasis progressed, suggesting that adjuvant therapy cannot be based on the presence of the clear cell renal cell carcinoma component. In this context, extensive tissue sampling is recommended to reveal the endocrine component that is the most aggressive element of such a composite carcinoma.

[Primary leiomyosarcoma of the epididymis: a case report with review of the literature]. / Léiomyosarcome de l'épididyme : à propos d'un cas avec revue de la littérature.

Primary epididymal leiomyosarcoma is uncommon: only 16 cases has been reported in the literature. We present an additionnal case in a 78-year-old man, treated for a prostatic adenocarcinoma by gonadorelin (LH-RH) analogue, who had an epididymal tumor. A right orchidectomy with high ligation of the spermatic cord was performed. The diagnostic of primary leiomyosarcoma of the epididymis was made. The patient is dead 2 years later with no recurrence of disease. A review of reported cases is made.

Reactive nodular fibrous pseudotumor: a first report of gastric localization and clinicopathologic review.

Reactive nodular fibrous pseudotumor (RNFP) of the gastrointestinal tract is a distinct benign lesion, which could originate from a reactive proliferation of multipotential subserosal cells. This is the first case to be reported in the stomach. It was fortuitously discovered in a 60-year-old man with history of bulbar ulcer and gastritis. Gross examination revealed three lesions in the gastric wall and an adjacent lesion in the lesser omentum. Histologically, lesions were composed of a proliferation of spindle and stellate cells in a dense collagenic hyalinized background containing a mononuclear cell inflammatory infiltrate with numerous lymphoid aggregates and plasma cells with perivascular disposition. Immunohistochemistry showed staining for cytokeratins (AE1/AE3), vimentin and smooth muscle actin, without staining for the neurofilament and S100 proteins, synaptophysin, calretinin, CD117 (c-kit), CD34, desmin, caldesmon or anaplastic lymphoma kinase (ALK-1). Complete excision was performed, and no evidence of disease was found 4 months later. After analysing clinical, morphological and immunohistochemical features of this entity, the main differential diagnoses will be discussed, including calcifying fibrous pseudotumor, which shares morphological characteristics with RNFP, but which immunohistochemistry and the ultrastructural study suggest that it may be a result of another reactive process.

[An isolated vasculitis of uterine cervix and isthmus]. / Une vascularite isolée du col et de l'isthme utérins.

Isolated lesions of vasculitis are described in different organs, notably female genital tract. Exhaustive clinic and paraclinic exams are necessary to exclude an occult systemic vasculitis. We report a case of vasculitis that was restricted to uterine cervix and isthmus, fortuitously discovered by a 45-years-old woman after hysterectomy. At histological examination, necrotizing vasculitis of small and medium-sized arteries was found, suggesting diagnosis of polyarteritis nodosa. There was no argument for systemic vasculitis.

[MDCT in the lateral decubitus position with Valsalva maneuver in the evaluation of abdominal wall hernias]. / Scanner multicoupe en latérocubitus avec manoeuvre de Valsalva dans l'étude des hernies de la paroi abdominale.

MDCT in the lateral decubitus position during Valsalva is sensitive in the detection of abdominal wall hernias and may increase the hernia size and possibly change its contents.