Kidney cancer characteristics and genotype-phenotype-correlations in Birt-Hogg-Dube syndrome

Birt-Hogg-Dube syndrome (BHDS) is a genetic tumor syndrome characterized by lung cysts, pneumothorax, fibrofolliculomas and renal cell cancer. The diagnosis of BHDS is usually considered if kidney cancer occurs before age 50 years, is multifocal and/or bilateral or of the oncocytoma/hybrid oncocytoma-chromophobe type. Using a sample of 50 BHDS families with a total of 178 patients we analyzed how many kidney cancer patients fulfilled one or more of these criteria. Furthermore, we addressed the question if genotype-phenotype-correlations exist that can be used for risk stratification. Renal cell cancer occurred in 34/178 (19.1%) patients, and the reported male bias was not observed. Furthermore, most kidney malignancies occurred after the age of 50 years. Thus, the majority of tumors did not show the typical hallmarks of BHDS. A below-average tumor frequency (17.2%) was observed for the known mutational hotspot c.1285delC/dupC that was the cause of BHDS in 24% of families. Unexpected was the high tumor frequency (66.7%) associated with mutation c.887C>G within a single family, a finding that merits further exploration

Cutaneous Squamous Cell Carcinoma with Perineural Invasion: Report on Eight Cases and Review of the Literature

Background: Perineural invasion (PNI) in cutaneous squamous cell carcinoma (SCC) is considered to be a negative prognostic factor. A lot of uncertainty remains regarding the classification, diagnosis, treatment and prognosis of SCC with PNI. Objective: To describe typical courses of SCC with PNI and associated findings in order to suggest an optimized diagnostic and therapeutic approach. Methods: We present eight cases of SCC with PNI, considering patient and tumor characteristics, histology, treatment and clinical course regarding local recurrence and metastasization. Results: SCC patients with PNI have a higher rate of local recurrences and greater risk for metastasization than SCC patients without PNI. Age ranged from 68 to 77 years, 6 patients were male and 2 female, with all tumors localized on the head. Three patients had chronic lymphocytic leukemia. Conclusion: Based on the data of this series and the current literature, we make suggestions for better diagnostic and therapeutic management

Negative regulation of EGFR signalling by the human folliculin tumour suppressor protein

Germline mutations in the Folliculin (FLCN) tumour suppressor gene result in fibrofolliculomas, lung cysts and renal cancers, but the precise mechanisms of tumour suppression by FLCN remain elusive. Here we identify Rab7A, a small GTPase important for endocytic trafficking, as a novel FLCN interacting protein and demonstrate that FLCN acts as a Rab7A GTPase-activating protein. FLCN-/- cells display slower trafficking of epidermal growth factor receptors (EGFR) from early to late endosomes and enhanced activation of EGFR signalling upon ligand stimulation. Reintroduction of wild-type FLCN, but not tumour-associated FLCN mutants, suppresses EGFR signalling in a Rab7A-dependent manner. EGFR signalling is elevated in FLCN-/- tumours and the EGFR inhibitor afatinib suppresses the growth of human FLCN-/- cells as tumour xenografts. The functional interaction between FLCN and Rab7A appears conserved across species. Our work highlights a mechanism explaining, at least in part, the tumour suppressor function of FLCN

Delayed diagnosis of Birt-Hogg-Dube syndrome might be aggravated by gender bias

Background Birt-Hogg-Dube syndrome is a rare genetic tumor syndrome characterized by renal cell cancer, lung bullae, pneumothorax, and fibrofolliculoma. Patients with such orphan tumor disorders are at risk of not receiving a timely diagnosis. In the present, gender-sensitive study, we analyzed the delay between onset of symptoms and diagnosis of Birt-Hogg-Dube syndrome. Methods Clinical data of 158 patients from 91 unrelated families were collected. FLCN mutation testing was performed in index patients and family members. Findings The occurrence of the first symptom (fibrofolliculoma, pneumothorax or renal cell cancer) was rarely followed by a timely diagnosis of Birt-Hogg-Dube syndrome and did so significantly less often in female (1.3%) compared to male (11.4%) patients (chi-square 6.83, p-value 0.009). Only 17 out of 39 renal cell cancers (7/17 female, 10/22 male patients) were promptly recognized as a symptom of Birt-Hogg-Dube syndrome. Patients in which renal cell cancer was initially not recognized as a symptom of Birt-Hogg-Dube syndrome waited 9.7 years (females SD 9.2, range 1-29) and 8.8 years (males, SD 4.1, range 2-11) for their diagnosis, respectively. Four (three female, one male) patients developed renal cell cancer twice before the genetic tumor syndrome was diagnosed. The delay between fibrofolliculoma or pneumothorax as a first symptom and diagnosis of Birt-Hogg-Dube syndrome was considerable but not significantly different between females and males (18.1/17.19 versus 16.1/18.92 years). Furthermore, 73 patients were only diagnosed due to family history (delay 15.1 years in females and 17.4 years in males). Interpretation The delay between onset of symptoms and diagnosis of Birt-Hogg-Dube syndrome can be substantial and gender-dependent, causing considerable health risks for patients and their families. It is therefore important to create more awareness of Birt-Hogg-Dube syndrome and resolve gender biases in diagnostic work-up. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/

Neues von der optischen Kohärenztomographie

Optical coherence tomography (OCT) has been able to establish itself in recent years not only in academic-scientific, but also in everyday dermatological practice. Its focus lies on epithelial tumors of the skin, which can be diagnosed intuitively and within a few seconds. Thus, basal cell carcinomas, actinic keratoses, and different stages of field cancerization can be diagnosed and monitored for response to therapy or possible recurrence. This often helps to avoid invasive sample extraction. Recently, the field of OCT and its latest advancement, dynamic OCT (D-OCT), has been expanded to include non-oncologic dermatological diseases. This encompasses inflammatory dermatoses and the analysis of physiological skin parameters such as hydration. Thanks to automated vascular imaging and the measurement of objective parameters such as epidermal thickness, blood flow at depth, optical attenuation coefficient, and skin roughness, more and more characteristics of the skin can be studied in a noninvasive and standardized way. New potential areas of application are eczema, contact allergic dermatitis, psoriasis, rosacea, telangiectasia, acute and chronic wounds, melasma and nevus flammeus but also melanocytic lesions

Line‐field confocal optical coherence tomography for the in‐vivo real‐time diagnosis of different stages of keratinocyte skin cancer: a preliminary study

Background: The treatment of keratinocyte cancers (KC) strictly depends on their differentiation and invasiveness. Non-invasive diagnostic techniques can support the diagnosis in real time, avoiding unnecessary biopsies. This study aimed to preliminarily define main imaging criteria and histological correlations of actinic keratosis (AK), Bowen\u2019s disease (BD) and squamous cell carcinoma (SCC) using the novel device line-field confocal optical coherence tomography (LC-OCT). Methods: Dermoscopy and LC-OCT images of 73 histopathologically confirmed lesions (46 AKs, 11 BD and 16 SCCs) were included in the study. Exemplary lesions (10 AKs, 5 BD and 5 SCCs) were additionally investigated with optical coherence tomography and reflectance confocal microscopy. Results: Most common LC-OCT findings of KC in the descriptive statistics were hyperkeratosis/parakeratosis, disruption of stratum corneum, broadened epidermis, basal and suprabasal keratinocyte atypia, dilated vessels/neoangiogenesis and elastosis/collagen alterations. In the univariate multinomial logistic regression, a preserved DEJ was less common in SCC compared with AK and BD, BD displayed marked keratinocyte atypia involving all epidermal layers (bowenoid pattern), while SCC showed ulceration, increased epidermal thickness, keratin plugs, acantholysis, not visible/interrupted DEJ and epidermal bright particles. LC-OCT increased the diagnostic confidence by 24.7% compared with dermoscopy alone. Conclusions: Our study describes for the first time specific LC-OCT features of different stages of KC and their histopathological correlates, focusing on keratinocyte morphology and architecture of the epidermis and DEJ. LC-OCT may open new scenarios in the bedside diagnosis, treatment planning and follow-up of KC

Innovation in Actinic Keratosis Assessment: Artificial Intelligence-Based Approach to LC-OCT PRO Score Evaluation

Actinic keratosis (AK) is a common skin cancer in situ that can progress to invasive SCC. Line-field confocal optical coherence tomography (LC-OCT) has emerged as a non-invasive imaging technique that can aid in diagnosis. Recently, machine-learning algorithms have been developed that can automatically assess the PRO score of AKs based on the dermo-epidermal junction’s (DEJ’s) protrusion on LC-OCT images. A dataset of 19.898 LC-OCT images from 80 histologically confirmed AK lesions was used to test the performance of a previous validated artificial intelligence (AI)-based LC-OCT assessment algorithm. AI-based PRO score assessment was compared to the imaging experts’ visual score. Additionally, undulation of the DEJ, the number of protrusions detected within the image, and the maximum depth of the protrusions were computed. Our results show that AI-automated PRO grading is highly comparable to the visual score, with an agreement of 71.3% for the lesions evaluated. Furthermore, this AI-based assessment was significantly faster than the regular visual PRO score assessment. The results confirm our previous findings of the pilot study in a larger cohort that the AI-based grading of LC-OCT images is a reliable and fast tool to optimize the efficiency of visual PRO score grading. This technology has the potential to improve the accuracy and speed of AK diagnosis and may lead to better clinical outcomes for patients

Ex vivo confocal laser scanning microscopy: A diagnostic technique for easy real-time evaluation of benign and malignant skin tumours

Ex vivo confocal laser scanning microscopy (ex vivo CLSM) is a novel diagnostic tool for a quick bedside evaluation of freshly excised tissue, comparable to histology. We aimed to assess the sensitivity and specificity of ex vivo CLSM in detecting malignant features, to validate its reliability in identifying various skin tumours based on a combination of confocal features and to evaluate the digital staining mode (DS). One-hundred twenty freshly excised skin samples from 91 patients were evaluated. Each lesion was screened for the presence of 23 predefined confocal criteria with ex vivo CLSM, followed by a histopathological examination. The diagnostic agreement between ex vivo CLSM and histology was 89.2%. The diagnostic accuracy of ex vivo CLSM in detecting malignancy reached a sensitivity of 98% and a specificity of 76%. Ex vivo CLSM enabled a rapid identification of the most common skin tumours, the tumour dignity and cytological features. The DS demonstrated a close resemblance to conventional histopathology