The evidence-based role of catecholaminergic PET tracers in Neuroblastoma. A systematic review and a head-to-head comparison with mIBG scintigraphy.

BACKGROUND: Molecular imaging is pivotal in staging and response assessment of children with neuroblastoma (NB). [123I]-metaiodobenzylguanidine (mIBG) is the standard imaging method; however, it is characterised by low spatial resolution, time-consuming acquisition procedures and difficult interpretation. Many PET catecholaminergic radiotracers have been proposed as a replacement for [123I]-mIBG, however they have not yet made it into clinical practice. We aimed to review the available literature comparing head-to-head [123I]-mIBG with the most common PET catecholaminergic radiopharmaceuticals. METHODS: We searched the PubMed database for studies performing a head-to-head comparison between [123I]-mIBG and PET radiopharmaceuticals including meta-hydroxyephedrine ([11C]C-HED), 18F-18F-3,4-dihydroxyphenylalanine ([18F]DOPA) [124I]mIBG and Meta-[18F]fluorobenzylguanidine ([18F]mFBG). Review articles, preclinical studies, small case series (< 5 subjects), case reports, and articles not in English were excluded. From each study, the following characteristics were extracted: bibliographic information, technical parameters, and the sensitivity of the procedure according to a patient-based analysis (PBA) and a lesion-based analysis (LBA). RESULTS: Ten studies were selected: two regarding [11C]C-HED, four [18F]DOPA, one [124I]mIBG, and three [18F]mFBG. These studies included 181 patients (range 5-46). For the PBA, the superiority of the PET method was reported in two out of ten studies (both using [18F]DOPA). For LBA, PET detected significantly more lesions than scintigraphy in seven out of ten studies. CONCLUSIONS: PET/CT using catecholaminergic tracers shows superior diagnostic performance than mIBG scintigraphy. However, it is still unknown if such superiority can influence clinical decision-making. Nonetheless, the PET examination appears promising for clinical practice as it offers faster image acquisition, less need for sedation, and a single-day examination.

Verrucous epidermal nevus as a manifestation of a type 2 mosaic PTEN mutation in Cowden syndrome.

Linear Cowden nevus, also known as linear PTEN nevus, is a type of epidermal nevus, first described in 2007, which is seen in patients with PTEN hamartoma tumor syndrome. It is considered to be a type 2 form of segmental mosaicism, and we suggest that it has certain clinical features that distinguish it from epidermal nevi seen in similar conditions, such as Proteus syndrome. We present a case of linear Cowden nevus in a 4-year-old boy and review the literature.

Neurofibromatosis type 1 families with first-degree relatives harbouring distinct NF1 pathogenic variants. Genetic counselling and familial diagnosis: what should be offered?

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder caused by pathogenic variants in NF1 Recently, NF1 testing has been included as a clinical criterion for NF1 diagnosis. Additionally, preconception genetic counselling in patients with NF1 focuses on a 50% risk of transmitting the familial variant as the risk of having a sporadic NF1 is considered the same as the general population. METHODS: 829 individuals, 583 NF1 sporadic cases and 246 patients with NF1 with documented family history, underwent genetic testing for NF1. Genotyping and segregation analysis of NF1 familial variants was determined by microsatellite analysis and NF1 sequencing. RESULTS: The mutational analysis of NF1 in 154 families with two or more affected cases studied showed the co-occurrence of two different NF1 germline pathogenic variants in four families. The estimated mutation rate in those families was 3.89×10-3, 20 times higher than the NF1 mutation rate (~2×10-4) (p=0.0008). Furthermore, the co-occurrence of two different NF1 germline pathogenic variants in these families was 1:39, 60 times the frequency of sporadic NF1 (1:2500) (p=0.003). In all cases, the de novo NF1 pathogenic variant was present in a descendant of an affected male. In two cases, variants were detected in the inherited paternal wild-type allele. CONCLUSIONS: Our results, together with previous cases reported, suggest that the offspring of male patients with NF1 could have an increased risk of experiencing de novo NF1 pathogenic variants. This observation, if confirmed in additional cohorts, could have relevant implications for NF1 genetic counselling, family planning and NF1 genetic testing.

Revisiting the UK Genetic Severity Score for NF2: a proposal for the addition of a functional genetic component.

BACKGROUND: Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder characterised by the development of multiple schwannomas, especially on vestibular nerves, and meningiomas. The UK NF2 Genetic Severity Score (GSS) is useful to predict the progression of the disease from germline NF2 pathogenic variants, which allows the clinical follow-up and the genetic counselling offered to affected families to be optimised. METHODS: 52 Spanish patients were classified using the GSS, and patients' clinical severity was measured and compared between GSS groups. The GSS was reviewed with the addition of phenotype quantification, genetic variant classification and functional assays of Merlin and its downstream pathways. Principal component analysis and regression models were used to evaluate the differences between severity and the effect of NF2 germline variants. RESULTS: The GSS was validated in the Spanish NF2 cohort. However, for 25% of mosaic patients and patients harbouring variants associated with mild and moderate phenotypes, it did not perform as well for predicting clinical outcomes as it did for pathogenic variants associated with severe phenotypes. We studied the possibility of modifying the mutation classification in the GSS by adding the impact of pathogenic variants on the function of Merlin in 27 cases. This revision helped to reduce variability within NF2 mutation classes and moderately enhanced the correlation between patient phenotype and the different prognosis parameters analysed (R2=0.38 vs R2=0.32, p>0001). CONCLUSIONS: We validated the UK NF2 GSS in a Spanish NF2 cohort, despite the significant phenotypic variability identified within it. The revision of the GSS, named Functional Genetic Severity Score, could add value for the classification of mosaic patients and patients showing mild and moderate phenotypes once it has been validated in other cohorts.

Manifestations, clinical course and prognostic markers in cutaneous polyarteritis nodosa.

BACKGROUND AND OBJECTIVES: Cutaneous polyarteritis nodosa (CPAN) is a comparatively rare form of vasculitis that affects small arteries and arterioles in the panniculus and dermo-subcutaneous junction. Limited information is available regarding its course in the European population. The aim of this study is to characterize the manifestations and prognostic markers of recurrence in CPAN. PATIENTS AND METHODS: We report a retrospective study of patients with clinical and histopathologic evidence of CPAN, which was treated at two tertiary referral centers in Spain between 1989 and 2019. RESULTS: 31 patients were included. The most frequent manifestation was subcutaneous nodules (90.3 %); ulcers were frequent at diagnosis (35.5 %). Two thirds of the patients had at least one extracutaneous manifestation. Seventeen patients (54.8 %) experienced relapse. The strongest predictor of recurrence was ulceration in the initial episode (OR 18.6; 95 % CI 2.73-38; p < 0.01). The pre-treatment results of laboratory parameters associated with inflammation (such as C-reactive protein and neutrophil-to-lymphocyte ratio) were significantly higher in the relapsing group. There were no disease-related deaths and none of the patients developed systemic PAN. CONCLUSIONS: Although CPAN is a vasculitis limited to the skin, symptoms may involve adjacent skeletal muscle or peripheral nerves. While the condition is not life-threatening, the presence of ulceration and elevation of certain laboratory parameters predicts a worse prognosis.

Trichophyton erinacei: an emergent pathogen of pediatric dermatophytosis / Trichophyton erinacei: un patógeno emergente en las dermatofitosis en niños

BACKGROUND: Dermatophytoses in children are common pathologies worldwide caused mainly by Trichophyton rubrum. However, due to the globalization and the atypical pets that people nowadays own, some zoonotic species are also involved in these lesions. CASE REPORT: We present two cases of tinea faciei caused by the zoonotic mould Trichophyton erinacei in two children that owned a guinea pig and a hedgehog, respectively. Mycological diagnosis was performed inoculating skin scales on Sabouraud-glucose agar plates supplemented with chloramphenicol, with and without gentamicin, and on Sabouraud-glucose agar tubes, with and without cycloheximide. Microscopical examination in both cases and ITS region sequencing to confirm the identification (performed in one of them) were compatible with T. erinacei. Multiple treatments like corticosteroids and antibiotics were prescribed prior to the accurate diagnosis. Finally, both patients received topical and oral terbinafine, respectively, the lesions being resolved entirely. CONCLUSIONS: Zoonotic fungi must be considered in the diagnosis of skin lesions. An accurate medical record, with a guided anamnesis about possible risk factors and an ongoing and open dialogue between health professionals, are essential to improve both the management of these exotic and zoophilic dermatophytoses

ANTECEDENTES: Las dermatofitosis son patologías comunes en niños y son causadas principalmente por Trichophyton rubrum. Sin embargo, debido a la globalización y a la presencia cada vez más frecuente de animales exóticos como mascotas, algunas especies zoonóticas menos habituales pueden convertirse en agentes causales. CASO CLÍNICO: Nuestro objetivo es describir dos casos de Tinea faciei causados por Trichophyton erinacei en dos niños que poseían, respectivamente, una cobaya y un erizo como mascotas. Se tomó muestra de escamas cutáneas que fueron inoculadas en placas de agar Sabouraud-glucosa suplementado con cloranfenicol, con y sin gentamicina, y en tubos de agar Sabouraud-glucosa con y sin cicloheximida. El examen microscópico fue compatible con Trichophyton erinacei, cuya identificación pudo ser confirmada por secuenciación de la región ITS en uno de los casos. Antes del correcto diagnóstico los pacientes habían recibido múltiples tratamientos (corticosteroides, antibióticos). Finalmente, los dos pacientes recibieron terbinafina tópica y oral, respectivamente, lo que llevó a la resolución completa de las lesiones. CONCLUSIONES: Los hongos zoonóticos deben ser considerados en el diagnóstico diferencial de las lesiones cutáneas. Una historia clínica con anamnesis guiada sobre posibles factores de riesgo, junto con una comunicación multidisciplinar fluida, es indispensable para mejorar el manejo de estas dermatofitosis

Trichophyton erinacei: an emergent pathogen of pediatric dermatophytosis.

BACKGROUND: Dermatophytoses in children are common pathologies worldwide caused mainly by Trichophyton rubrum. However, due to the globalization and the atypical pets that people nowadays own, some zoonotic species are also involved in these lesions. CASE REPORT: We present two cases of tinea faciei caused by the zoonotic mould Trichophyton erinacei in two children that owned a guinea pig and a hedgehog, respectively. Mycological diagnosis was performed inoculating skin scales on Sabouraud-glucose agar plates supplemented with chloramphenicol, with and without gentamicin, and on Sabouraud-glucose agar tubes, with and without cycloheximide. Microscopical examination in both cases and ITS region sequencing to confirm the identification (performed in one of them) were compatible with T. erinacei. Multiple treatments like corticosteroids and antibiotics were prescribed prior to the accurate diagnosis. Finally, both patients received topical and oral terbinafine, respectively, the lesions being resolved entirely. CONCLUSIONS: Zoonotic fungi must be considered in the diagnosis of skin lesions. An accurate medical record, with a guided anamnesis about possible risk factors and an ongoing and open dialogue between health professionals, are essential to improve both the management of these exotic and zoophilic dermatophytoses.

Are there distinct clinical and pathological features distinguishing idiopathic from drug-induced subacute cutaneous lupus erythematosus? A European retrospective multicenter study.

BACKGROUND: Clinical and pathologic criteria to distinguish drug-induced subacute lupus erythematosus (DI-SCLE) from idiopathic (I-SCLE) are controversial. OBJECTIVE: The aim of the survey was a retrospective analysis of a consistent number of iatrogenous and idiopathic SCLE cases, by means of clinical and histopathologic investigation. METHODS: Eleven European university dermatology units collected all diagnosed cases from January 2000 to December 2016. Board-certified dermatopathologists reviewed the histopathologic specimens. Statistical analysis included Student t test, exact test of goodness-of-fit, Fisher's exact test, and the Cochran-Mantel-Haenszel test for repeated measures. RESULTS: Out of 232 patients, 67 (29%) belonged to the DI-SCLE group. Patients with DI-SCLE were significantly older and reported more systemic symptoms than those with I-SCLE. No statistical differences were found for presentation pattern or serology, while histopathology showed a significant association of mucin deposition (P = .000083), direct immunofluorescence positivity for granular immunoglobulin M, and C3 deposits on the basement membrane zone (P = .0041) for I-SCLE and of leukocytoclastic vasculitis (P = .0018) for DI-SCLE. LIMITATIONS: This is a retrospective study. CONCLUSION: An integrated clinical and immunopathologic evaluation is useful to differentiate I-SCLE from DI-SCLE. Older age at onset and more frequent systemic symptoms characterize DI-SCLE. Mucin deposition and immunofluorescence findings are found in I-SCLE, and leukocytoclastic vasculitis is found in DI-SCLE.

One-step nucleic acid amplification for intraoperative analysis of sentinel lymph node in papillary thyroid carcinoma.

Objective Lymphadenectomy in papillary thyroid carcinoma (PTC) is controversial. It is indicated whenever metastases have been proven before or during surgery and as a prophylactic treatment in high-risk patients. However, 30-50% of cN0 patients become pN1 postoperatively. In PTC, selective-sentinel-lymph-node-biopsy (SLNB) with conventional intraoperative analysis is 8% false negative. One-step nucleic acid amplification (OSNA) is a molecular technique which allows real-time detection of mRNA encoding for cytokeratin 19. OSNA has been introduced in intraoperative analysis of several tumors to reduce false-negative rates and distinguish micrometastasis from macrometastasis. Our objective was to evaluate the impact of the introduction of OSNA in the intraoperative evaluation of the sentinel node (SN) in PTC. Design We analyzed a series of 35 patients subjected to SLNB. Methods All the dissected nodes, SN and non-SN, were evaluated with OSNA and cytology. Results We obtained a total of 110 SN. SLNB proved positive in 14 patients (40%) with cytology and in 23 (65.7%) with OSNA (P < 0.001). In the 29 patients with subsequent lymphadenectomy we obtained 360 lymph nodes ((52 positive in cytology (14.4%) and 107 in OSNA (29.7%)). Lymphadenectomy proved positive in 16 patients according to cytology (55%) and in 24 according to OSNA (83%) (P = 0002). The majority of patients with micrometastasis in SN showed only micrometastasis in lymphadenectomy. Conclusions The present study shows selective-sentinel-lymph-node-biopsy with one-step nucleic acid amplification technique to be feasible in papillary thyroid carcinoma. The quantitative nature of one-step nucleic acid amplification paves the way toward a more personalized surgical approach, limiting lymphadenectomy to patients with intraoperative evidence of macrometastasis in the sentinel node.

Subcutaneous panniculitis-like T-cell lymphoma: Clinical features, therapeutic approach, and outcome in a case series of 16 patients.

BACKGROUND: Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare primary cutaneous lymphoma of mature cytotoxic T cells. Initially, patients with SPTCL were treated with doxorubicin-based polychemotherapy. OBJECTIVE: To analyze clinical, biologic, immunophenotypical, molecular, imaging, treatment, and outcome data reflecting the current state of knowledge. METHODS: A retrospective multicenter study of 16 patients with SPTCL that was diagnosed between 1996 and 2016. RESULTS: The female-to-male ratio was 1.7. The median age at diagnosis was 46.5 years. Patients presented with multiple nodular or plaque-like lesions preferentially affecting the legs and/or trunk. Histopathology typically showed a lobular panniculitis with individual adipocytes surrounded by atypical lymphocytes, usually with a CD3+, CD4-, CD8+, CD56-, TIA1 cytotoxic granule associated RNA binding protein 1-positive phenotype and high proliferation rate. SPTCL was associated with autoimmune diseases in 25% of patients, and with the development of hemophagocytic syndrome in 18% of patients. Oral steroids alone or in combination with low-dose methotrexate or cyclosporine A were the most common initial treatment, achieving a complete response in 85% of the treated patients. The median follow-up time was 14 months. The 5-year disease-specific survival rate was 85.7%. LIMITATIONS: This was a retrospective study. CONCLUSIONS: SPTCL has an excellent prognosis. Immunosuppressive agents can be considered for first-line treatment.

Early Genetic Diagnosis of Neurofibromatosis Type 2 From Skin Plaque Plexiform Schwannomas in Childhood.

Importance: Neurofibromatosis type 2 (NF2) is a devastating genetic condition characterized by the development of multiple tumors of the nervous system. An early diagnosis of individuals with NF2 would facilitate treatment and reduction of disease impact because most severe effects of the disease do not usually develop before adolescence. Little attention has traditionally been paid to dermatological signs in NF2. However, skin plaques are commonly seen in patients with NF2, normally appearing either at birth or early childhood, providing an opportunity for early NF2 detection and testing. Objective: To determine the clinical utility of skin plaque identification and characterization in children for reaching an early diagnosis of patients with NF2 and to evaluate their molecular pathogenesis and their use in the genetic diagnostics of NF2. Design, Setting, and Participants: Diagnostic test study by the histological and genetic characterization of skin plaques from patients with NF2. Patients were 7 individuals with NF2 or clinical suspicion of NF2 treated at the Spanish Reference Center on Phakomatoses. Main Outcomes and Measures: Histological evaluation of all skin plaques was performed. Fresh skin plaques were cultured to obtain Schwann cells and the NF2 gene was genetically analyzed. For all 7 patients, NF2 clinical history was reviewed. Results: In all 7 patients (4 male and 3 female), all skin plaques analyzed were histologically characterized as plexiform schwannomas. Genetic analysis of primary Schwann cell cultures derived from them allowed the identification of a constitutional and a somatic NF2 mutation. Genetic testing allowed the early diagnosis of NF2 in a child only exhibiting the presence of skin plaques. Most of the patients with NF2 analyzed had an early presentation of skin plaques and a severe NF2 phenotype. Conclusions and Relevance: This work emphasizes the clinical utility of a careful dermatological inspection and the correct identification of skin plaques in children for an early diagnosis of NF2. We show for the first time that Schwann cells derived from skin plaque plexiform schwannomas bear the double inactivation of the NF2 gene and thus constitute an excellent source of tissue for genetic testing, especially in the context of mosaicism.

Pediatric Nuclear Medicine and its Development as a Specialty.

Pediatric Nuclear Medicine (PNM) offers to the pediatrician noninvasive procedures, with high clinical impact and low dosimetry. New techniques have been adapted to children, diminishing doses, always looking for less dosimetry, higher sensitivity and higher resolution images. PNM is and will remain a minority subspecialty, but highly complex for general NM physicians due to the different diagnostics in children and due to the higher technical complexity of the examinations. General NM physicians have to be trained and regularly receive CME in this field.