Latissimus dorsi free flap reconstruction of a temporal defect following pediatric oncologic surgery: Case report + literature review.

INTRODUCTION: Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children and adolescents. Around 35 % of pediatric sarcomas occur in the head and neck region. Consequently, RMS is considered the most common type of childhood malignancy diagnosed in this region. OBSERVATION: We report the clinical case of a 6 years old patient, who presented a large temporal hollowing following oncological excision surgery for temporal rhabdomyosarcoma. He underwent surgical reconstruction to fill the right temporalis fossa using a latissimus dorsi muscle free flap micro-anastomosed to the lingual vessels. DISCUSSION: This clinical case highlights the value of plastic surgery in oncological reconstruction, which, combined with a multidisciplinary and collective approach, enables a holistic approach and facilitates socio-psychological integration after oncological surgery in the pediatric population.

Unclassifiable interstitial lung disease and autoimmunity: Towards IPAF in children?

INTRODUCTION: Interstitial pneumonia with autoimmune features (IPAF) has been defined for adults with interstitial lung disease (ILD) and autoimmunity who do not meet the criteria for a specific connective tissue disease (CTD). We aimed to determine whether IPAF criteria could apply to children. METHODS: We retrospectively studied patients with ILD and autoimmunity followed at Necker Hospital between 2008 and 2019. Children were classified according to specific CTD and IPAF criteria. The epidemiology and course of the disease were studied according to the final diagnosis. RESULTS: Among 27 patients, 6 fulfilled the criteria for IPAF and represented 4.5% of all patients with ILD during the study period. Other diagnoses included juvenile dermatomyositis (30%), overlap syndromes (19%), systemic lupus erythematosus (15%), systemic sclerosis (7%), mixed CTD (4%), and rheumatoid arthritis (4%). IPAF patients were more frequently boys versus CTD-ILD patients (67% vs. 14%, p = .02). Two patients had severe respiratory distress that led to death for one of them. The course was favorable for the others, with a good response to steroids. The course tended to be more favorable for IPAF patients than for those with CTD-ILD (0% lung fibrosis in the IPAF group vs. 43% in the CTD-ILD group, p = .07). CONCLUSION: We confirmed the existence of IPAF in children. Its prevalence was lower than in adults but comparable to that found for other pediatric series. Boys were more highly represented than in CTD-ILD. The course was favorable for most cases. Larger and more prospective studies are needed to confirm these results.

[Pediatric very early onset inflammatory bowel disease: Role of pathology]. / Maladies inflammatoires intestinales pédiatriques de survenue très précoce : place de l'anatomie pathologique.

Inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, are a heterogeneous group of multifactorial pathologies, often polygenic, due to a dysregulated immune response in a genetically susceptible host. In children under 6 years of age, a significant proportion of IBD, named "very early onset inflammatory bowel diseases" (VEO-IBD), are monogenic disorders in more than one third of cases. Over 80 genes have been linked to VEO-IBD and pathological descriptions are sparce. In this clarification, we describe the clinical aspects of monogenic VEO-IBD and the main causative genes, as well as the various histological patterns observed in intestinal biopsies. The management of a patient with VEO-IBD should be a coordinated effort by a multidisciplinary team including pediatric gastroenterologists, immunologists, geneticists, and of course pediatric pathologists.

[Digestive infectious pathology: Diagnoses not to be missed]. / Pathologie infectieuse du tube digestif : diagnostics à ne pas manquer.

The recent context of COVID-19 has renewed the interest of pathologists in diseases of infectious origin. This interest is even stronger in the gastrointestinal tract where symptoms are aspecific, often frustrating with a normal endoscopic appearance sometimes leading to diagnostic erraticity. In this context, systematic biopsies performed by the clinician are sometimes the only way to reach a diagnosis. Nevertheless, the precise diagnosis of these pathologies requires a good knowledge of the context in which they occur, the histopathological aspect and a rigorous analysis using special stains and/or immunohistochemical analyses. Some infectious diseases of the gastrointestinal tract are well known to pathologists who are widely called upon to diagnose them (Helicobacter pylori gastritis, Candida albicans oesophagitis or CMV colitis), but others are more difficult to diagnose. In this article, we will present, after having recalled the various useful special stains, rare or difficult to diagnose bacterial or parasitic pathologies "not to be missed" in the digestive tract.

DOCK11 deficiency in patients with X-linked actinopathy and autoimmunity.

Dedicator of cytokinesis (DOCK) proteins play a central role in actin cytoskeleton regulation. This is highlighted by the DOCK2 and DOCK8 deficiencies leading to actinopathies and immune deficiencies. DOCK8 and DOCK11 activate CDC42, a Rho-guanosine triphosphate hydrolases involved in actin cytoskeleton dynamics, among many cellular functions. The role of DOCK11 in human immune disease has been long suspected but, to the best of our knowledge, has never been described to date. We studied 8 male patients, from 7 unrelated families, with hemizygous DOCK11 missense variants leading to reduced DOCK11 expression. The patients were presenting with early-onset autoimmunity, including cytopenia, systemic lupus erythematosus, skin, and digestive manifestations. Patients' platelets exhibited abnormal ultrastructural morphology and spreading as well as impaired CDC42 activity. In vitro activated T cells and B-lymphoblastoid cell lines from patients exhibited aberrant protrusions and abnormal migration speed in confined channels concomitant with altered actin polymerization during migration. Knock down of DOCK11 recapitulated these abnormal cellular phenotypes in monocytes-derived dendritic cells and primary activated T cells from healthy controls. Lastly, in line with the patients' autoimmune manifestations, we also observed abnormal regulatory T-cell (Treg) phenotype with profoundly reduced FOXP3 and IKZF2 expression. Moreover, we found reduced T-cell proliferation and impaired STAT5B phosphorylation upon interleukin-2 stimulation of the patients' lymphocytes. In conclusion, DOCK11 deficiency is a new X-linked immune-related actinopathy leading to impaired CDC42 activity and STAT5 activation, and is associated with abnormal actin cytoskeleton remodeling as well as Treg phenotype, culminating in immune dysregulation and severe early-onset autoimmunity.

Malignant Superficial Mesenchymal Tumors in Children.

Malignant superficial mesenchymal tumors are a very diverse group of neoplasms with few clinical and radiological discriminatory factors. Hence, some of these cancers are rarely suspected based on clinical and radiological grounds, others may be easily misdiagnosed, and the histological analysis of a biopsy or resection is central in the diagnostic process. In children, the age at presentation is a major element of the differential diagnosis. Some tumors have a very distinct epidemiology, while others may be seen at any age. More recently, the advances in molecular biology have greatly improved the diagnosis of mesenchymal tumors and new entities are still being described. In the present review, we provide an overview of the diversity of malignant superficial mesenchymal tumors in children, including new and/or rare entities. We discuss the important diagnostic features, be they clinical, histological, or molecular. Special attention was given to the genetic features of these tumors, particularly when they were helpful for the diagnosis or treatment.

Systemic inflammatory syndrome in children with FARSA deficiency.

Variants in aminoacyl-tRNA synthetases (ARSs) genes are associated to a broad spectrum of human inherited diseases. Patients with defective PheRS, encoded by FARSA and FARSB, display brain abnormalities, interstitial lung disease and facial dysmorphism. We investigated four children from two unrelated consanguineous families carrying two missense homozygous variants in FARSA with significantly reduced PheRS-mediated aminoacylation activity. In addition to the core ARS-phenotype, all patients showed an inflammatory profile associated with autoimmunity and interferon score, a clinical feature not ascribed to PheRS-deficient patients to date. JAK inhibition improved lung disease in one patient. Our findings expand the genetic and clinical spectrum of FARSA-related disease.

Establishing diagnostic criteria for mastocytosis in skin biopsies.

AIMS: The diagnosis of mastocytosis in skin biopsies can be challenging - particularly in cases with very few mast cells. More diagnostic criteria are needed. METHODS AND RESULTS: We analyzed 103 skin biopsies from patients with mastocytosis and compared them with biopsies from inflammatory skin lesions and normal skin. Using CD117 immunostaining, we determined the mast cell distribution pattern, the percentage of mast cells in the inflammatory infiltrate, and the mast cell count per mm². We found that a sheet-like or subepidermal distribution of mast cells was specific for mastocytosis. The most significant feature was the percentage of mast cells and not the mast cell count. We found that a mast cell percentage above 40% was fully specific in both adults and children but lacked sensitivity, especially in adults. In children, all cases with a percentage below 40% harbored a number of mast cells above 90 per mm², allowing a straightforward diagnosis. In adults, the diagnosis was more challenging and cases with less than 40% of mast cells could be diagnosed on account of a number of mast cells above 40 per mm², with 88.5% sensitivity and 95.2% specificity. Additional signs might be useful in difficult cases. However, CD25 immunostaining was not useful. CONCLUSIONS: We confirmed that the criteria currently applied in the bone marrow were not appropriate for the skin. Accordingly, we developed an algorithm for the diagnosis of mastocytosis in skin biopsies with a high level of interrater reproducibility (mean kappa 0.8).

Update on Superficial Spindle Cell Mesenchymal Tumors in Children.

The diagnosis of cutaneous and subcutaneous spindle cell neoplasms in children is often challenging and has potential therapeutic and prognostic implications. Although correctly diagnosing dermatofibrosarcoma protuberans and infantile fibrosarcoma is paramount, pathologists should not ignore a number of diagnostic pitfalls linked to mostly rare tumors with completely different clinical outcomes. In the last decade, a spectrum of novel entities has been described; information from molecular biology has helped to shape this new landscape for spindle cell tumors. Here, we review the most noteworthy neoplasms in this spectrum, with a focus on their histological similarities: fibroblastic connective tissue nevus, medallion-like dermal dendrocyte hamartoma, or plaque-like CD34-positive dermal fibroma, which share features with fibrous hamartoma of infancy; lipofibromatosis and lipofibromatosis-like neural tumor; and plexiform myofibroblastoma, a recently described neoplasm that should be distinguished from plexiform fibrohistiocytic tumor. These tumors also have genetic similarities, particularly gene rearrangements involving NTRK3 or NTRK1. These genetic features are not only essential for the differential diagnosis of infantile fibrosarcoma but are also of diagnostic value for lipofibromatosis-like neural tumors. The more recently described RET, RAF1, and BRAF gene fusions are also discussed.

A New Digital Method for Counting Mast Cells in Cutaneous Specific Lesions of Mastocytosis: A Series of Adult Cases of Mastocytosis With Clinical-Pathological Correlations.

ABSTRACT: Cutaneous mastocytosis is characterized by the abnormal accumulation of mast cells in the skin. However, mast cell counting is not always easy and reproducible with classical methods. This work aims to demonstrate the reliability, usability, and virtues of a new software used on digital tablets for counting mast cells in cutaneous specific lesions of mastocytosis, to assess differences in mast cell counts between clinical subtypes of mastocytosis in the skin, and to consider the feasibility of applying a diagnostic mast cell count cutoff to urticaria pigmentosa, which is the most frequent form of cutaneous mastocytosis. Using a new digital tablet software that was accessible by multiple observers through its own wireless network and allowed high resolution of the image without data compression, we counted the number of mast cells on slides of patients and control skins immunostained for CD117. We found that our counting method was highly reproducible and that the new software allowed very quick counting. We evidenced strong differences in the mast cell count between most of the clinical subtypes of mastocytosis in the skin. However, when applied to a subset of patients with urticaria pigmentosa, a diagnostic cutoff in the mast cell count lacked sensitivity. Thus, our digital method for counting CD117-immunostained mast cells was highly accurate and was of a significant value for the diagnosis of mastocytosis in the skin. However, some subtypes with low mast cell counts will still require the application of additional diagnostic criteria.

PHOX2B Immunostaining: A Simple and Helpful Tool for the Recognition of Ganglionic Cells and Diagnosis of Hirschsprung Disease.

Hirschsprung disease (HD) is a congenital disorder of the enteric nervous system that occurs in ∼1 in 5000 live births. It is characterized by the absence of ganglionic cells (GCs) in the distal intestine. The diagnosis relies on the thorough analysis of a rectal suction biopsy (RSB), which must show a complete absence of GCs after careful examination of at least 100 serial sections. Such a negative characteristic explains the difficulty of this diagnosis. Moreover, GCs may be immature in very young or preterm born children, making them hard to recognize. Therefore, ancillary techniques have been developed as diagnostic help, such as acetylcholinesterase histochemistry and calretinin immunostaining. These techniques reveal only indirect clues, focusing mainly on the changes in nerve fibers, but not on GCs themselves. As PHOX2B has been shown to be a very specific transcription factor in GCs and in progenitor enteric nerve cells, we have assessed (i) PHOX2B immunostaining in immature enteric ganglia and (ii) the use of PHOX2B immunostaining for the recognition of GCs on RSBs for suspicion of HD. We have observed PHOX2B expression in all GCs, both mature and immature, and its complete absence in Hirschsprung cases. We suggest that the use of PHOX2B immunostaining is of great help (i) in the recognition of GCs on RSBs regardless of their differentiation and therefore (ii) in the diagnosis of HD.

Epineural glomus tumor of the posterior interosseous nerve: Case report.

Among peripheral nerve sheath tumors, epineural glomus tumors represent a rare differential diagnosis for peripheral nerve schwannoma, displaying the same appearance on MRI. Here we present the case of a 68-year-old man complaining of pain in the left forearm, with paresthesias in the first three fingers. MRI demonstrated a round mass along the course of the posterior interosseous nerve with homogeneous contrast enhancement. Complete surgical removal successfully relieved the symptoms. Pathological analysis led to the diagnosis of glomus tumor of uncertain malignant potential. This is to our knowledge the first reported case of epineural glomus tumor of the radial nerve.

[A misleading breast metastasis of medullary thyroid carcinoma]. / Métastase mammaire d'un carcinome médullaire thyroïdien : un challenge diagnostique.

Recognition of mammary metastases by pathologists is fundamental because their prognosis and treatment are different from those of primary mammary carcinomas. We report the case of a 54-year-old woman presenting on her mammography a left breast nodule known for 5 years, having discreetly increased in size. Breast ultrasound showed a regular 1.2cm hypoechogenic nodular formation. A microbiopsy was performed. On microscopic examination, we observed a tumor proliferation realizing nests within a small, richly vascularized stroma. The tumor cells had a moderately abundant, eosinophilic, granular cytoplasm and a rounded, slightly atypical nucleus. One mitosis was found for 10 fields at×400 magnification. Tumor cells did not express hormone receptors but chromogranin A, synaptophysin, TTF1 and thyrocalcitonin. The proliferation index established by the anti-Ki67 antibody was 5 %. The diagnosis was a secondary localization of a well-differentiated neuroendocrine tumor which immunohistochemical profile firstly suggests a thyroid origin. We later learned that the patient had a history of total thyroidectomy 13 years ago. It was a sporadic medullary carcinoma of the thyroid. Bone scintigraphy revealed a lacunar lesion of the posterior part of the right iliac wing suspicious of secondary location. This right iliac lesion was biopsied. It was also a localization of the medullary thyroid carcinoma. The final diagnosis is a metastatic medullary thyroid carcinoma, slowly progressive, the mammary metastasis having probably existed for 5 years.