When the second comes first- rhabdomyosarcoma preceding heritable retinoblastoma- a case report.

BACKGROUND: Retinoblastoma (rb) is the most frequent intraocular tumor, accounting for 3% of all childhood cancers. Heritable rb survivors are germline carriers for an RB1 mutation and have a lifelong risk to develop non-ocular second primary tumors (SPTs) involving multiple other organs like the bones, soft tissues, or skin. These SPTs usually become manifest several years succeeding the diagnosis of rb. In our instance, however, a non-ocular SPT presented prior to the diagnosis of heritable rb. CASE PRESENTATION: We report a rare case of a monozygotic twin who presented with primary rhabdomyosarcoma (RMS) preceding the manifestation of heritable rb. The rb was diagnosed when the child developed strabismus while already on therapy for the RMS. The child underwent therapy for both as per defined treatment protocols. The rb regressed well on treatment, but the RMS relapsed and the child developed multiple refractory metastatic foci and succumbed to his disease. CONCLUSIONS: Non-ocular SPTs like sarcomas are usually known to manifest in heritable rb survivors with a lag of two to three decades (earlier if exposure to radiation is present) from the presentation of the rb. However, in our case, this seemed to be reversed with the RMS being manifest at an unusual early age and the rb being diagnosed at a later point in time.

Prenatal magnetic resonance imaging of complex female genitourinary system abnormalities, what the fetal medicine specialist needs to know.

Complex female genitourinary system anomalies include a wide spectrum of uncommon pathologies, caused from the abnormal separation of the urorectal septum and the urogenital sinus in early embryonic life. The resulting fusion of the distal urinary, genital and intestinal tracts increases the risk of death in utero and alters the normal organ functionality and the quality of life in survivors. An accurate prenatal identification of these pathologies depends mainly on prior suspicion at ultrasound screening, but also requires a solid knowledge of embryology and familiarity with the different patterns of malformation. Prenatal MRI provides an excellent anatomic evaluation of the fetal anatomy that may improve the diagnosis in complex cases with inconclusive echographic findings. The additional information can help both families and medical teams to better evaluate the severity of the pathology and the postnatal prognosis and therefore to better orientate the management during pregnancy, at delivery and after birth. This review article describes the embryological basis and the clinical findings of the most relevant pathologies included in the spectrum. It also describes the imaging signs on prenatal MRI studies in a series of confirmed cases and proposes a diagnostic algorithm based on imaging findings for guiding prenatal diagnosis.

Prenatal imaging of anorectal malformations - 10-year experience at a tertiary center in Switzerland.

BACKGROUND: Anorectal malformation is a spectrum of congenital defects of the distal bowel, mostly diagnosed at birth. OBJECTIVE: To describe the prenatal imaging findings of anorectal malformations, explore the causes of the low rates of prenatal diagnosis, compare the accuracy of prenatal ultrasound (US) and magnetic resonnance imaging [MRI] and evaluate the relevance of information obtained at MRI. MATERIALS AND METHODS: Children treated for anorectal malformation at our hospital and with available prenatal studies were retrospectively identified and included in the study. We reviewed prenatal imaging exams, listed findings suggestive of the diagnosis, and compared results with the final classification. RESULTS: Fourteen fetuses and neonates - eight with intermediate-high type anorectal malformation and six with cloacae - fulfilled the inclusion criteria. All had associated congenital anomalies. Prenatal exams included 13 US and 8 MRI exams, with 7 children having both exams. Suggestive findings for anorectal malformation were detected in 50% of the cases prenatally and in 85% upon review. They were prospectively detected in 31% and 50% of the cases at US and MRI and retrospectively in 62% and 100% at US and MRI, respectively. MRI was superior to US because it improved the diagnosis, especially in cloacae, and provided relevant additional information that changed management in two cases. CONCLUSION: The most important signs suggesting anorectal malformation are an absent target sign and anomalous distal bowel wall and rectal fluid. Complementary prenatal MRI improves the diagnosis of anorectal malformation.

Imaging findings of bronchial atresia in fetuses, neonates and infants.

Congenital lung malformations are increasingly detected before birth. However, bronchial atresia is rarely identified in utero and not always recognized in neonates. There are two types of atresia: 1) proximal, located at the level of the mainstem or the proximal lobar bronchi, which is extremely rare and usually lethal during pregnancy, causing a tremendous volume increase of the distal involved lung with secondary hypoplasia of the normal lung, and 2) peripheral, located at the segmental/subsegmental bronchial level, which may present as an isolated lesion or as part of a complex congenital malformation. Prenatal findings are mostly nonspecific. Postnatal exams show overinflated lung areas and focal bronchial dilations. The typical fluid-filled bronchoceles are not always observed in neonates but develop progressively in the first months of life. This pictorial essay describes the spectrum of imaging findings of bronchial atresia in fetuses, neonates and infants.

Development of MDS in Pediatric Patients with GATA2 Deficiency: Increased Histone Trimethylation and Deregulated Apoptosis as Potential Drivers of Transformation.

GATA2 deficiency is a heterogeneous, multisystem disorder associated with a high risk of developing myelodysplastic syndrome (MDS) and the progression to acute myeloid leukemia. The mechanisms underlying malignant transformation in GATA2 deficiency remain poorly understood, necessitating predictive markers to assess an individual's risk of progression and guide therapeutic decisions. In this study, we performed a systematic analysis of bone marrow biopsies from 57 pediatric MDS patients. Focusing on hematopoiesis and the hematopoietic niche, including its microenvironment, we used multiplex immunofluorescence combined with multispectral imaging, gene expression profiling, and multiplex RNA in situ hybridization. Patients with a GATA2 deficiency exhibited a dysregulated GATA2 transcriptional network. Disease progression (GATA2-EB, n = 6) was associated with increased GATA2 mRNA levels, restored expression of the GATA2 target EZH2, and increased H3K27me3. GATA2-EB was further characterized by the high expression of the anti-apoptotic protein BCL2, a feature absent in children with a GATA2 deficiency and refractory cytopenia of childhood (GATA2-RCC, n = 24) or other pediatric MDS subgroups (RCC, n = 17; MDS-EB, n = 10). The multispectral imaging analysis of additional BCL2 family members revealed significantly elevated Mediators of Apoptosis Combinatorial (MAC) scores in GATA2-EB patients. Taken together, our findings highlight the potential drivers of disease progression in GATA2 deficiency, particularly increased histone trimethylation and dysregulated apoptosis. Furthermore, upregulated BCL2 and EZH2 and increased MAC scores provide a strong rationale for the use of venetoclax and azacitidine in therapeutic regimens for GATA2-EB.

Neuroblastic Tumors of the Adrenal Gland in Elderly Patients: A Case Report and Review of the Literature.

Background: Neuroblastic neoplasms (NN) include ganglioneuromas (GN), ganglioneuroblastomas (GNB), and neuroblastomas (NB). They generally arise in childhood from primitive sympathetic ganglion cells. Their incidence in adults, especially among elderly, is extremely low. Case Presentation: This is the case of a 74-year-old woman with history of abdominal pain, weakness and night sweating since several months. Blood pressure was normal. CT-scan showed a 10 cm left adrenal mass, without other pathologic findings. An open left-sided adrenalectomy was performed. Recovery was uneventful with hospital length of stay of 8 days. Based on morphological, immunohistochemical, and molecular features the diagnosis was a nodular GNB. A positron emission tomography (PET) performed 6 weeks after the resection did not show any residual tumor or distant metastases. The patient was followed-up with annual clinical and radiological exams. Conclusion: This case presentation, associated with a review of the literature, illustrates the importance to include NN in the preoperative differential diagnosis of adrenal tumors in adults and highlights the need for multidisciplinary patient work-up and management.

Agenesis of the Corpus Callosum with Facial Dysmorphism and Intellectual Disability in Sibs Associated with Compound Heterozygous KDM5B Variants.

We studied a family in which the first-born child, a girl, had developmental delay, facial dysmorphism, and agenesis of the corpus callosum (ACC). The subsequent pregnancy was interrupted as the fetus was found to be also affected by ACC. Both cases were heterozygous for two KDM5B variants predicting p (Ala635Thr) and p (Ser1155AlafsTer4) that were shown to be in trans. KDM5B variants have been previously associated with moderate to severe developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), and dysmorphism in a few individuals, but the pathogenetic mechanisms are not clear yet as patients with both monoallelic and biallelic variants have been observed. Interestingly, one individual has previously been reported with ACC and severe ID in association with biallelic KDM5B variants. Together with the observations in this family, this suggests that agenesis of the corpus callosum may be part of the phenotypic spectrum associated with KDM5B variants and that the KDM5B gene should be included in gene panels to clarify the etiology of ACC both in the prenatal and postnatal setting.

Decreased Fetal Movements: A Sign of Placental SARS-CoV-2 Infection with Perinatal Brain Injury.

Neonatal COVID-19 is rare and mainly results from postnatal transmission. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), however, can infect the placenta and compromise its function. We present two cases of decreased fetal movements and abnormal fetal heart rhythm 5 days after mild maternal COVID-19, requiring emergency caesarean section at 29 + 3 and 32 + 1 weeks of gestation, and leading to brain injury. Placental examination revealed extensive and multifocal chronic intervillositis, with intense cytoplasmic positivity for SARS-CoV-2 spike antibody and SARS-CoV-2 detection by RT-qPCR. Vertical transmission was confirmed in one case, and both neonates developed extensive cystic peri-ventricular leukomalacia.

AID protein expression in chronic lymphocytic leukemia/small lymphocytic lymphoma is associated with poor prognosis and complex genetic alterations.

The biological behavior of chronic lymphocytic leukemia and small lymphocytic lymphoma is unpredictable. Nonetheless, non-mutated IgV(H) gene rearrangement, ATM (11q22-23) and p53 (17p13) deletion are recognized as unfavorable prognosticators in chronic lymphocytic leukemia. The mRNA expression of activation-induced cytidine deaminase (AID), an enzyme indispensable for somatic hypermutation processes, was claimed to be predictive of non-mutated chronic lymphocytic leukemia cells in blood. Here, we evaluated AID protein expression compared with known molecular and immunohistochemical prognostic indicators in 71 chronic lymphocytic leukemia/small lymphocytic lymphoma patients using a tissue microarray approach. We found AID heterogeneously expressed in tumor cells as shown by colocalization analysis for CD5 and CD23. Ki-67 positive paraimmunoblasts of the proliferation centers displayed the highest expression. This observation is reflected by a significant association of AID positivity with a high proliferation rate (P=0.012). ATM deletion was detected in 10% (6/63) of patients and p53 deletion in 19% (13/67) of patients. Moreover, both ATM (P=0.002) and p53 deletion (P=0.004) were significantly associated with AID. IgV(H) gene mutation was seen in 45% (27/60) of patients. Twenty-five percent (17/69) of patients with AID-positive chronic lymphocytic leukemia/small lymphocytic lymphoma displayed a shorter survival than AID-negative chronic lymphocytic leukemia/small lymphocytic lymphoma patients (61 vs 130 months, P=0.001). Although there was a trend, we could not show an association with the IgV(H) gene mutation status. Taken together, our study shows that AID expression is an indicator of an unfavorable prognosis in chronic lymphocytic leukemia/small lymphocytic lymphoma patients, although it is not a surrogate marker for the IgV(H) status. Furthermore, the microenvironment of proliferation centers seems to influence AID regulation and might be an initiating factor in its transformation.

Extranodal manifestation of Rosai-Dorfman disease without involvement of lymph nodes.

BACKGROUND: Rosai-Dorfman disease is an uncommon sinus histiocytosis with massive lymphadenopathy. Rosai-Dorfman disease without lymphadenopathy is extremely rare. Extranodal pseudotumoral masses can occur--and have been identified and described--in the orbit, skin, bone, and upper respiratory tract. Because of its rareness, Rosai-Dorfman is seldom considered in the clinical differential diagnosis, particularly if extranodal manifestations predominate. METHODS AND RESULTS: We present herein a patient with extranodal manifestation of Rosai-Dorfman disease in the orbit and parotid without typical initial lymph node involvement that reacted on steroid therapy. CONCLUSIONS: The correct diagnosis of this entity with the knowledge that it can occur without lymphadenopathy is important. For these patients, diagnosis must be based on histologic and immunohistopathologic findings after surgical biopsy. Steroid therapy can be used for treatment.

Primary blastomycosis of oral cavity.

BACKGROUND: Blastomycosis is an uncommon male-predominant disease caused by the fungus Blastomyces dermatitidis. The lungs are most commonly affected, and other organs are usually involved by dissemination. Clinical feature and pathohistologic findings are similar to the appearance of squamous cell carcinoma. METHODS AND RESULTS: A 52-year-old male patient who has lived as a farmer on the countryside in Argentina for 35 years presented with an initial histopathologic diagnosis of a squamous cell carcinoma of the right lower jaw. There was no history of pulmonary disease, in particular fever, coughing, or hemoptysis. Final pathohistologic evaluation after resection revealed B. dermatitidis infection. This article presents the first described case of oral manifestation of B. dermatitidis infection in Switzerland. CONCLUSIONS: Manifestation of blastomycosis in oral tissue can mimic the feature of a squamous cell carcinoma and can therefore be a diagnostic pitfall that head and neck surgeons and a pathologist should be aware of.

Compassionate Use of Letermovir in a 2-Year-Old Immunocompromised Child With Resistant Cytomegalovirus Disease.

Little information on the efficacy and pharmacokinetics of letermovir among immunocompromised children is currently available. We describe here the use of letermovir in a 2-year-old immunocompromised child with ganciclovir-resistant cytomegalovirus disease who required extracorporeal membrane oxygenation. Detailed information on therapeutic-drug-monitoring measures and dosage adjustments for letermovir is provided.

Translocation-positive low-grade fibromyxoid sarcoma: clinicopathologic and molecular analysis of a series expanding the morphologic spectrum and suggesting potential relationship to sclerosing epithelioid fibrosarcoma: a study from the French Sarcoma Group.

Low-grade fibromyxoid sarcomas (LGFMS) bear either the t(7,16) (q32-34;p11) or t(11,16) (p11;p11) translocations, resulting in FUS-CREB3L2 or FUS-CREB3L1 fusions, respectively. Heretofore, fusion transcripts were mainly detected in frozen tissues, using reverse transcription-polymerase chain reaction. In this study, we aimed to develop a reliable method to detect these in paraffin-embedded tissues, and to examine the clinicopathologic characteristics of a series of translocation-positive LGFMS. Sixty-three neoplasms with typical morphologic features of LGFMS and 66 non-LGFMS tumors selected for their resemblance to LGFMS (LGFMS-like tumors) were examined. RNA of sufficient quality could be extracted from 111/129 (86%) cases (59 LGFMS, 52 non-LGFMS). Of all, 48/59 (sensitivity, 81%) LGFMS contained detectable transcripts (45 FUS-CREB3L2, 3 FUS-CREB3L1). Most relevant clinicopathologic features of fusion-positive LGFMS included predominance in lower extremities (22/48; thigh: 13/48), deep situation (46/48), and occasional presence of unusual histologic features, for example, hypercellular areas (16/48), foci of epithelioid cells (13/48), and giant rosettes (6/48). Most tumors expressed EMA (41/45), at least focally, CD99 (38/41) and bcl-2 (36/41) while being essentially negative for CD34 (2/45), mdm2 (1/41), smooth muscle actin (1/45), S100 protein (0/46), desmin (0/44), h-caldesmon (0/42), keratins (0/44), and CD117 (0/40). Eleven presumed LGFMS were fusion negative. Of all, 7/52 non-LGMFS neoplasms contained FUS-CREB3L2 transcripts, of which 4 had been diagnosed as sclerosing epithelioid fibrosarcoma. In conclusion, FUS-CREB3L1/L2 fusion transcripts can be detected in paraffin-embedded LGFMS in a sensitive manner, using reverse transcription-polymerase chain reaction. Most fusion-positive LGFMS are EMA-positive and CD34/S100/smooth muscle actin negative. The presence of epithelioid cells and fusion transcripts in both LGFMS and a subset of sclerosing epithelioid fibrosarcoma suggest that these neoplasms might be related.

[The place of the pathologist in the management of tumors of soft tissue]. / Tumeurs des tissus mous: rôle du pathologiste dans l'approche diagnostique.

Soft tissue tumors represent a heterogeneous group of lesions which include benign and malignant (sarcomas) mesenchymal proliferations. Sarcomas are rare and represent a real challenge in terms of diagnosis and therapy for the multidisciplinary medical team. The pathologist has to establish the correct diagnosis by answering several questions: is the lesion benign or malignant? if malignant, is it a sarcoma? and what type of sarcoma is it? He has to inform the clinician regarding the potential presence of prognostic factors. Careful evaluations of surgical margins of the resection specimen or of tumor response to neoadjuvant chemotherapy are additional aspects of the pathologic report. Optimal management of the patient depends on a close collaboration between pathologists, surgeons, radiologists, oncologist and radiotherapists.

Primary clear cell sarcoma of the ileum: an uncommon and misleading site.

A clear cell sarcoma, arising primarily in the ileum of a 35-year-old man, is reported. Histologically, the neoplasm infiltrated the full thickness of the intestinal wall. It consisted of strands and sheets of round to spindle-shaped cells with clear to eosinophilic cytoplasm, vesicular nuclei and prominent nucleoli. Vascular invasion was present at diagnosis. Tumour cells expressed S-100 protein, melan-A and tyrosinase. They were negative for HMB45, CD117, cytokeratins, epithelial membrane antigen, smooth muscle actin, desmin, CD31, CD34, chromogranin and synaptophysin. Reverse transcription-polymerase chain reaction analysis performed on paraffin-embedded tissue showed EWS-ATF1 fusion transcripts representative of the t(12;22) (q13;q12) clear cell sarcoma reciprocal translocation. The patient, who developed liver metastases 2 months after diagnosis, died of disease at 15 months. This case demonstrates that the gastrointestinal tract is a potential site for primary clear cell sarcoma of soft tissues, and, furthermore, that cytogenetics and/or molecular techniques play a central role in the diagnosis.

[Thymic neuroendocrine tumors: report on 6 cases]. / Les tumeurs neuroendocrines du thymus.

AIM: the aim of our study was to analyze a series of 6 thymic neuroendocrine tumors (TNET). METHODS: we report the clinical and pathological features of 6 TNET reclassified according to the last WHO classification (2004). RESULTS: there were 4 men and 2 women, (mean age of 61.3 years), presenting with local symptoms in 4 cases. The tumors were reclassified as 3 atypical carcinoids (AC), 2 small cell carcinomas (SCC) and 1 large cell neuroendocrine carcinoma (LCNEC). Cytokeratin, EMA and neuroendocrine markers were expressed in poorly-differentiated tumors. Two patients were lost of follow-up. Two patients with AC died of disease at 20 and 36 months. One patient with SCC died of disease at 2 years and the patient with the LCNEC died of disease in 3 months. CONCLUSION: TNET are poor prognosis tumors with a prognosis similar to thymic carcinomas. Adequate surgical resection is a strong prognosis factor.

[Sarcomatoid carcinoma of small intestine: diagnostic problems raised by an unusual tumor]. / Carcinome sarcomatoïde de l'intestin grêle: problèmes diagnostiques posés par une tumeur inhabituelle.

Sarcomatoid carcinomas involving the intestinal tract are rare and usually associated with poor prognosis. We report a case of sarcomatoid carcinoma of the ileum, diagnosed in a 61-year-old man. The patient presented with acute intestinal occlusion. Surgical resection of the ileum was performed. At macroscopic examination, two large polypoid masses were found. Frozen section examination suggested the diagnosis of malignant stromal tumor. At histological examination, both tumors were formed by pleiomorphic, large spindle cells, presenting numerous mitoses and marked nuclear atypia. Immunohistochemical examination showed that tumor cells coexpressed vimentin and epithelial markers (cytokeratins, EMA). The final diagnosis was monomorphic sarcomatoid carcinoma. The patient deceased with metastatic disease after 3 months of follow-up. This report underlines the potential diagnostic problems raised by this unusual type of carcinoma and emphasizes the role of immunohistochemistry in assessing the correct diagnosis.