Francesca Diomedi Camassei

Eosinophilic Esophagitis and Barrett’s Esophagus: An Occasional Association or an Overlap Disease?

Background: Esophageal diseases are common in infants and children, and may present with several clinical and pathological aspects. Eosinophilic esophagitis (EE) is characterized by inflammatory, predominantly eosinophilic infiltrate (≧15 eosinophils per high-power field (HPF)) that is not responsive to acid suppression therapy. An immunoallergic pathogenesis has been hypothesized, likely related to food allergy. Barrett’s esophagus (BE) is due to chronic gastroesophageal reflux. The pathological consequence is the replacement of normal stratified squamous epithelium by columnar mucosa with goblet cells. Methods: We present 2 children with a history of food allergy. Endoscopy revealed linear furrows and yellow plaques in the mid-distal esophagus. Results: In both patients histology showed a high number of eosinophils (>30 at HPF) in the mid-distal esophagus and intestinal metaplasia with goblet cells in distal esophagus. Diagnosis of EE associated to BE was made. Restriction diet was administered to treat EE whereas, in 1 case, laparoscopic fundoplication was performed to treat BE. Follow-up showed a remission of endoscopic and histological aspects. Conclusions: The unusual, possibly fortuitous association of EE and BE, two conditions differing in etiopathogenesis, clinical and pathological features, calls for a correct diagnosis to offer suitable treatment and prognosis.

Nephroblastoma: Multidrug-resistance P-glycoprotein expression in tumor cells and intratumoral capillary endothelial cells

The development of chemoresistance in a variety of cancers seems related to overexpression of the P-glycoprotein (P-gp) drug pump. Nephroblastoma, the most common malignant renal tumor of childhood, usually is responsive to treatment, and prognosis is favorable in most cases. However, the disease in a subset of patients is refractory to treatment, and the disease follows an aggressive course. To study P-gp expression in this tumor and its correlation with outcome, tumor samples from 93 patients were examined by immunohistochemical analysis. P-gp expression was determined separately in both tumor cells and intratumoral capillary endothelium. The likelihood ratio test, the Kaplan-Meier method, and the log-rank test were used to evaluate its association with clinical course, grade, stage, and administration of preoperative chemotherapy. The results for the majority of nephroblastomas were variably positive; in 43 (46%) of them, newly formed capillary endothelial cells also stained positive. While no association of P-gp expression in tumor cells with clinical course, stage, and grade could be demonstrated, positivity in endothelial cells correlated significantly with unfavorable outcome, suggesting that chemoresistance depended on an active blood-tumor barrier. Previous chemotherapy induced P-gp overexpression in tumor cells.

NEOPLASTIC DISEASE AND DELETION 22q11.2: A MULTICENTRIC STUDY AND REPORT OF TWO CASES

Deletion 22q11.2 is a chromosomal abnormality detected in young patients with clinical manifestations of the DiGeorge/velocardiofacial syndrome. Conotruncal heart defects are also associated with del22q11.2. An association of these cardiac malformations with neoplasias has been observed. Our series includes two cases of malignancies, a hepatoblastoma and a renal-cell carcinoma, arising in children with complex cardiac malformations. The aim of the study was to determine if the deletion at 22q11.2 was present and could be responsible for both pathological processes. Del22q11.2 was identified in both cases. Comparative genomic hybridization revealed terminal gains on chromosomes 1q and Xq and terminal loss on 1p in the hepatoblastoma, and gains in 1p, 12q, 16p, 20q, 22q, and whole chromosome 19 and loss of Xq in the renal-cell carcinoma. Our results confirm a common genetic basis for cardiac malformations, and del22q11.2 presents a risk factor for the development of pediatric tumours.

Pituicytoma and cushing's disease in a 7-year-old girl: A mere coincidence?

Pituicytoma is a tumor extremely rare in childhood, with only 4 cases reported in literature. It is thought to arise from the specialized glial elements called “pituicytes.” The association of pituicytoma and Cushing’s disease (CD) has been described only once so far, in an adult patient. A 7-year-old girl was referred for clinical signs of hypercortisolism, and a diagnosis of CD was made. MRI revealed 2 pathologic areas in the pituitary gland. The patient underwent surgery, with microscopic transsphenoidal approach, and a well-circumscribed area of pathologic tissue was identified and removed. Surprisingly, histologic and immunohistochemical study provided unequivocal evidence of pituicytoma. No pituitary adenoma could be identified. For persistent hypercortisolism, the patient necessitated transsphenoidal endoscopic reintervention and 2 other lesions were removed. By immunohistological examination, these lesions were confirmed to be corticotropin-secreting adenoma. Unfortunately, there was no postoperative decrease in corticotropin and cortisol levels, and the patient underwent bilateral laparoscopic adrenalectomy. Considering that we report a second case of association of pituicytoma and corticotropin-secreting adenoma, that CD is infrequent, and pituicytoma is extremely rare in childhood, the coexistence of these 2 tumors should not be considered a mere coincidence. To date, there is no conclusive evidence about the origin of these different subtypes of pituitary tumors. This case supports the hypothesis that these tumors share a common progenitor cell, which could be the folliculostellate cell.

Expression of Glial Cell Line-Derived Neurotrophic Factor and Neurturin in Mature Kidney, Nephrogenic Rests, and Nephroblastoma: Possible Role as Differentiating Factors

Kidney development involves a series of complex interactions between the ureteric bud and undifferentiated mesenchyme, resulting in the production of the nephron unit. Among locally derived soluble factors, a particular relevance has been recognized to glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) for the mesenchyme-to-epithelial conversion of a metanephron. Nephroblastoma is a developmental tumor of the kidney deriving from metanephric blastema that mimics renal development and may offer an adequate model of human nephrogenesis. We investigated the immunohistochemical expression of GDNF, NTN, and their receptors (GFRα1, 2, and 3, and Ret) in normal human kidney and in 42 nephroblastomas, 20 of which were associated with nephrogenic rests (group A) and 22 were not (group B). We compared the immunostaining pattern in group A vs. group B and correlated clinical course with stage, grade, presence of nephrogenic rests, and immunohistochemical findings. GDNF, NTN, and their receptors were expressed in mature kidney and in 67% (GDNF) and 33% (NTN) of tumors, particularly in the epithelial component; precursor lesions were negative. No significant differences of expression were observed between groups A and B tumors. Low stage (P = 0.012), absence of nephrogenic rests (P = 0.016), intense expression of GDNF (P = 0.034), and NTN (P = 0.05) were associated with a more favorable outcome. Besides inductive activity in nephrogenesis, GDNF and NTN may play a role in maintaining differentiation and survival functions in mature kidney and may contribute to induce differentiation of nephroblastoma cells toward the less aggressive epithelial component. The pathway of activation seems to follow an autocrine/paracrine mechanism, as neurotrophic factors, GFRα1-2-3 receptors and Ret are coexpressed.

IDO1 involvement in mTOR pathway: a molecular mechanism of resistance to mTOR targeting in medulloblastoma

Medulloblastoma (MB) is the most common malignant brain tumor in children. Despite therapeutic advancements, high-risk groups still present significant mortality. A deeper knowledge of the signaling pathways contributing to MB formation and aggressiveness would help develop new successful therapies. The target of rapamycin, mTOR signaling, is known to be involved in MB and is already targetable in the clinical setting. Furthermore, mTOR is a master metabolic regulator able to control cell growth versus autophagy decisions in conditions of amino-acid deprivation that can be due to IDO1 enzymatic activity. IDO1 has been also implicated in the regulation of inflammation, as well as of T cell-mediated immune responses, in a variety of pathological conditions, including brain tumors. In particular, IDO1 induces expansion of regulatory T-cells (Treg), preventing immune response against tumor cells. Analysis of 27 MB tissue specimens for the expression of both mTOR and IDO1 showed their widespread expression in all samples. Testing their cooperation in vitro, a significant involvement of IDO1 in mTOR immunogenic pathway was found, able to counteract the aim of rapamycin treatment. In MB cell lines, inhibition of mTOR strongly induced IDO1 expression and activity, corroborating its ability to recruit Treg cells in the tumor microenvironment. The mTOR/IDO1 cross talk was found to be strictly specific of MB cells. We demonstrated that mTOR pathway cross talks with IDO1 pathway to promote MB immune escape, possibly contributing to failure of mTOR- targeted therapy.

Behavioral disorders as unusual presentation of pediatric extraventricular neurocytoma: report on two cases and review of the literature

BackgroundExtraventricular neurocytomas (EVNs) are rare parenchymal brain tumors, distinct from central neurocytomas that are typically located within the supratentorial ventricular system. Seizures and headache represent the most common symptoms of extraventricular neurocytomas in the cerebral hemisphere both in adult and pediatric population.Case presentationWe describe two cases of pediatric EVN with clinical onset characterized by behavioral and attention deficit/ hyperactivity disorders. The association between behavioral/attention disorders in childhood and the presence of a frontal neurocytoma has never been described before. Furthermore, inappropriate levels of inattention, hyperactivity and impulsivity are common among the neurobehavioral and developmental disorders in childhood. We reviewed 43 pediatric cases of extraventricular neurocytoma included in the PubMed database and their clinical presentation, and we never found this unusual relationship.ConclusionIn childhood, the attention/hyperactivity disorders seem to be often over-diagnosed. When these deficits are more subtle and do not well-fit in a specific neurocognitive disorder, the clinicians should have a suspicion that they might mask the clinical features of a frontal lesion. This paper is focused on the clinical presentation of the extraventricular neurocytoma and the possible organic etiology of an attention and hyperactivity deficit.

Metastatic Group 3 Medulloblastoma in a Patient With Tuberous Sclerosis Complex: Case Description and Molecular Characterization of the Tumor

Medulloblastoma is the most common pediatric brain tumor. We describe a child with tuberous sclerosis complex that developed a Group 3, myc overexpressed, metastatic medulloblastoma (MB). Considering the high risk of treatment‐induced malignancies, a tailored therapy, omitting radiation, was given. Based on the evidence of mammalian target of rapamycin mTORC, mTOR Complex; RAS, Rat sarcoma; RAF, rapidly accelerated fibrosarcoma (mTOR) pathway activation in the tumor, targeted therapy was applied resulting in complete remission of disease. Although the PI3K/AKT/mTOR signaling pathway plays a role in MB, we did not find TSC1/TSC2 (TSC, tuberous sclerosis complex) mutation in our patient. We speculate that a different pathway resulting in mTOR activation is the basis of both TSC and MB in this child; H&E, haematoxilin and eosin; Gd, gadolinium.

Acute kidney transplant rejection mediated by angiotensin II type 1 receptor antibodies in a pediatric hyperimmune patient

BackgroundSeveral cases of severe antibody-mediated rejection (AMR) secondary to antibodies against the angiotensin II type 1 receptor (AT1R-Ab) have been described with variable outcome.Case-Diagnosis/TreatmentWe report the case of a 13-year-old boy whose first kidney transplant failed due to steroid-resistant acute cellular rejection, with the subsequent development of sensitization. He received a second kidney transplant which was complicated by early humoral rejection, with weakly positive staining for the complement degradation product C4d. Test results were negative for donor-specific antibodies against human leukocyte antigens (HLA-DSA) and MHC class I-related chain A (MICA) but positive for AT1R-Ab. Retrospective testing of the sera collected during the first kidney transplant was also positive for AT1R-Ab. We therefore hypothesized that the failure of the first transplant was secondary to the same cause. Losartan was immediately introduced into the therapeutic regimen, and the patient showed an excellent clinical and histological recovery.ConclusionsTesting for AT1R-Ab in any hypertensive patient with acute rejection who tests negative or weakly positive for C4d and negative for HLA-DSA and who is refractory to therapy is highly advisable. Pre-transplant AT1R-Ab may be indicative of the outcome in patients whose first transplant failed. Prompt initiation of treatment with losartan—immediately after transplantation in patients with pre-existing AT1R-Ab—should be encouraged.

Role of Immunohistochemistry in the Identification of Supratentorial C11ORF95-RELA Fused Ependymoma in Routine Neuropathology

Ependymomas (EPs) are tumors of the brain and spinal cord constituting ∼10% of the childhood central nervous system neoplasms and about 30% in children aged <3 years. Their anatomic distribution varies according to the age, with those arising in the supratentorial (ST) compartment, spinal cord being more common in older children and adults, and those at the infratentorial location are more common and occurring more frequently in infants and children. Recently, molecular classification of EP subgroups has been proposed and a supratentorial ependymoma subgroup characterized by RELA-fusion genes (ST-EP-RELA) has been established. It would be useful to define a standardized, robust method for the diagnosis of these relevant fusion genes. We used real-time polymerase chain reaction, conventional real-time polymerase chain reaction, and Sanger sequencing to characterize RELA fusion status in formalin-fixed paraffin-embedded samples from 42 ST-EPs (12 adults and 30 pediatric). We tested p65/RELA and L1CAM protein immunohistochemistry for their ability to predict RELA-fusion status. We reviewed clinical data to assess significant associations in this anatomic subgroup. Of the 42 patients, we identified RELA-fusion genes in 17 cases. L1CAM immunostaining displayed 94% sensitivity, 76% specificity, 73% positive predictive value (PPV), 95% negative predictive value (NPV). The p65/RELA immunostaining displayed 100% sensitivity, 92% specificity, 89.5% PPV, 100% NPV. Concordant double immunostaining improves PPV to 92.5% and maintains 100% NPV. Immunohistochemistry using both p65/RELA and L1CAM antibodies is valuable for ST-EP-RELA diagnosis: the negativity with both antibodies consistently predicts the absence of RELA fusions, whereas verification of fusion transcripts by molecular analyses is warranted only in single-positive or double-positive staining cases.