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Liver tissue from autopsies of 29 cases of children with acquired immunodeficiency syndrome (AIDS) were collected from three major South America (SA) pediatric hospitals. The hepatopathologic findings were classified in the same fashion as in a series of 61 children with AIDS from North America (NA): inflammation, nonspecific, lymphoproliferative disorders, and giant cell transformation. By comparing both groups, we noted that the SA children were younger at time of death which was consistent with a more rapid progression of the disease. Opportunistic infections varied with a higher prevalence of cytomegalovirus (CMV) infection in SA children. The histopathologic features of CMV in the livers of SA children were associated with a conspicuous inflammation absent in the NA group. Finally, different nonspecific hepatic changes were found in SA children, including one case of peliosis hepatis. [ABSTRACT FROM AUTHOR]

Liver tissue from autopsies of twenty-nine cases of children with AIDS were collected from three major South America (SA) pediatric hospitals. The hepatopathologic findings were classified in the same fashion as in a series of sixty-one children with AIDS from North America (NA): inflammation, nonspecific, lymphoproliferative disorders, and giant cell transformation. By comparing both groups, we noted that the SA children were younger at time of death consistent with a more rapid progression of the disease. Opportunistic infections varied with a higher prevalence of Cytomegalovirus (CMV) infection in SA children. The histopathologic features of CMV in the liver of SA children were associated with a conspicuous inflammation absent in the NA group. Finally, different non-specific hepatic changes were found in SA children, including one case of peliosis hepatis. [ABSTRACT FROM AUTHOR]

The development of a second malignancy after the diagnosis of childhood acute lymphoblastic leukemia (ALL) is a rare event. Certain second malignancies have been linked with specific elements of leukemia therapy, yet the etiology of most second neoplasms remains obscure and their optimal management strategies are unclear. This is a first comprehensive report of non-Hodgkin lymphomas (NHLs) following pediatric ALL therapy, excluding stem-cell transplantation. We analyzed data of patients who developed NHL following ALL diagnosis and were enrolled in 12 collaborative pediatric ALL trials between 1980-2018. Eighty-five patients developed NHL, with mature B-cell lymphoproliferations as the dominant subtype (56 of 85 cases). Forty-six of these 56 cases (82%) occurred during or within 6 months of maintenance therapy. The majority exhibited histopathological characteristics associated with immunodeficiency (65%), predominantly evidence of Epstein-Barr virus-driven lymphoproliferation. We investigated 66 cases of post-ALL immunodeficiency-associated lymphoid neoplasms, 52 from our study and 14 additional cases from a literature search. With a median follow-up of 4.9 years, the 5-year overall survival for the 66 patients with immunodeficiency-associated lymphoid neoplasms was 67.4% (95% confidence interval [CI], 56-81). Five-year cumulative risks of lymphoid neoplasm- and leukemia-related mortality were 20% (95% CI, 10.2-30) and 12.4% (95% CI, 2.7-22), respectively. Concurrent hemophagocytic lymphohistiocytosis was associated with increased mortality (hazard ratio, 7.32; 95% CI, 1.62-32.98; P = .01). A large proportion of post-ALL lymphoid neoplasms are associated with an immunodeficient state, likely precipitated by ALL maintenance therapy. Awareness of this underrecognized entity and pertinent diagnostic tests are crucial for early diagnosis and optimal therapy., (© 2023 by The American Society of Hematology.)

Previous studies have suggested that macrophages may contribute to acute Leptospira dissemination, as well as having a major role in kidney fibrosis. Our aim was to characterize the role of macrophages and galectin 3 (Gal-3) on the survival, clinical course, bacterial burden, interstitial nephritis, and chronic kidney fibrosis in Leptospira interrogans serovar Copenhageni (LIC)-induced experimental murine leptospirosis. C57BL/6J mice depleted of macrophages by liposome-encapsulated clodronate treatment and infected with LIC presented a higher bacterial burden, had reduced subacute nephritis and enhanced chronic kidney fibrosis relative to untreated, infected mice. Moreover, LIC infection in mice whose Gal-3 was disrupted ( Lgals3 - /- ) had a higher bacterial burden and enhanced subacute nephritis and chronic kidney fibrosis when compared to C57BL/6J wild-type mice. Chronic fibrosis did not correlate with higher transcription levels of TGF-β1 or IL-13 in the kidneys. Kidney fibrosis was found in chronically infected rats as well as in wild infected rats. On the other hand, human fibroblast cultures exhibited enhanced differentiation to myofibroblasts after treatment with LIC. Our results demonstrate that macrophages and Gal-3 play a critical role in controlling the LIC burden but has a minor role in subsequent fibrosis. Instead, kidney fibrosis was better correlated with bacterial burden. Taken together, our results do not support a role for macrophages to disseminate leptospires during acute infection, nor in chronic kidney fibrosis.

Gliofibroma is a relatively rare variant of a mixed glial-fibrous tumor more frequent in children than in adults. It has been reported to appear all along the neuraxis, with predilection for the midline. Its evolution is usually benign, although few examples have shown either multiple sites of involvement or leptomeningeal dissemination. Some authors regard it as part of the desmoplastic astrocytoma spectrum. We report here four examples of this rare condition which exemplify its histological patterns and biological behavior, and provide a review of the literature. Even though this tumor is commonly regarded as heterogeneous and with variable course, our literature review points to a set of clinical and pathological traits that are constant, such as age, location and gross and histological characteristics, as well as a predictable evolution. Currently, this tumor is not included in the WHO Classification of CNS tumors.

NETosis is a process by which neutrophils extrude their DNA together with bactericidal proteins that trap and/or kill pathogens. In the present study, we evaluated the ability of Leptospira spp. to induce NETosis using human ex vivo and murine in vivo models. Microscopy and fluorometric studies showed that incubation of human neutrophils with Leptospira interrogans serovar Copenhageni strain Fiocruz L1-130 (LIC) resulted in the release of DNA extracellular traps (NETs). The bacteria number, pathogenicity and viability were relevant factors for induction of NETs, but bacteria motility was not. Entrapment of LIC in the NETs resulted in LIC death; however, pathogenic but not saprophytic Leptospira sp. exerted nuclease activity and degraded DNA. Mice infected with LIC showed circulating NETs after 2 days post-infection (dpi). Depletion of neutrophils with mAb1A8 significantly reduced the amount of intravascular NETs in LIC-infected mice, increasing bacteremia at 3 dpi. Although there was a low bacterial burden, scarce neutrophils and an absence of inflammation in the early stages of infection in the kidney and liver, at the beginning of the leptospiruric phase, the bacterial burden was significantly higher in kidneys of neutrophil-depleted-mice compared to non-depleted and infected mice. Surprisingly, interstitial nephritis was of similar intensity in both groups of infected mice. Taken together, these data suggest that LIC triggers NETs, and that the intravascular formation of these DNA traps appears to be critical not only to prevent early leptospiral dissemination but also to preclude further bacterial burden.

Leptospirosis is a global zoonosis caused by pathogenic Leptospira, which can colonize the proximal renal tubules and persist for long periods in the kidneys of infected hosts. Here, we characterized the infection of C57BL/6J wild-type and Daf1-/- mice, which have an enhanced host response, with a virulent Leptospira interrogans strain at 14 days post-infection, its persistence in the kidney, and its link to kidney fibrosis at 90 days post-infection. We found that Leptospira interrogans can induce acute moderate nephritis in wild-type mice and is able to persist in some animals, inducing fibrosis in the absence of mortality. In contrast, Daf1-/- mice showed acute mortality, with a higher bacterial burden. At the chronic stage, Daf1-/- mice showed greater inflammation and fibrosis than at 14 days post-infection and higher levels at all times than the wild-type counterpart. Compared with uninfected mice, infected wild-type mice showed higher levels of IL-4, IL-10 and IL-13, with similar levels of α-smooth muscle actin, galectin-3, TGF-β1, IL-17, IFN-γ, and lower IL-12 levels at 90 days post-infection. In contrast, fibrosis in Daf1-/- mice was accompanied by high expression of α-smooth muscle actin, galectin-3, IL-10, IL-13, and IFN-γ, similar levels of TGF-β1, IL-12, and IL-17 and lower IL-4 levels. This study demonstrates the link between Leptospira-induced murine chronic nephritis with renal fibrosis and shows a protective role of Daf1.

Cryptosporidium parvum subtype IIaA21G1R1 oocysts were used to infect dexamethasone immunosuppressed N: NIH Swiss mice. This is the first Cryptosporidium mouse model in which the relationship between infection and apoptosis has been histologically studied at each portion of the gut in order to observe this dynamic in chronic cryptosporidiosis. Histology showed developmental stages in the duodenum, proximal and distal jejunum, ileum, cecum and colon, with the small intestine remaining infected until day 35 post infection. At proximal jejunum an inverse correlation between infection and apoptosis was observed at days 28 and 35 p.i. Data suggests that jejunum could be an interesting place to carry out further studies on the dynamics of Cryptosporidium infection and apoptosis. Based on these findings, this mouse model was useful to evaluate clinical, parasitological and histological aspects of C. parvum subtype IIaA21G1R1 infection, and it will be an appropriate tool to investigate different aspects of Cryptosporidium infection., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Little is known of early histologic changes in the mucosa of the colon aside from the polyps in Juvenile Polyposis. Provided with a surgical specimen of a total colectomy of a 6-year-old boy with this condition, this report describes those changes. The mucosa depicted a peculiar serrated profile of the uppermost part of the crypts due to elongation of them, dilated openings, and scant stroma. Also present were frequent aberrant crypts. Early juvenile polyps presented associated with lympho-glandular sites as distorted and microcystically dilated crypts containing granular and filamentous mucoid material. The findings possibly represent the abnormal cytologic potential of this genetic condition.

Hemorrhagic colitis (HC) is a severe manifestation of the hemolytic uremic syndrome (HUS). We performed a retrospective analysis of patients with HC with the following aims: (1) to characterize the clinicopathologic features; (2) to evaluate mortality rate; (3) to analyze severity of renal and central nervous system (CNS) disease. Patients with HC assisted between 1981-2009 were evaluated and compared with a control group of 137 patients without HC. Among 987 patients with diarrheal prodrome (D) + HUS, 54 (5.5%) presented HC. Clinical findings included abdominal pain (96%), distension (93%), hematochezia (44%), and abdominal mass (11%). Surgery was indicated in 35 patients (65%), and 17 (48.5%) required bowel resection. Transverse and ascending colon were most frequently affected. Macroscopic evaluation showed bowel necrosis (18) and perforation (12). Histologic evaluation (29) showed that 25 (86.2%) had necrosis of the affected segment (transmural in 21). A leukocyte count >20,000/mm(3) and hematocrit >30% were more common in HC patients than in controls (p < 0.001 and p < 0.0001, respectively). Mortality rate was higher in HC patients (33.3%) than in controls (1.4%; p < 0.0001). Dialysis >10 days, seizures, and coma were more frequent in HC patients than in controls (p < 0.0001). In summary, most patients had prominent abdominal findings, and almost 2/3 patients required surgery. Transverse/ascending colon was most affected, and the main histologic finding was transmural necrosis. Higher hematocrit and leukocytosis were frequent. Mortality rate was extremely high, and most had long-lasting anuria and severe neurologic involvement.

Adrenal agenesis (AA) defined by the complete absence of development of adrenals is a rare anomaly, which is documented mainly in experimental animals and less frequently in human subjects in the literature. This study was aimed at describing the varied phenotype of this condition in two stillborn and one termination of pregnancy fetuses and two neonates, the associated abnormalities and the difficulties encountered to achieve the prenatal diagnosis. Five cases with AA diagnosed at post-mortem examination were selected and their characteristics were analyzed. The detection of this unusual condition has usually been made as an incidental discovery at post-mortem examination. None of the cases described in this series had been diagnosed at prenatal ultrasonography. Respiratory distress was the commonest clinical presentation in the liveborn. Maternal diabetes was associated with one case. Anomalies of kidneys, lungs, spleen, and blood vessels were associated with two of the cases. No gonadal abnormalities were detected in any of the cases. These cases illustrate the varied clinical presentation of this rare condition and confirm the difficulty in achieving a prenatal diagnosis.

Terminal osseous dysplasia (TOD) is an X-linked dominant male-lethal disease characterized by skeletal dysplasia of the limbs, pigmentary defects of the skin, and recurrent digital fibroma with onset in female infancy. After performing X-exome capture and sequencing, we identified a mutation at the last nucleotide of exon 31 of the FLNA gene as the most likely cause of the disease. The variant c.5217G>A was found in six unrelated cases (three families and three sporadic cases) and was not found in 400 control X chromosomes, pilot data from the 1000 Genomes Project, or the FLNA gene variant database. In the families, the variant segregated with the disease, and it was transmitted four times from a mildly affected mother to a more seriously affected daughter. We show that, because of nonrandom X chromosome inactivation, the mutant allele was not expressed in patient fibroblasts. RNA expression of the mutant allele was detected only in cultured fibroma cells obtained from 15-year-old surgically removed material. The variant activates a cryptic splice site, removing the last 48 nucleotides from exon 31. At the protein level, this results in a loss of 16 amino acids (p.Val1724&#95;Thr1739del), predicted to remove a sequence at the surface of filamin repeat 15. Our data show that TOD is caused by this single recurrent mutation in the FLNA gene., (Copyright 2010 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

This case report describes the recognition of nodular and asymmetric perivascular clusters of myofibrolasts-leiomuscular cells in the stroma of immature chorionic villi associated with a fetus delivered at 26 weeks gestation with a peculiar variation of bone dysplasia syndrome and oligohydramnios. Although myofibroblasts are known to exist at these sites, the finding may represent an unusual mesenchymal dysplasia of the placenta perhaps related to the syndrome.

Langerhans cells histiocytosis (LCH) affecting the skin most commonly has clinical and histopathologic diagnostic features. We are reporting two examples of Langerhans cell (LC) hyperplasia recognized in the skin biopsies of two children initially interpreted as LCH. The first was an 8-year-old boy finally interpreted as having an atypical type of contact dermatitis, while the second, an 8-year-old girl, was assumed to have Pytiriasis lichenoides et varioliformis acuta. None showed evidences of scabies. Both presented spongiotic dermatitis with numerous CD1a+ cells. As more cases of LC hyperplasia are recognized, new details emerge helping in the differential diagnosis. Strict clinical-pathologic correlation is suggested in order to avoid misdiagnosis.

Arrhythmogenic ventricular cardiomyopathy (AVC) presents with fat replacement of the myocardium, most commonly of the right ventricle, and ventricular arrhythmias. We report an 11-year-old boy with Noonan syndrome, ventricular arrhythmias, and an ultrasound depicting hypertrophy of the ventricular septum with subaortic stenosis. A surgical resection of the left side of the ventricular septum revealed a thick fibroelastotic endocardium covering a broad band of mature adipose tissue focally containing myocardial cells, fibrosis and chronic inflammatory infiltrates. The two layers covered a band of hypertrophic myocardiocytes with mild interstitial fibrosis. Arrhythmogenic ventricular cardiomyopathy has not been previously reported in the Noonan syndrome.

Purpose: To present an infant with bilateral ocular and skin involvement by juvenile xanthogranuloma and the results of treatment with vinblastine., Methods: Analysis of the clinical and histopathologic data and the results of the treatment., Results: After 14 months' evolution with no response to other treatments, the lesions responded to a course of vinblastine (6 mg/m2/weekly, corrected for weight), which was followed by a maintenance treatment for 52 weeks., Conclusions: The treatment protocol used in the present case may prove useful for similar patients. We found no other report describing these results.

A 5-year-old girl known to have congenital dyshormonogenetic hypothyroidism since birth and under appropriate treatment (without goiter) developed a thyroid nodule which was found in the clinical follow-up. Fine-needle aspiration biopsy of the nodule allowed to diagnose a papillary thyroid carcinoma, a diagnosis which was certified by the surgical specimen exam. Dyshormonogenetic goiter may rarely associate with thyroid carcinoma. The present case appears unique since goiter was not present., ((c) 2009 Wiley-Liss, Inc.)

We are reporting the case of a young infant presenting with a cutaneous tubular bridge running from the dorsal aspect of the middle third of the thigh to the middle third of the leg resulting in a permanent flexion position of the limb. This finding was associated with another related to the amniotic band syndrome. Surgical resection showed a tube formed exclusively by normal skin tissue. The case appears unique although related lesions have been reported in the literature.

We report the case of an 8-year-old boy with the phenotypic features of Coffin-Siris syndrome diffuse hypertrichosis, flat occiput, scant scalp hair, flat supraorbital arch, triangular eyebrows, horizontal palpebral fissure, anteverted nares, triangular philtrum, coarse lips, high-arched palate, micrognathia, low set and dorsaly rotated ears, short neck, wide thorax, widely set nipples, transverse palmar crease, psychomotor delay, urinary malformations (paraurethral diverticulum, hypoplasia of left kidney associated with vesicoureteral reflux grade 3-4), bilateral inguinal hernia, and dorsolumbar kyphoscoliosis. In the follow-up he presented a retroperitoneal neuroblastoma. Although this type of tumor has been referred to develop in several genetic and mutimalformative syndromes, it seems that present association has not been previously reported.

A 10-year-old female with atrial septal defect presented with bilateral ovarian mature cystic teratomas. Three spleniculi adjacent to the main spleen were noticed while the endoscopic surgery. Two years later a heart tumor was discovered which led to death. Pathologic examination of samples of the mass proved it to be a liposarcoma. The unusual combination of atrial septal defect, f-anisosplenia (female, congenital heart disease, multiple unevenly-sized spleens, left lung type pulmonary isomerism), bilateral ovarian mature cystic teratomas and liposarcoma of the heart appears to be a unique presentation.

A case of giant congenital urethral polyp on a female newborn is reported. The lesion appeared as a large fleshy, exuberant tumor at the introitus between the labia minora. The mass was constituted by orderly arranged layers of transitional and squamous epithelium outside and loose connective tissue and smooth muscle in its core. The patient was treated by simple excision of the lesion.

We are reporting the case of a 17-year-old girl with kidney transplant under immunosuppressive treatment. Evidences of transplant malfunction led to urinary cytology to rule out BKV infection. The smears showed the presence of koilocytes. Gynecologic examination revealed numerous condylomatous lesions in the vulva, vagina, and cervix. PAP smears showed cells with moderate to severe koilocytic dysplasia. PCR performed on material retrieved from both the smears showed HPV18 DNA sequences. Koilocytes have rarely been documented in urinary cytologic examination. Since post-transplant immunosuppressed patients are prone to develop florid and extensive HPV infections, urinary cytology may prove useful for routine search of cells with this virus cytopathic effect.

We report the case of a 10-year-old girl presenting with linear IgA disease of childhood who in the follow-up at age 16 developed hematuria and proteinuria resulting from IgA nephropathy. The combination of linear IgA disease and Berger nephropathy appears to be extremely uncommon but clinical alertness to this association might discover additional cases.

We present the case of a 23-year-old woman with a parotid gland tumor, the fine-needle aspiration biopsy smears of which showed epithelial cells with wide cytoplasm, isolated or arranged in micropapillary groups together with psammoma bodies. The surgical specimen contained a 5-cm tumor with the histologic features of an acinic cell carcinoma (ACC) with papillary areas. Notably, the cells of the tumor seemed to follow a sequence from large cells with rounded nuclei with open chromatin and prominent nucleoli to vacuolated cells with granular material, and finally to cells undergoing apoptosis. This finding was followed by the appearance of concentrically laminated, round to polygonal, Congo red-positive, birefringent bodies that in areas accumulated and formed extensive areas with massive deposits. The picture suggested that those amyloid bodies (psammoma bodies) resulted from the accumulation of residual masses of apoptotic cells. Huge globular amyloid deposits, the suggested name for this material irrespective of the type of amyloid, have not been previously reported in ACC of salivary gland.

Congenital cystic airway malformation/congenital pulmonary airway malformation (CCAM/CPAM) of the lung is a rare but well-described malformative lesion of pulmonary parenchyma characterized by the abnormal maturation of airways along with an increase in terminal respiratory structures, resulting in cysts of variable sizes. Five types have been classified based on morphological analysis. Although the etiology of the lesion is still unclear, recent data suggest that bronchial atresia is a predisposing/associated anomaly. A described association between type 1 CCAM/CPAM and bronchioloalveolar carcinoma suggests that type 1 CCAM/CPAM may predispose to malignant transformation by as yet unidentified tumorigenic mechanisms. Here we studied epidermal growth factor receptor (EGFR) and K-RAS oncogene, 2 biological markers closely associated with tumorigenesis and altered in many types of tumors, including lung carcinomas. For this purpose, we used immunohistochemistry and gene sequencing in paraffin-embedded tissue. Our results demonstrate expression of EGFR in types 1 and 3 CCAM/CPAM, with a distinctive distribution and intensity, compared with that of type 2. Of special interest, mucinous areas in 2 cases of type 1 CCAM/CPAM lacked EGFR expression, whereas adjacent epithelial cystic linings were strongly positive. This supports the hypothesis that mucinous differentiation in CCAM/CPAM, always present in cases with malignant transformation, could be related to other molecular pathways. The K-RAS gene was screened for mutations usually found in lung carcinomas; however, no mutations were present in any of the studied samples. These findings support the notion that EGFR may play an important role in the pathogenesis and phenotype of CCAM/CPAM.

Diverse clinical and pathologic experiences seem to have led to the idea that celiac disease is a spectrum in both categories. Conflicting results emerging from different reports have produced a large amount of confusion on the subject. This article discussed histopathology findings in 10 children with positive autoantibodies for celiac disease but without clinical evidence of malabsorption. The patients were evaluated following a detailed video-endoscopic study sampling the proximal (first and second) and distal (third and fourth) duodenal parts separately and processed apart. The procedure consistently revealed advanced villous atrophy in the proximal duodenal mucosa associated with mild to absent involvement of the distal segments. The data here presented favor the interpretation that (1) the presence of autoantibodies for celiac disease is always associated with mucosal damage, (2) mucosal damage in the absence of malabsorption is always evident in the proximal duodenum, and (3) the mucosal biopsy in search for the telltale damage needs to be done in separate samples of proximal and distal duodenal mucosa. This procedure may result in a better understanding of the dynamics of mucosal damage in celiac disease.