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Massive perivillous fibrin deposition (MPFD) and the related entity of maternal floor infarction (MFI) are uncommon placental disorders of unknown etiology, associated with adverse obstetric outcome and a significant risk of recurrence. We describe a 19-year-old mother with untreated syphilis who delivered a male neonate with low birth weight, skin desquamation, and pneumonia. Placenta examination showed the expected changes for syphilis but unexpectedly, also showed MPFD. To our knowledge, this is the first report of MPFD associated with placental syphilis, thus expanding the list of etiologies that may be related to MPFD/MFI. It is postulated that the syphilis infection in our case led to a hypercoaguable state, eventually resulting in MPFD. In the right clinical setting, syphilis might be considered in the differential diagnosis when MPFD/MFI is observed on placental examination. The recurrence risk of MFPD/MFI associated with infections is believed to be lower than idiopathic cases and, by extrapolation, this lower risk should apply to syphilis as well.

Background NanoString technology is an innovative barcode-based system that requires less tissue than traditional techniques and can test for multiple fusion transcripts in a single reaction. The objective of this study was to determine the utility of NanoString technology in the detection of sarcoma-specific fusion transcripts in pediatric sarcomas.Design Probe pairs for the most common pediatric sarcoma fusion transcripts were designed for the assay. The NanoString assay was used to test 22 specific fusion transcripts in 45 sarcoma samples that had exhibited one of these fusion genes previously by reverse transcription polymerase chain reaction (RT-PCR). A mixture of frozen (n = 18), formalin-fixed, paraffin-embedded (FFPE) tissue (n = 23), and rapid extract template (n = 4) were used for testing.Results Each of the 22 transcripts tested was detected in at least one of the 45 tumor samples. The results of the NanoString assay were 100% concordant with the previous RT-PCR results for the tumor samples, and the technique was successful using both FFPE and rapid extract method.Conclusion Multiplexed interrogation for sarcoma-specific fusion transcripts using NanoString technology is a reliable approach for molecular diagnosis of pediatric sarcomas and works well with FFPE tissues. Future work will involve validating additional sarcoma fusion transcripts as well as determining the optimal workflow for diagnostic purposes.

Many anatomic pathology laboratories no longer have electron microscopy facilities. A retrospective review of autopsies was performed to identify cases of inborn errors of metabolism (IEM) and determine the contribution of electron microscopy in making the diagnosis in those cases. Over a period of 17 years, there were 900 perinatal and pediatric autopsies. There were 7 cases (1%) of IEM, including 4 cases of Pompe disease, 1 case of I-cell disease, 1 case of bile acid synthesis defect, and 1 case of mitochondrial disease (Leigh syndrome). Electron microscopy was important in the diagnosis of I-cell disease and Pompe disease in our series. This technique enabled a prenatal diagnosis to be made from a chorionic villus biopsy in 2 cases with a positive family history. In less developed countries where upfront genetic testing may be too expensive and may need international referral, electron microscopy can still be useful for diagnosis of IEM, providing an affordable alternative with a more rapid turnaround time compared to gene mutation analysis or enzyme assay. Results can be used both for patient management and as a screen for which cases might benefit from genetic testing.

The pulmonary neuroendocrine system includes pulmonary neuroendocrine cells (PNECs) and neuroepithelial bodies (NEBs) that are distributed throughout respiratory epithelium and regulate lung growth and maturation antenatally. Abnormalities in this system have been linked to many hypoxia-associated pediatric pulmonary disorders. Hemoglobin (Hb) Bart disease is a severe form of α-thalassemia resulting in marked intrauterine hypoxia with hydrops fetalis (HF) and usually death in utero. Affected fetuses can serve as a naturally occurring human model for the effects of intrauterine hypoxia, and we postulated that these effects should include changes in the pulmonary neuroendocrine system. Bombesin immunostaining was used to assess PNECs and NEBs in stillborn fetuses with Hb Bart HF (n= 16) and with HF from other causes (n= 14) in comparison to non-HF controls. Hb Bart HF showed a significant increase in the proportion of PNECs in respiratory epithelium (P = .002), mean number of NEB nuclei (P = .03), and mean size of NEBs (P = .002), compared to normal non-HF controls. Significant differences were not observed between HF due to other causes and non-HF controls with normal lungs. Non-HF controls with pulmonary hypoplasia showed significant increases in PNECs compared to HF cases not due to Hb Bart HF, implying HF alone does not cause such increases. In contrast, no significant differences were noted between non-HF controls with pulmonary hypoplasia and Hb Bart cases. Hb Bart HF may provide a useful model for studying the pulmonary neuroendocrine system under chronic intrauterine hypoxia.

Maternal floor infarction is a rare and idiopathic placental disorder associated with adverse obstetric outcomes and a high rate of recurrence in subsequent pregnancies. The pathogenesis of maternal floor infarction is unclear but has been linked to diverse underlying maternal conditions, including gestational hypertension/preeclampsia, immune-mediated diseases, and thrombophilia. Few reports link maternal floor infarction to fetoplacental conditions. We report a 34-week, macerated, growth-restricted male fetus for which the placenta showed maternal floor infarction. The umbilical cord showed excessive coiling and a single umbilical artery. These cord changes are postulated to have resulted in increased placental villous resistance and decreased fetal blood flow, creating a hydrostatic pressure gradient between the villous stroma and the intervillous space. The pressure changes could then lead to trophoblast damage and fibrinoid deposition, contributing to the maternal floor infarction in this case.

Congenital tuberculosis involving the placenta is an infrequent diagnosis, and the typical features of tuberculous placentitis involve a granulomatous reaction, reflecting a delayed hypersensitivity immune response in the host. However, the first reaction of the placenta to organisms hematogenously transmitted from the maternal circulation typically involves the innate immune response, manifesting as an acute neutrophilic villitis or intervillositis or both. This acute pattern of response to mycobacteria has only been documented rarely. We present a case of acute mycobacterial infection occurring in a preterm female with 28-weeks gestation, who was delivered by cesarean section because of fetal distress and who was subsequently confirmed to have congenital tuberculosis. The placenta showed an acute chorioamnionitis associated with acid-fast bacilli consistent with Mycobacteria tuberculosis.The mother was found to have a necrotizing granulomatous deciduitis, and that was postulated to have resulted in the direct spread of mycobacteria to the amniotic cavity. Thus, our case extends the acute placental response to mycobacteria to include chorioamnionitis. Although extremely rare, mycobacteria should be considered in the differential diagnosis of infectious agents causing acute chorioamnionitis, especially in geographic areas where tuberculosis is more prevalent.

We report a renal tumor detected by prenatal ultrasound and resected at 2 months of age. This 9-cm, solid mass was composed of tubular and papillary structures lined by small, uniform epithelial cells. There was local invasion into renal parenchyma and a tumor deposit in a hilar lymph node. The tumor was immunopositive for WT1, pankeratin, and CD10; focally positive for CK7; and negative for EMA and TFE3. Based on morphology and immunophenotype, the favored diagnosis was metanephric adenoma over Wilms tumor, renal cell carcinoma, and nephrogenic rest. However, metanephric adenoma only occasionally occurs in children and has never been reported prenatally. Alternatively, this tumor might be a congenital Wilms tumor that differentiated completely. Although the nature of the tumor remains unconfirmed, resection appears to have been curative; the patient remains disease-free 18 months following surgery alone.

The distribution of lipid in the fetal adrenal cortex is reported to correlate with the duration of hypoxia and degree of fetal stress. The original studies were based on Oil Red O staining, requiring frozen tissue that is often not available. To investigate the reliability of these observations, the distribution of lipid in the fetal adrenal cortex was studied in hydrops fetalis (HF) of different etiologies, using immunostaining for adipophilin on formalin-fixed material. Twenty cases of HF due to hemoglobin (Hb) Bart were compared to 34 cases of HF due to other causes. In the fetal zone, lipid distribution was more diffuse in Hb Bart HF compared to other causes of HF, including those due to anemia, supporting the concept that increased lipid in the fetal zone is associated with severity of hypoxia. A more diffuse distribution of lipid correlated with adrenal cytomegaly (P< 0.01) and extramedullary hematopoiesis (P< 0.01) but not Hb level (P= 0.68) nor compact cell change (P= 0.7) or cystic degeneration (P= 0.07) in the definitive zone. A greater degree of cystic degeneration correlated with lower gestational age, rather than the specific etiology of HF. Thus, cystic degeneration is more a reflection of the onset of fetal stress than severity. The combined histologic changes in the fetal and definitive zones of the adrenal gland provide complementary information about fetal status in HF. Immnunostaining for adipophilin circumvents the need for frozen tissue for assessing lipid content by Oil Red O staining, facilitating studies based on archival material.

Genitourinary tract malformations causing hydrops fetalis are rare. The authors report a case of a female delivered at 32 weeks gestational age following a prenatal diagnosis of an abdominopelvic cystic mass with hydrops fetalis. The neonate was persistently hypoxic with unstable cardiovascular status and survived only 7 days. At autopsy, a cystic malformation replaced the vagina and uterus, associated with lower vaginal atresia and anorectal agenesis. The cyst had interfered with the normal process of Müllerian duct fusion, leading to a longitudinal vaginal septum and bifurcation of endocervix, with absent uterus and fallopian tubes. The urinary bladder was compressed by the cyst, resulting in bilateral hydronephrosis. The cyst impeded the inferior vena caval and umbilical venous circulations and impinged upon the thoracic cavity with resultant pulmonary hypoplasia. This malformation, which might be termed “cystic dysplasia” of the vagina, represents an extreme form of hydrometrocolpos that resulted in hydrops fetalis.

Fibroblastic and myofibroblastic tumors constitute an important group of neoplasms in children and adolescents. These span the full spectrum of clinical behavior, ranging from benign to intermediate and malignant. We report a case of a benign mesenchymal tumor with myofibroblastic differentiation in a 9-year-old girl arising in the left groin that met the histologic features described for myofibroblastoma in adults. Two types are recognized in adults: angiomyofibroblastoma and mammary-type myofibroblastoma of soft tissue. Our case shared features of both these subtypes but was not typical of either one, and we therefore designated our case simply as “myofibroblastoma.” Our case showed expression of estrogen receptor protein, which is characteristic of adult lesions, but not a deletion of 13q14, as has been reported in some adult cases. In the English-language literature, only 6 cases have been reported in patients under 21 years of age, and all but 1 were teenagers. Pediatric surgeons, oncologists, and pathologists should be aware that such a benign entity can occur in this patient population and could be confused with other lesions, including malignant ones.

In hydrops fetalis (HF) the placenta can be markedly enlarged and the villi show stromal edema, increased Hofbauer cells, and reduced numbers of capillaries. Hemoglobin (Hb) Bart is the most severe form of thalassemia, causing HF due to profound anemia. We report a previously undescribed histologic finding based on a review of Hb Bart HF cases, termed “peripheral villous stromal hypercellularity.” This change was noted in 15 of 18 (83%) placentas with Hb Bart HF but not in placentas of 21 cases of HF due to other causes, including 11 cases involving anemia. The hyperplastic stromal cells were determined to be myofibroblastic by immunohistochemistry and electron microscopy, associated with a more complex capillary network in villi than is seen with other causes of HF. The authors hypothesize that this angiogenesis in villi is a response to fetal anemia from Hb Bart. In turn, there is increased villous blood flow, resulting in edematous villous stroma, leading to narrowing of the intervillous space in the placenta. Hyperplasia of myofibroblasts might then be a compensatory change, in that contraction by these cells would reduce the vascular lumina and the size of placental villi, thereby widening the intervillous space to improve capacity for maternal blood circulation. Curiously, this histologic change was restricted to cases of HF caused by Hb Bart. We speculate that in Hb Bart disease, the hypoxia and hydrops develop earlier in gestation, compared to other causes of HF, allowing the time for these adaptive changes to occur in the placenta.

Adrenocortical cytomegaly (AC) is a relatively uncommon phenomenon but tends to occur in certain situations, including specific congenital anomalies and hydrops due to maternal-fetal Rhesus incompatibility. Because the pathology in the latter condition does not differ greatly from hemoglobin (Hb) Bart hydrops fetalis, we performed a retrospective review of fetal and perinatal autopsy cases with Hb Bart to determine the prevalence of AC in that condition. Over a 10-year period (2001–2010) at King Chulalongkorn Memorial Hospital, there were 16 hydropic cases confirmed to have Hb Bart. Adrenocortical cytomegaly was found in 13 cases (81%). For comparison, we determined the occurrence of AC in cases of hydrops fetalis not due to Hb Bart (n= 33) and a heterogeneous group of congenital anomalies (n= 34). Adrenocortical cytomegaly was identified in only 1 case of Beckwith-Wiedemann syndrome and 2 cases of anencephaly. Thus, AC is a common finding in cases of Hb Bart, a finding not previously documented. Moreover, our study suggests that Hb Bart is one of the conditions most commonly associated with AC. The reasons for this are not known. The mean Hb levels for the hydrops cases with Hb Bart and those with other forms of anemia showed no significant difference (P= 0.63), nor was there any significant difference in Hb levels between cases of Hb Bart with and without AC. Nonetheless, the consistency of AC in cases of Hb Bart suggests that further study of this particular group of patients might shed light on the pathogenesis of this poorly understood pathologic finding.

Massive hepatomegaly is a common finding in hydrops fetalis (HF) arising from hemoglobinopathies. It has been suggested that extramedullary hematopoiesis, which is markedly increased in response to anemia, plays a principal role in hepatomegaly via sinusoidal obstruction and distortion of the intrahepatic architecture. To test this concept, the authors compared 20 cases of a-thalassemia (hemoglobin Bart, 15 cases; hemoglobin H, 5 cases) with 19 cases of HF arising from other causes and 39 control nonhydrops cases. The mean liver weight in a-thalassemia cases was significantly heavier than in control cases and in hydrops fetalis cases due to other causes (P< 0.01). This was not explainable on the basis of extramedullary hematopoiesis (erythropoiesis or myelopoiesis) or hemosiderin deposition, since cases of HF from other causes, especially related to anemia, showed similar findings to a-thalassemia cases. While these processes no doubt contribute to hepatic weight, the major factor would still be high-output cardiac failure causing hepatic congestion.

The coexistence of a persistent left superior vena cava (PLSVC) and congenital anomalies, both cardiac and noncardiac, is well documented, but whether PLSVC contributes to the development of cardiac malformations is controversial. We conducted a retrospective review of perinatal and pediatric autopsies to determine the association between PLSVC and other congenital anomalies. Of 362 patients, 91 (25%) had congenital heart disease and 19 (5.2%) had PLSVC. Eight cases (47%) were associated with specific syndromes, including heterotaxy syndrome, trisomy 18, trisomy 13, and Jacobsen syndrome. Seventeen cases of PLSVC (89%) were associated with congenital heart disease, most of which were complex. Isolated PLSVC was found in 2 cases (11%). Eight of the 19 PLSVC cases (47%) were associated with hypoplastic left heart syndrome (HLHS), a result that was statistically significant (P= 0.041). Left ventricle inflow/outflow obstruction is believed to be a critical pathogenic factor in the development of HLHS. Whereas 5 of 8 cases of HLHS had additional obstructive cardiac outflow tract lesions, 3 of 8 cases did not. PLSVC is known to be able to compromise left ventricle inflow via a dilated coronary sinus, and we speculate that PLSVC may have played a contributing role in the pathogenesis of HLHS in these three cases. As an isolated lesion, PLSVC would not be sufficient to cause HLHS, but it might contribute in combination with other obstructive lesions, or in the setting of other genetic and/or environmental factors still to be defined for HLHS. A larger series will be needed to confirm this hypothesis.

The purpose of this study was to analyze the cause of hydrops fetalis (HF) among fetal deaths in the central region of Thailand. Autopsy reports diagnosed as HF from 1999 to 2008 at King Chulalongkorn Memorial Hospital were retrieved, and the pathologic findings, clinical information, fetal ultrasonographic studies, and laboratory investigations were reviewed. There were 78 stillborn autopsies during this 10-year period; the mean gestational age was 28 weeks. The causes of fetal hydrops were identified in 88.5%; no cases of immune hydrops were detected. Anemia was the predominant cause of HF (n= 33; 42.2%): related to homozygous α-thalassemia (n= 17; 21.8%), twin-twin transfusion syndrome (n= 8; 10.2%), hemoglobin H (n= 3; 3.8%), lung hemorrhage (n= 1; 1.3%), adrenal hemorrhage (n= 1; 1.3%), and 3 cases of unspecified etiology (3.8%). Other causes of high-output failure included mass lesions resulting in vascular shunting (n= 2; 2.6%) and 1 case each (1.3% each) of maternal diabetes mellitus, intestinal lymphangiectasia, and Beckwith-Wiedemann syndrome. Causes resulting in low-output cardiac failure were congenital heart disease (n= 16; 20.5%) and thoracic space-occupying lesions (n= 7; 9%). The remaining causes included fetal infection (n= 5; 6.4%), congenital abnormalities suggestive of a chromosomal or genetic basis (n = 2; 2.6%), and 1 case (1.3%) of placental vascular thrombosis. Nine cases (11.5%) had no identifiable cause. Thus, the most common cause of HF in this series was homozygous α-thalassemia, reflecting the geographic location of this series.

Lymphadenoma of the salivary gland is a rare benign tumor with only 11 reported cases in the English language literature, most of which have occurred in adults. We report a case of a lymphadenoma occurring in the parotid gland of a 15-year-old girl. The tumor was composed of variably sized cystic cavities within abundant reactive lymphoid tissue. The cystic spaces were filled with eosinophilic secretions with occasional histiocytes. Many of these features were also apparent on cytologic preparations. The cysts were lined by epithelium lacking atypia and showed luminal and abluminal differentiation both by immunohistochemistry and by electron microscopy. Tumor cells were not cycling as determined by MIB1 immunostaining, and the tumor karyotype was normal. This is only the second case to be reported in the pediatric age group. Ultrastructural features and karyotype analysis are reported for the first time. Although this tumor is rarely encountered by pediatric pathologists, awareness of its existence is important to distinguish it from possible malignant mimics, such as lymphoepithelial carcinoma and metastatic mucoepidermoid carcinoma in a lymph node.

Maternal floor infarction (MFI) is an unusual, idiopathic placental disorder characterized by deposition of amorphous fibrinoid material along the maternal aspect of the intervillous space. This condition is associated with poor perinatal outcome—in particular, spontaneous abortion—fetal growth restriction, and stillbirth, with a high recurrence rate in subsequent pregnancies. It is unknown whether MFI is a single entity or the common end point of different insults. Most studies have linked MFI to underlying maternal disorders including gestational hypertension, autoimmune disease, and thrombophilia. In contrast, there have been only a few case reports regarding the possibility of a fetal basis for MFI. We report 2 cases of MFI in fetuses who suffered from oligohydramnios as a result of bilateral cystic renal dysplasia. These 2 cases suggest the concept that fetoplacental factors may also play a role in MFI. It is speculated that the mechanism might involve changes in intrauterine hydrostatic pressure gradients.

Both excessively long umbilical cord (ELUC) and fetal thrombotic vasculopathy (FTV) have been associated with adverse perinatal outcomes, in particular, fetal loss and long-term neurological complications. The etiologies of these conditions are unclear and are likely multifactorial. Excessively long umbilical cord has been associated with FTV and fetal demise, with cases generally showing other cord abnormalities and only localized FTV. We report a 37-week male stillborn fetus whose placenta had a 113-cm-long umbilical cord with no other cord abnormalities associated with “massive” FTV (ie, >25% of the placental mass). This case illustrates the unusual occurrence of FTV of such severe extent in association with ELUC leading to fetal demise. This case illustrates that ELUC alone may be enough to predispose the placenta to massive FTV.

Meckel-Gruber syndrome (MKS) is a fatal, autosomal recessive disorder characterized by malformation of central nervous system, particularly occipital encephalocele, bilateral renal dysplasia, and polydactyly. However, the clinical findings of this syndrome encompass various organ abnormalities as a result of genetic heterogeneity. The associated heart anomaly in MKS is inconstant. Its prevalence is rare and no striking or specific cardiac defects have been documented. We present a case of MKS with combined cor triatriatum sinistrum (left atrium divided into upper and lower compartment by a thin membrane) and hypoplastic left heart syndrome (underdeveloped mitral valve, left ventricle, and aorta) in a 33-week male fetus that was ultrasonographically detected and confirmed by autopsy. In addition to the cardiac defects, the patient was found to have postaxial polydactyly of 4 extremities, Dandy-Walker malformation, bilateral renal cystic dysplasia, and hepatic plate malformation. To the best of our knowledge, this is the first time that a combination of cor triatriatum sinistrum and hypoplastic left heart syndrome in MKS has been reported in the literature.

Alveolar rhabdomyosarcoma (RMS) is 1 of 2 main subtypes of RMS in the pediatric age group and tends to occur in the extremities. The urogenital tract is another common site for RMS, but this typically involves the embryonal subtype including sarcoma botryoides. We report a 28-year-old male with a prostatic tumor that was excised en bloc and showed a RMS with separate areas of embryonal and solid alveolar morphologies at the light microscopic level. Both areas showed diffuse nuclear expression for myogenin, and both areas expressed the PAX3-FKHRfusion gene, a genetic change associated with alveolar but not embryonal RMS. A review of the literature documented only 5 cases of RMS primary to the prostate showing alveolar or mixed histology. Ours is the 6th case and the 1st with molecular findings. Although the diagnostic category of mixed embryonal/alveolar RMS remains in use, the nature of this type of RMS is incompletely understood. In our case, although the morphology was mixed embryonal/alveolar, at the genetic level this tumor was alveolar in nature.

Epithelioid sarcoma is a rare soft-tissue tumor that usually occurs in young adults, with a median age of 26 years. This malignancy has been divided into distal and proximal types. The latter is found in proximal body sites including the head and neck region. We present a rare case of parotid proximal-type epithelioid sarcoma in a 1-year-old male child; this is the 4th reported case in the literature and the youngest in a pediatric patient to date. The tumor showed prominent rhabdoid features by light microscopy. Immunohistochemical studies revealed positive staining to cytokeratin (AE1/AE3), epithelial membrane antigen, vimentin, and BAF47. Thus, while the tumor resembled a malignant rhabdoid tumor, the positive staining for BAF47 supported instead a diagnosis of epithelioid sarcoma, according to our current understanding of these 2 tumor types. Also, the clinical course was not the typical aggressive behavior of a rhabdoid tumor. The patient underwent radical parotidectomy without adjuvant therapy and remained disease-free at follow-up, 14 months after surgery.

Recent studies have shown a significant involvement of insulin-like growth factor (IGF) signaling components in the pathogenesis of rhabdomyosarcoma (RMS). Furthermore, there has been some evidence to indicate that differential expression of IGF pathway genes can distinguish RMS subtypes. The present study utilized immunohistochemistry to determine the expression patterns of IGF1, IGF2, IGF binding protein 2 (IGFBP2), IGF receptor 1 (IGF1R), and IGF receptor 2 (IGF2R) in 24 embryonal RMS (ERMS) and 8 alveolar RMS (ARMS). A majority of tumors were positive for IGF2, IGFBP2, IGF1R, and IGF2R and negative for IGF1 expression. However, only IGF2 showed a significant difference in expression between the ERMS and ARMS subtypes, with higher levels of expression in ERMS (P= 0.0003). Within the ARMS subtype, IGF2 positivity was limited to PAX/FKHRtranslocation-negative tumors. The staining pattern for all 5 proteins was diffuse cytoplasmic in the majority of tumors. Analysis of RMS cell lines by real-time reverse transcriptase–polymerase chain reaction for IGF2expression revealed significantly higher mean expression levels in ERMS and translocation-negative ARMS cell lines when compared to translocation-positive ARMS cell lines (P= 0.0027). Stable introduction of PAX3/FKHRinto an ERMS cell line also demonstrated a significant reduction in IGF2expression. The results of this study show that expression of the IGF2 ligand is associated with translocation-negative tumors and may serve as a diagnostic aid in distinguishing RMS subtypes. Furthermore, the in vitro results are supportive of a role for the PAX3/FKHRfusion gene in the inhibition of IGF2 expression.

The intermediate protein nestin is expressed in proliferating embryonic tissues and adult tissues undergoing repair. Recently this protein been identified in rodent podocytes. Its role in this cell is unknown, since podocytes are believed to be terminally differentiated and nondividing. We report the first study of nestin in human kidney. Nestin expression in normal mature human glomeruli was confined to podocytes. In developing kidney, nestin was detected in metanephric blastema and in podocytic cells at all stages of glomerular development. Nestin co-localized with vimentin but not with actin or heavy chain myosin IIA, using a mouse podocyte cell line. Knockdown of nestin in a murine podocyte cell line failed to produce any obvious phenotypic change or alteration in vimentin distribution but was associated with increased cell cycling. A survey of glomerular diseases failed to identify any condition lacking nestin, indicating that the protein is critical for some aspect of podocyte function. Perhaps through an association with vimentin, nestin serves to bolster the mechanical strength of these cells that experience high tensile stress during glomerular filtration. Nestin was also expressed in podocytes that are reported to be ‘dysregulated’ (lacking podocyte markers). Thus, nestin has a potential as a reliable podocyte marker, even for podocytes that are not completely differentiated (for example, during development) or ‘dedifferentiated’ in glomerular disease.

Pediatric undifferentiated soft tissue sarcomas represent a major challenge for pathologists and clinicians. The goal of this study was to identify cases that warranted this diagnosis by current standards of analysis and then determine if there are clinicopathological commonalities that may be useful for diagnosis, management, and prognosis. Eighteen potential patients were identified using the institutional pathology database. Three cases were reclassified as specific sarcomas, and 2 cases had insufficient material for molecular analysis, leaving 13 cases for pathological review and 12 patients for radiological and clinical review. There were 7 males and 6 females. The median age at diagnosis was 11 years (1 month to 16 years). Tumors commonly involved the trunk (7 of 13; 54%) and ranged in size from 1.7 to 14.5 cm (mean, 6.7 cm). Eleven patients received ifosfamide/etoposide chemotherapy and 4 received irradiation. Five-year event-free and overall survival (EFS and OS) rates were 54% and 74%, respectively. The predominant histological pattern was round to plump spindled cells forming sheets (9 of 13; 69%) and severe atypia was associated with decreased survival (P= 0.048). Immunohistochemistry showed positivity for vimentin (92%), CD117 (92%), and vascular endothelial growth factor (69%), and 8% to 23% showed focal positivity for epithelial, neural, or myogenic markers. Tumors were uniformly negative for translocations associated with pediatric sarcomas. The presence of certain common morphological and immunohistochemical features in the absence of specific molecular genetic abnormalities allows for a diagnosis of pediatric undifferentiated soft tissue sarcoma; however, whether this group of neoplasms forms a unique category of tumors or a common precursor pathway for a number of different sarcomas awaits further study.

Rhabdomyosarcoma (RMS) is a soft tissue tumor of childhood frequently diagnosed between the first and fifth year of life. Children with the Beckwith-Wiedemann syndrome (BWS), a congenital overgrowth syndrome characterized by exomphalos, macroglossia, and macrosomia, have an increased risk of developing childhood tumors including Wilms tumor, hepatoblastoma, neuroblastoma, and RMS. Although an association between RMS and the BWS is well accepted, only four cases have been reported to date, and of these, three were reported as embryonal RMS. Based on these data, an association between BWS and embryonal RMS has been proposed. We report three additional cases of BWS with RMS and review the clinical data for each patient as well as the pathology of their tumors. All three cases of BWS had histology consistent with alveolar RMS and were diagnosed at 6 weeks and 5 and 13 years of age. In two of these BWS cases, constitutional defects of 11p15 imprinting were demonstrated. Furthermore, cytogenetic analysis of the tumors did not detect the t(2;13) or t(1;13) translocations that generate the PAX3- or PAX7-FKHR fusion proteins common to alveolar RMS. These observations suggest that the development of alveolar RMS tumors in BWS may occur without the chromosomal rearrangement producing the PAX-FKHR fusion protein. In summary, we present three new cases of RMS demonstrating a new association between BWS and an uncommon subtype of alveolar RMS. The absence of the translocations commonly associated with alveolar rhabdomyosarcoma suggests a common 11p15 pathway for alveolar RMS and BWS.

Abstract: Anaplastic large cell lymphoma (ALCL) was proposed as a clinicopathologic entity over 14 years ago, but has been somewhat controversial due to the variability of its defining features and variable occurrence in different age-groups. To evaluate this entity in a pediatric population, 36 cases of childhood large cell lymphoma were evaluated for abnormalities of the anaplastic lymphoma kinase (ALK) gene that has been associated with ALCL morphology and immunophenotype. ALK abnormalities were evaluated by assay for the t(2;5)(p23;q35) translocation by RT-PCR and/or expression of NPM-ALK fusion protein by immunohistochemistry. Results showed 17 patients to have evidence of ALK gene expression. All of these children (mean age, 9.3 years) had tumors that were of T-cell phenotype (with the exception of a single case of null phenotype) and that expressed CD30. In contrast, 19 children with no evidence of ALK expression were older (mean, 12.7 years), and the majority (12/19) had tumors of B-cell phenotype. CD30 was also diffusely expressed in 8 of these 19 tumors. The difference in mean age between the two groups was statistically significant (P= 0.015). In three cases tested for both ALK and the t(2;5), ALK protein was detected in the absence of the t(2;5) translocation but no cases showed the reverse pattern, consistent with ALK fusion to genes other than NPM or activation of the ALK gene by another mechanism. These findings provide further support that ALK-positive ALCL is a distinct pathologic entity among pediatric large cell lymphomas primarily characterized by expression of T-cell markers, CD30, and EMA, and by a younger mean age.

Pleuropulmonary blastoma (PPB) is a rare, malignant intrathoracic pediatric tumor. It arises from the lung, pleura, or mediastinum and its pathogenesis and relationship to other pediatric solid tumors is not well understood. In this study, a case of PPB in a 3-year-old girl was studied using a combination of molecular genetic methods and cytogenetics. Molecular analysis of the commonly encountered fusion translocation gene products of pediatric solid tumors failed to detect a rearrangement. Cytogenetic analysis, supplemented by multicolor spectral karyotyping (SKY), identified an unbalanced translocation between chromosomes 1 and X, resulting in additional copies of 1q, an extra copy of Xq, and loss of part of Xp. In addition, trisomy 8 was detected. The identification of new chromosomal alterations and confirmation of previously reported ones in this rare neoplasm helps to improve our understanding of its pathogenesis and association with other pediatric tumors.

Maternal floor infarction (MFI) and massive perivillous fibrin deposition (MPFD) are overlapping placental disorders of unknown etiology, associated with adverse obstetric outcome, and a significant risk of recurrence. We describe a 31-year-old mother with asymptomatic thrombocytopenia throughout pregnancy and a positive lupus anticoagulant. She delivered a normal female neonate at term, whose weight was small for gestational age, with a placenta weighing less than the 10thpercentile. Placental examination showed MPFD together with excessive subchorionic fibrinoid deposition. The placenta showed diffuse C4d deposition and an immune-mediated reaction was postulated for the pathogenesis of the placental changes. We suggest that excessive subchorionic fibrinoid deposition may be part of the morphologic spectrum of MFI/MPFD.

ABSTRACT: We report the clinical, pathologic, and genetic features of renal malignancy in two children with diffuse cystic hyperplasia. Both presented with massive bilateral nephromegaly. Neither had a family history or clinical findings suggestive of tuberous sclerosis or von Hippel–Lindau disease. The kidneys of both children were extensively replaced by tubulocystic hyperplasia with large eosinophilic epithelial cells. The masses of hyperplastic tissue were nodular, compressing remnants of uninvolved renal parenchyma. Tubulopapillary carcinoma was present in both children, one of whom had bilateral multicentric carcinoma. No loss of heterozygosity was detected in the tumors at the TSC1, TSC2, or VHL gene regions, and no alterations in the VHL gene were detected using single-strand conformation polymorphism analysis. These cases of bilateral renal enlargement with diffuse cystic hyperplasia appear to represent a new clinical syndrome that may warrant bilateral nephrectomy because of the risk of malignancy.

ABSTRACT: Chromosome translocations found in neoplasms often result in the creation of hybrid genes encoding chimeric proteins. Desmoplastic small round cell tumor (DSRCT) is a recently described aggressive malignancy associated with a unique chromosomal translocation t(11;22)(p13;q12). This translocation has recently been characterized, revealing the rearrangement and fusion of the WT1 gene on chromosome 11 to the EWS gene on chromosome 22. Fusion of these two genes results in the production of a putative oncogenic protein composed of the zinc finger DNA-binding domains of WT1 linked to the potential transcriptional regulatory domains of EWS. The typical chimeric transcript consists of the first 7 exons of EWS and the last 3 exons of WT1. We report here the first case of DSRCT with a variant EWS-WT1 chimeric product that includes 9 exons of EWS and 3 exons of WT1.

ABSTRACT: The WT1 gene is normally expressed in fetal kidney and mesothelium, and its expression has been suggested as a marker for Wilms tumor and mesothelioma. We examined WT1 expression levels by reverse-transcriptase polymerase chain reaction (RT-PCR) in 38 childhood small-cell tumors including Wilms tumor, embryonal and alveolar rhabdomyosarcoma, Ewing sarcoma, lymphoma, desmoplastic small round-cell tumor (DSRCT), synovial sarcoma, extrarenal rhabdoid tumor, and two tumors that were atypical for this group of tumors. WT1 expression was only detected in Wilms tumor, rhabdoid tumor, and in these two cases of uncertain histogenesis. Both arose in the peritoneal cavity and by immunohistochemistry were diffusely positive for vimentin, keratin, and desmin. Tonofilaments were identified by electron microscopy in one of the cases. RT-PCR failed to detect the t(11;22) translocation associated with DSRCT in either case. Our results suggest that WT1 expression is an unusual feature of childhood non-Wilms tumors and, in the right setting, it may indicate a mesothelial origin. The expression of WT1 may play a role in mesodermal cells acquiring epithelial characteristics, a concept supported by the mixed epithelial and mesenchymal phenotype of these two cases.

ABSTRACT: Diffuse leiomyomatosis (DL) is rare condition characterized by proliferation of smooth muscle in the upper gastrointestinal tract. Most cases are associated with X-linked Alport syndrome and have partial deletions in the genes encoding both the α5 and α6 chains of collagen type IV. We studied aspects of cell-matrix interaction of myocytes in an esophagogastrectomy specimen from a 12-year-old patient with DL. Myocytes had central areas of cytoplasmic rarefaction, which were actin positive and desmin poor, with the reverse pattern of staining at the cell periphery. Electron microscopy (EM) showed that the areas of rarefaction consisted of disorganized aggregates of filaments. The basement membranes ranged from thickened to thinned or absent. Immunohistochemical staining for the α1–α4 chains of collagen type IV, the α1, α2, β2, and γ1 chains of laminin, nidogen, type VI collagen, and fibronectin was normal. There was loss of the α5 and α6 chains of collagen type IV and the β1 chain of laminin. Normal staining for α1, α2, α3, α4, α6, α8, and β1 integrins was noted. Staining for α5 integrin varied from normal to reduced or negative in different cells. In DL, a primary abnormality of basement membrane may be associated with disorganization of the contractile apparatus and alterations of certain integrins. This may reflect a disturbance of cell-matrix interactions that play a role in cell differentiation and internal organization.

ABSTRACT: Melanotic neuroectodermal tumor of infancy is a rare but well-recognized entity in pediatric pathology. However, the relationship of this tumor to other pediatric small cell tumors with neuroectodermal features (such as neuroblastoma, Ewing sarcoma/peripheral primitive neuroectodermal tumor, and desmoplastic small round cell tumor) is undetermined. Molecular genetic studies of melanotic neuroectodermal tumor of infancy have not been reported. We studied three typical cases of melanotic neuroectodermal tumor of infancy in an attempt to link this tumor to other small cell tumors with well-characterized molecular genetic changes. Tests performed included: detection of MYCN gene amplification and deletion of 1p (all 3 cases), and presence of the t(11;22)(q24;q12) and the t(11;22)(p13;q12) translocations (2 of 3 cases). None of these tests yielded positive results. Thus, there is no genetic basis at present to link melanotic neuroectodermal tumor of infancy to neuroblastoma, Ewing sarcoma/peripheral primitive neuroectodermal tumor, or desmoplastic small round cell tumor.

ABSTRACT: The field of molecular genetics continues to see an ever increasing number of applications to pediatric tumor analysis. Studies in pediatric tumors have identified novel genes and other genetic changes, a large number of which reflect one of the following mechanisms: (1) activation of proto-oncogenes; (2) loss of tumor suppressor genes; or (3) creation of novel fusion proteins. At least one of these mechanisms is operational in each of the following pediatric tumors: neuroblastoma, Ewing sarcoma and peripheral primitive neuroectodermal tumor (pPNET), intra-abdominal desmoplastic small-cell tumor, rhabdomyosarcoma, synovial sarcoma, and Wilms tumor. Out of this research has come not only an increased understanding of oncogenesis but also, for each of the tumors listed above, diagnostic and/or prognostic markers that can be used by the pathologist and oncologist to improve overall patient management.