Pediatric and Developmental Pathology

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.

Massive myocardial calcification (MMC) in the perinatal period is an unusual finding considered to be a unique tissue reaction. This report summarizes the clinical and pathologic findings of seven cases of perinatal MMC. All patients presented clinical evidence of myocardial damage. In two cases arrhythmia was detected in utero. Four cases presented with hydrops, one of which was associated with major heart malformation. One case was a trisomy 13. Three cases had polyhydramnios. Our results demonstrate that calcification follows progressive stages from patches of calcified myocardial cells (stage I), to coagulative and colliquative myocytolysis with clusters of interstitial mononucleated cells (stage II), to collapsing fibrosis with granulation tissue and multinucleated regenerative myocardial cells (stage III), and finally to fibrous scars containing entrapped remaining myocardial cells (stage IV). Literature review and our findings suggest that perinatal MMC results from different conditions inducing hypoxic–ischemic damage that later is followed by progressive scarring if the patient survives the acute stage. The lesion may represent the human counterpart of the so-called dystrophic cardiac calcinosis in mice. This disease is related to an abnormality at the Dyscalc locus of proximal chromosome 7 (syntenic with human chromosome 19q13 and 11p15).

Although respiratory syncytial virus (RSV)-infected infants may present with apnea, the role that RSV plays in sudden infant death syndrome (SIDS) is speculative. To determine whether RSV is associated with bronchiolitis in these patients, we examined histologic sections of lungs from 41 apparent SIDS cases and compared the results with those of enzyme-linked immunofluorescent assay (EIA) from nasal washings. Bronchiolitis was defined by a bronchiolar inflammatory cell infiltrate plus epithelial necrosis. A positive EIA was associated with bronchiolitis in 8 instances, compared with 6 having a positive EIA and negative histology, 14 having a negative EIA and positive histology, and 13 having EIA and histology both negative. These results yield a predictive value of a positive test of 57% and a predictive value of a negative test of 48% (P > .9 by chi square analysis). Although RSV of the upper respiratory tract may be related to SIDS, our results indicate that EIA of nasal washings is not predictive of bronchiolitis, and we recommend other means of verification of histologic results.

Choriocarcinoma arising in the placenta, or intraplacental choriocarcinoma, has seldom been reported, particularly in the absence of maternal metastases. Reluctance to diagnose choriocarcinoma in the presence of chorionic villi can delay diagnosis; however, timely diagnosis of choriocarcinoma is prognostically important, both for the mother and infant. We report the clinicopathologic findings in five mothers and infants in whom choriocarcinoma was identified in the placenta. None of the mothers had a history of gestational trophoblastic disease in previous pregnancies. Three placentas were similar with a single small lesion grossly suggesting a small infarct; microscopically these consisted of infarcted areas surrounded by choriocarcinoma. These three mothers were unusual in that none had metastatic choriocarcinoma; two were treated with chemotherapy and remained disease-free; the third was lost to follow-up shortly following delivery. The remaining two mothers had known pulmonary metastases at time of delivery. One of these latter two placentas contained a large marginal lesion microscopically identified as choriocarcinoma. The fifth placenta had rare microscopic foci of choriocarcinoma, and sheets of necrotic choriocarcinoma were identified in “blood clot” submitted with the placenta. In four of the five cases the choriocarcinoma appeared to be arising from otherwise normal chorionic villi, and in no case was there invasion of the villous stroma. All of the infants survived, and none had evidence of choriocarcinoma. These cases support the concept that choriocarcinoma associated with otherwise normal pregnancy arises in the placenta and may be more common than reported.

Benign melanocytic lesions in children may give cause for some concern histologically. This is because they represent a specific entity, or they reflect the state of evolution of the lesion or the anatomical location. This latter phenomenon has been poorly documented in children. In this study, we address the problem of atypical features frequently seen in benign nevi from acral sites in a group of patients aged 18 years or less. Twenty-one cases (12 female, 9 male) were identified from the Department of Pathology files during the years 1975–1988. All were Caucasian. Histological examination revealed that 6 cases were congenital and 15 were aquired; of these, 19 cases (90%) had a junctional component and all of these exhibited architecture atypia in the form of either lentiginous proliferation (84%) or confluence of junctional nests (84%). Forty-two percent (8/19) showed a mixture of both. Thirty-seven percent (7/19) exhibited transepidermal elimination of melanocytic nests, with 13/19 (68%) showing single cell infiltration of the epidermis. Atypical size, shape, and location of the junctional nests were present in 10/19 cases (53%). Within this group there appears to be no relationship between the age of the patient and the degree of architectural atypia. Mild cytological atypia was common. This report stresses the importance of anatomic subsite in the assessment of melanocytic lesions in children as well as in adults.

Two male fetuses (18 and 22 weeks gestation) and a 3-month-old male infant (full sibling of the younger fetus) who were diagnosed with Walker-Warburg syndrome (WWS) on the basis of neuropathologic autopsy findings in brain, eyes, and muscle also had micro-orchia and, microscopically, diffuse gonadoblastoid dysplasia in the testes. Both fetuses also had a miniature left ureter and cystic dysplastic left kidney. Testes from control fetuses of 17–24 weeks gestation with normal karyotype and no central nervous system abnormalities (group A, n = 50), a variety of central nervous system abnormalities (group B, n = 50), or an autosomal aneuploidy syndrome with or without central nervous system abnormalities (group C, n = 30) had no diffuse dysplasia, although a single gonadoblastoid seminiferous tubular profile was present in three controls. Testicular morphology was normal in older fetuses and infants with a wide variety of central nervous system malformations (group D, n = 50). We found no evidence of hypogonadotrophic hypogonadism in the three WWS cases to account for the small penis and incompletely descended testes commonly reported in this condition. We concluded that the apparent specificity of the gonadoblastoid testicular dysplasia to WWS suggests that the gene defect directly affects testicular development.

Metatropic dysplasia accounts for approximately 5% of cases recorded by the International Skeletal Dysplasia Registry, with a single recorded lethal case. Four forms of the disease are currently recognized: type I, lethal autosomal recessive form; type II, nonlethal autosomal recessive form with survival to childhood; type III, autosomal dominant form with typical features, and type IV, a mild form with uncertain inheritance. The literature contains few well-documented reports of the histopathologic findings in metatropic dysplasia. In this report, we present the radiologic and histopathologic features in a case of type I metatropic dysplasia, with the unusual features of a persistent tail, unique lung dysmorphology, and thyroidal agenesis.

A newborn female infant was found to have a unique and previously unreported group of anomalies: (1) mitral and aortic atresia with a highly obstructive atrial septum; (2) hypoplasia of the right lung with a crossover segment involving the right lower lobe; (3) normally connected pulmonary veins, two from the left lung and one from the right; and (4) a large anomalous branch of the right pulmonary vein of scimitar configuration that anastomosed with the normally connected right pulmonary vein and with the inferior vena cava (IVC). The scimitar vein appeared obstructed at its junction with the right pulmonary vein and at its junction with the inferior vena cava within the hepatic parenchyma. To our knowledge, this is the first report of a scimitar-like vein coexisting with mitral and aortic atresia and connecting both with the right pulmonary vein and with the inferior vena cava. The highly obstructed left atrium was partially decompressed by retrograde blood flow via the normally connected right pulmonary vein to the anomalous scimitar venous pathway and thence to the inferior vena cava via a pulmonary-to-IVC collateral vein.

Two cases of sacral chordoma in a 7-year, 9-month-old boy and a 3-year, 4-month-old boy are presented. In addition to the typical histology of conventional chordoma, both tumors showed the less differentiated sarcomatoid appearance of atypical chordoma in the major portion. Immunohistochemically, in both cases neoplastic cells in areas of conventional as well as atypical chordoma were positive for keratins (CAM 5.2, AE1 and AE3), epithelial membrane antigen, vimentin, S-100 protein, carcinoembryonic antigen, and glial fibrillary acidic protein. Both patients underwent resection of the tumor and chemotherapy. In comparison with conventional chordomas in adults, however, these two tumors showed more aggressive clinical course and were less amenable to therapeutic control. The older boy died of multiple metastasis 1 year after initial diagnosis. At the last follow-up, 15 months after initial diagnosis, the younger boy was alive, but with recurrent and metastatic disease of the left parasacral area and chest wall. Our studies of these two cases and the reported cases suggest that sacral chordoma in children has distinctive clinico-pathologic features denoting a highly aggressive tumor and that it should be treated as such.

Ebstein's anomaly is a congenital deformity of the tricus-pid valve consisting mainly of leaflet malinsertion. Clinical presentation varies from asymptomatic patients to those with congestive heart failure secondary to significant valvular regurgitation and low right ventricular output. We report here the case of an infant with a diagnosis of corrected transposition of the great arteries and Ebstein's deformity of the left-sided tricuspid valve who developed pulmonary hypertension and endocardial fibroelastosis, two unusual associations with this lesion. We also discuss the pathophysiology of this association and related literature.

We report a neonate with neonatal hemochromatosis (NH), renal tubular dysgenesis (RTD), and hypocalvaria. NH is a fatal condition of the newborn, characterized by severe idiopathic liver failure of intrauterine onset and siderosis, intra- and extrahepatic, with sparing of the reticuloendothelial system. RTD is characterized by short, abnormally developed cortical tubules that lack proximal tubule differentiation. Although both NH and RTD have been reported as entities with a genetic component, similar findings can be secondary to in utero insults. Hypocalvaria has been reported in association with fetal hypoxia including that secondary to angiotensin converting enzyme inhibitors. This 38-week-old infant died at 8.5 h. The small nodular liver weighed 44 g. Grossly, the kidneys were normal. Hypocalvaria was present. Microscopically, the hepatic parenchyma was distorted by fibrous tracts, proliferation of bile ducts, and abundant iron deposition in hepatocytes. Extrahepatic siderosis in the pancreas, myocardium, and other organs was consistent with NH. Proximal convoluted tubules were not seen on routine stains and markers for proximal tubules were negative. Previous reports have linked NH with RTD and RTD with hypocalvaria. This infant had all three of these rare conditions, which have been hypothesized or shown to be due to genetic factors, hypoxia, or drugs. The etiology in this case is unknown.

We report the third known case of mesenchymal hamartoma of the liver (MHL) with a balanced translocation involving a common breakpoint, 19q13.4. A common clonal chromosome abnormality appears to characterize an important subset of MHL, some of which may be low-grade neoplasms. We found no consistent karyotype abnormality in a post-treatment sample of embryonal sarcoma of the liver (ESL). Reports of coexistent MHL and ESL in two patients and detection of 19q abnormalities in two ESLs appear to support Stocker's hypothesis of a histogenetic link between these two rare liver lesions. More data are needed to clarify this relationship. It is possible that MHLs are etiologically heterogenous and may be developmental disorders, disruptions, or neoplasms.

Proteus syndrome is an extremely rare, complex hamartomatous disorder with markedly variable clinical expression. We present a case of Proteus syndrome with multiple disfiguring soft tissue masses that were present since early childhood. The lesions involved predominantly the right side of the body and included scoliosis, macrodactyly, and limited hyperostosis in the right foot. There was no evidence of cranial or skin lesions. The patient underwent multiple resections of soft tissue masses, including an amputation of the right foot because of severe gait disturbance. All specimens exhibited lipomatous lesions that were probably hamartomatous rather than neoplastic. She carried a diagnosis of neurofibromatosis for more than a decade, but a re-evaluation of clinical features and pathological findings prompted the diagnosis of Proteus syndrome. We believe that a more informed evaluation of the pathology material may help to identify this rare entity.

The pathologic assessment of definitive surgical specimens in patients treated for osteosarcoma can be rapidly accomplished using a few pieces of special equipment. Rapid decalcification with formic acid–formalin and routine tissue processing allow the histology laboratory to rapidly prepare histologic slides for pathologic evaluation. A simple qualitative assessment of tumor response to chemotherapy allows the pathologist to classify the tumor response rapidly and reproducibly, and a simple report format allows for unambiguous communication with the patient and physician.