Cellular Peripheral Neural Tumors (Neurofibromas) in Children and Adolescents: A Clinicopathological and Immunohistochemical Study

Nine examples of a cellular peripheral neural tumor (CPNT) were identified in a review of 139 peripheral nerve sheath neoplasms in children, which included 60 neurofibromas and 16 malignant peripheral nerve sheath tumors. The mean age at diagnosis of these nine patients was 7 years, with six presenting in the first decade of life and four were noted at birth. The male:female ratio was 0.5. Topographically, the tumors were located in the extremities, 4; head and neck, 3; and trunk, 2. One or another stigmata of von Recklinghausen's neurofibromatosis (VRN) was present in four patients. After initial resection, seven children remained well, but two developed a recurrence; the histology was identical to the original tumor in one case but overt malignant transformation had occurred in the second. This case was the only tumor-related death in this series. The CPN as a circumscribed but nonencapsulated mass measuring 1.8-7.5 cm in greatest dimension in the subcutaneous and deep soft tissues and had a compact spindle cell pattern, occasional mitoses, and minor foci of typical neurofibroma. Immunohistochemical staining revealed vimentin expression in all seven cases, Leu-7 in six, myelin basic protein and S-100 protein in five, desmin in one, and actin in none. In contrast to neurofibroma and malignant peripheral nerve sheath tumors, CPNT tended to occur earlier, either congenitally or in the first decade, and slightly more commonly in females. The anatomical distribution and pattern of immunoreactivity were similar to neurofibroma. However, the cellularity and mitotic activity of these neoplasms were sufficiently disquieting as to raise concerns about the prognosis, and in one case, the tumor behaved in an unequivocally malignant fashion. When a peripheral neural tumor with the pathologic features described in this study is encountered, wide excision and careful clinical follow-up are recommended.     

Peripheral Neurogenic Tumors of the Soft Tissues in Children and Adolescents: a Clinicopathologic Study of 139 Cases

A review of over 900 soft tissue neoplasms in children and adolescents revealed 139 neurogenic tumors in 122 patients from newborn to 20 years of age, which had been accessioned in a 2 5-year period. Based upon clinicopathologic criteria, 84 (60%) tumors were regarded as unequivocally benign or borderline and the remaining 55 (40 %) were malignant. The average age at diagnosis for the entire series was 10 years; the sex distribution was approximately equal; and the trunk (66, 48%) was the most frequent topographic site, followed by the head and neck (39, 29%) and extremities (31, 23%). Eighteen tumors (13%) were recognized at birth. Twenty-one patients (17%) had the stigmata of von Recklinghausen's neurofibromatosis (VRN). Neurofibromas and cellular peripheral nerve sheath tumors accounted for 43% (60 cases) of the diagnoses; these 60 neoplasms occurred in 41 patients, 12 of whom had VRN. The second largest category of neoplasms (38 cases, 28%) was the primitive neuroectodermal tumor (PNET) including the subset of “malignant small cell tumor of thoracopulmonary origin” or Askin tumor. The PNETs other than the Askin tumor (26 cases) presented mainly on the trunk (63%) and head and neck region (33 %), showed a male predilection (58 %) and had a mean age at diagnosis of 7 years. Askin tumors (12 cases) were, by definition, confined to the chest wall or thoracic cavity, showed a female predilection (71%), and presented in the second decade (82%, mean age 14 years). There were 16 (11%) malignant peripheral nerve sheath tumors, seven of which occurred in children with VRN. Six other categories of neurogenic tumors constituted the remaining cases. Our findings indicate that neurogenic neoplasms are an important nosologic group of soft tissue tumors in the pediatric population.     

Immunohistochemical Study of Neuroblastoma and Related Tumors with Anti-S-100 Protein Antibody

Histological sections of 36 cases of neuroblastema and related tumors were studied with anti-S-100 protein antibody (PAP method). Schwann cells in the ganglioneuromas and ganglioneuroblastomas always strongly stained. In addition, varying numbers of spindle-shaped or elongated positively staining cells, which were probably Schwann cells and their precursor cells, were demonstrated in ganglioneuroblastoma and differentiating neuroblastoma. Undifferentiated round cell neuroblastoma showed no reaction. Immunohistochemical findings of these cases were classified into four groups (+ +, +, ±, -) according to the number of the positive cells and compared with prognosis, histological typing, location of the tumors, stage, and age at surgery. The cases with many positive cells, group (+ +) showed excellent prognosis, and group (-) showed very poor prognosis. The results of this study indicate that S-100 protein staining provides a reliable objective method for evaluation of differentiation of the neuroblastoma cells toward Schwann cells, which appears to be an important factor to predict prognosis.     

Soft Tissue Tumors in First Year of Life: A Report of 190 Cases

A comprehensive review of soft tissue tumors in children and adolescents disclosed the presence of 190 neoplasms in 183 patients, which were diagnosed in infants between birth and 12 months of age; these infants represented approximately 20% of our entire pediatric soft tissue tumor series. In excess of 75% of cases were pathologically benign with the hemangioendothelioma, lymphangioma, and fibromatosis-myofibromatosis constituting the majority of cases in this category. Fibrous histiocytoma and lipoblastoma were the other two benign entities. Congenital-infantile fibrosarcoma was considered a borderline tumor because of its infrequently manifested potential for metastasis; none of the 13 cases in the present study behaved in a malignant fashion. Embryonal rhabdomyosarcoma and peripheral primitive neuroectodermal tumor were the two principal types (17 of 27 cases) of malignant soft tissue tumors. In contrast to soft tissue tumors in the first two decades, those in the first year of life were more often benign despite their cellularity and presence of mitotic activity. Fibroblastic-myofibroblastic tumors were more frequent in this young age group, whereas neurogenic and myogenic tumors were relatively more common in children older than 1 year of age. The trunk and head and neck region were the preferred topographic sites rather than the extremities, which was the case in children beyond the first year of life.     

Fibroblastic-Myofibroblastic Tumors in Children and Adolescents: A Clinicopathologic Study of 108 Examples in 103 Patients

A review of over 900 soft tissue tumors in children and adolescents revealed 108 fibroblastic-myofibroblastic tumors in 103 patients from newborn to 20 years of age, which had been accessioned in a 25-year period. Based on clinicopathologic criteria, 82 (76%) were regarded as benign, 14 (13%) as borderline, and 12 (11%) as malignant. The average age at diagnosis for the entire series was 7 years with a male/female ratio of 1.8:1. The most frequent topographic site was the extremities (48, 44%), followed by the trunk (31, 29%) and the head and neck region (27, 25%). Virtually 50% (51 tumors) of cases were diagnosed during the first year of life, and 73 (71%) occurred in the first decade. The known recurrence rate was 16% (17 cases). Fibromatoses of various subtypes accounted for 95% of the histologically benign group. Infantile myofibromatosis was the most frequent form of fibromatosis, followed by aggressive (desmoid) fibromatosis (20 cases, 19%). Ninety percent of infantile myofibromatoses were diagnosed in the first year of life. In contrast, 70% of aggressive fibromatoses occurred in the second decade. Associated conditions included familial desmoid fibromatosis, Gardner syndrome, and previous surgery. The borderline category was represented by the 14 (13% of the series) congenital-infantile fibrosarcomas. All of the 14 (13%) malignant tumors were classic adult-type fibrosarcomas that occurred only in later childhood and adolescence. Fibromatosis colli, fibrous hamartoma of infancy, juvenile nasopharyngeal angiofibroma, Dupuytren-type fibromatosis, infantile digital fibromatosis, juvenile aponeurotic fibroma, unclassified fibromatoses, and fibroma of tendon or nerve sheath constituted the remaining cases.     

Mesothelial and Related Neoplasms in Children and Adolescents: A Clinicopathologic and Immunohistochemical Analysis of Eight Cases

Mesothelioma is a neoplasm that occurs infrequently in childhood: only an estimated 2-5% of all cases present in the first two decades of life. The diagnosis may be perplexing because of its rarity and its pathologic similarities to other papillary or spindle cell neoplasms in the pediatric age group. We have studied eight cases of mesothelial or submesothehal-derived neoplasms of pleural (four cases) and peritoneal (four cases) origin in patients 4 to 17 years of age at diagnosis. Microscopically, six were epithelial, with papillary, tubuloglandular, and solid patterns. Two tumors were predominantly fibrous appearing, one a localized pleural fibroma and the other a diffuse pleural sarcomatoid mesothelioma. All of the tumors were immunoreactive for vimentin, and all except the pleural fibroma stained for either cytokeratin, epithelial membrane antigen, or both. None reacted with antibodies to carcinoembryonic antigen, placental alkaline phosphatase, or Leu-M1. At last follow-up, three patients were dead of tumor, three were alive and well, and two had been recently diagnosed and were undergoing treatment. These results indicate that the immunohistochemical profile delineated for mesothelioma in adults is equally applicable to mesothelial neoplasms in younger patients and is useful in establishing a diagnosis. The prognosis for malignant mesothelioma in childhood appears to be as unfavorable as the adult counterpart, with the possible exceptions of certain clinicopathologic subtypes.     

Bone Marrow Metastasis in Ewing's Sarcoma and Peripheral Primitive Neuroectodermal Tumor: An Immunohistochemical Study

Bone marrow metastases from small round cell tumors can present diagnostic difficulties. In this study, we assessed the value of immunohistochemistry, using two monoclonal antibodies to CD99, for the diagnosis of metastatic disease in bone marrow trephine specimens from patients with Ewing's sarcoma or primitive neuroectodermal tumor (PNET). The proportions of specimens showing metastases were 10.3% with routine staining and 20.7% with immunohistochemistry. The specimens that were negative on conventional light microscopy and positive with immunohistochemistry all showed other abnormalities. The results do not support the routine use of immunohistochemistry in specimens that are normal by conventional light microscopy, but indicate that useful information may be gained in cases where marrow histology is obscured by fibrosis, necrosis, or distortion artefact. Neither of the two antibodies tested was superior for this purpose. Received January 17, 1997; accepted May 22, 1997     

CONGENITAL ALVEOLAR PROTEINOSIS IN THE NETHERLANDS: A Report of Five Cases with Immunohistochemical and Genetic Studies on Surfactant Apoproteins

Congenital alveolar proteinosis is a recently described cause of lung dysfunction and respiratory distress in term neonates. In several cases a deficiency or insufficiency of surfactant apoprotein B SP-B has been caused by a frameshift mutation in the gene encoding SP-B. Five full-term children in three unrelated families from The Netherlands are reported. Immunohistochemistry demonstrated large amounts of surfactant proteins A and C SP-A and SP-C and precursors in alveolar cells and in intra-alveolar material. Results were positive for antibovine SP-B antibody but negative for antipig SP-B1 antibody, most probably reflecting differences in the antibody specificity. The findings suggest abnormal SP-B function. In two sibs, no pre-SP-C was demonstrated in the alveoli, although it was found in considerable amounts in alveolar cells. One such case has previously been reported. In two families, the parents were heterozygous for the 121 ins 2 mutation in the SP-B gene. Our findings suggest that congenital alveolar proteinosis may result from abnormalities in one or more of the surfactant proteins.     

Undifferentiated sarcomas of children: Pathology and clinical behavior—an Intergroup Rhabdomyosarcoma Study

Undifferentiated soft tissue sarcoma (UND-STS) is the most poorly defined tumor eligible for Intergroup Rhabdomyosarcoma Studies (IRS). Recent IRS UND-STS experience was reviewed to assess the histologic characteristics and clinical behavior of undifferentiated sarcomas. Of the 1,527 patients entered on IRS-III and IRS pilot-IV, 96 had tumors classified by the IRS Pathology Committee as UND-STS. Of these, 52 had adequate histologic material for this study. After application of immunohistochemistry, 18 tumors were reclassified, mostly as embryonal rhabdomyosarcomas (RMS), primitive neuroectodermal tumors, and intra-abdominal desmoplastic small round cell tumors. The remaining 34 UND-STS had a diffuse hypercellular histologic pattern made up of sheets of medium-sized cells. The tumor cells had a minimal to moderate amount of cytoplasm and a variable nuclear morphology, predominately vesicular with finely granular chromatin. Except for reactivity with antibodies against vimentin, most tumors had a negative immunohistochemical profile. The 5 year Kaplan-Meier survival estimate for patients with non-metastatic disease was 72%, a significant improvement when contrasted with patients diagnosed to have UND-STS in IRS-I and IRS-II. Med. Pediatr. Oncol. 29:170–180, 1997. © 1997 Wiley-Liss, Inc.     

Epithelioid Sarcoma in Childhood: An Immunohistochemical, Electron Microscopic, and Clinicopathologic Study of 11 Cases Under 15 Years of Age and Review of the Literature

Epithelioid sarcoma in a rare tumor and most of the cases occur in young adults. It is rare in childhood. We have been able to obtain data and histologic material for 11 patients with this disease. The primary sites were head and neck in three patients, inguinal region in one, and extremities in seven. The age range of the patients was 12 weeks to 13 years. There was a preponderance of males over females with a ratio of 1.75. The tumors presented with a typical nodular necrotizing pattern. In three cases giant osteoclast-like cells were present. The immunohistochemistry and electron microscopy showed features consistent with previous observations on epithelioid sarcomas. In one case islands of small dark cells noted on light microscopy were surrounded by basal lamina on electron microscopy. The cells inside the nests were undifferentiated. Six tumors studied by flow cytometry were in DNA diploid range. On follow-up, five children are alive and well 2 to 7 years after treatment. Three children died of tumor progression with metastases to lymph nodes and lungs. One child had been diagnosed only recently, and in one the disease has run a protractive course with multiple recurrences. The behavior of these epithelioid sarcomas in children is similar to that seen in adults, the prognosis being dependent on radical tumor surgery preventing recurrent disease. Long-term follow-up is necessary because the tumor may recur many years after the primary tumor was removed.     

Cell Kinetic Analysis in Pediatric Brain and Spinal Tumors: A Study of 117 Cases with Ki-67 Quantitation and Flow Cytometry

We present cell kinetic data including Ki-67 quantitation and flow cytometry on 117 pediatric brain/spinal cord tumors and review the literature. Although, in general, these proliferation indices are in agreement with the histologic grade, they are useful in prognostication in some instances when the histological features of malignancy are equivocal. Specific examples in which flow cytometry may prove particularly useful in this context are childhood ependymomas, which do not show frank anaplasia but have cellular foci with focal increase in mitoses, and choroid plexus neoplasms, where elevated S phase fractions have been associated with an adverse outcome. Thus Ki-67 quantitation and flow cytometry not only serve as useful adjuncts to conventional histologic grading but also in specific instances may provide new information on tumor prognosis.     

Total Anomalous Pulmonary Venous Drainage Associated with Fatal Outcome in Infancy and Early Childhood: An Autopsy Study of 52 Cases

Clinicopathological details of 52 cases of total anomalous pulmonary venous drainage (TAPVD) taken from pediatric autopsy files from hospitals in Adelaide (Australia) Oxford and Edinburgh (United Kingdom) between 1957 and 1990 are presented. The patients ranged in age from a stillborn girl to a 15-month-old boy, with 42 cases (81%) dying in the first 3 months of life. While many patients had signs of a congenital cardiovascular anomaly prior to death, including tachypnea, tachycardia, central cyanosis, cardiac failure, heart murmurs, and difficulty in feeding, it was noteworthy that eight patients (16%) presented as sudden and unexpected death in the absence of significant antemortem symptoms and signs. Anomalous pulmonary venous drainage was also unsuspected prior to death in a total of 26 cases (53%) of those where relevant history was available (49 cases). Twelve infants (23%) underwent surgical correction, none of whom survived more than several weeks. TAPVD was isolated in 30 cases (58%) and was associated with other cardiac or congenital anomalies in 22 patients (42%). Just under half of nonisolated cases comprised the asplenia-heterotaxy syndrome. The points of drainage of the anomalous pulmonary veins were to the infradiaphragmatic veins (n = 21, 40%), left innominate vein (n = 13, 25%), coronary sinus (n = 7, 13%), right superior vena cava (n = 4, 8%), inferior vena cava above the diaphragm (n = 2, 4%), right innominate vein (n = 2, 4%), mixed left innominate vein and coronary sinus (n = 1, 2%), azygos vein (n = 1, 2%), and mixed right superior vena cava and left hemiazygos vein (n = 1, 2%). Twenty-three of 47 cases (49%) that were specifically examined revealed obstruction of the pulmonary veins or pulmonary hypertensive vascular changes on histology. These results emphasize that TAPVD needs to be excluded at autopsy as a causal factor in cases of sudden infant death even in the absence of antemortem symptoms and signs. Clues at autopsy include abnormal mobility of the heart, visceral situs inversus, and polyasplenia. The diversity of pulmonary-systemic venous anastomoses necessitates careful in situ dissection above and below the diaphragm and consideration of postmortem angiography.