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PNET and Ewing sarcoma are pathologically distinct entities with very similar clinical and radiological characteristics. Immunohistochemical studies are needed to distinguish PNET from Ewing sarcoma, with the former being characterized by neural differentiation. We present the case of a 17-year-old man with immunohistochemically confirmed PNET in the cervical vertebrae.
We report a case of a primary renal primitive neuroectodermal tumour in a 24-year-old man associated with multiple pulmonary metastases. Histologically, the bulk of the kidney was replaced by a small round-cell tumour with numerous true Homer-Wright rosettes and perivascular pseudorosettes; wide-spread vascular invasion was noted. There was no evidence at autopsy of a primary tumour elsewhere. Immunohistochemically, the tumour cells stained strongly positive for O-13, a monoclonal antibody, which recognizes a recently described cell membrane glycoprotein (p30/32MIC2), more weakly for NSE and at least focally for PGP 9.5; the tumour did not stain for other neural markers, cytokeratin, leucocyte common antigen, or desmin. The differential diagnosis of small round-cell tumours in this location and the relation of primitive neuroectodermal tumours and Ewing's sarcoma are discussed.
Five cases of ovarian tumor with an exclusive or almost exclusive malignant neuroectodermal composition are reported. Four of them were unquestionably primary, but one, although probably primary, was possibly metastatic from the adrenal gland. The ages of the four patients with tumors in the former category ranged from 13 to 17 with an average of 15 years; the fifth patient was 18 years old. The presenting symptoms were similar to those of other ovarian cancers. Two of the definitely primary tumors were pure while two others contained minor foci of mature teratoma. Only one of the four patients with an unquestionable primary ovarian tumor survived for more than 7 years; the others died of tumor from 2 months to almost 4 years postoperatively. The fifth patient presented with unilateral ovarian involvement by neuroblastoma and abdominal metastases; autopsy over 6 months later revealed involvement of both adrenal glands. This case appears to be the first recorded case of neuroblastoma presenting clinically as a primary ovarian cancer.
A 6-month-old female presented with a swelling of the left superior maxillary bone. A radiograph revealed a radiolucent lesion in the left anterior maxilla, and CT, showed a solid mass. At surgery, the lesion was a cystic dental tumor of ectopic location which was treated by excision. The pathological diagnosis was melanotic neurorectodermal tumor. This is an uncommon benign tumor of the neural crest origin that occurs mainly in the maxilla (70% of cases) but can occur in other areas such as the skull and the mandible. CT reveals a hyperdense mass and MR shows a hypointense mass on T1-weighted images and an iso-intense mass on T2-weighted images. The evolution is usually benign after surgical removal.
In a 15-year-old girl with right upper arm tumor diagnosed at first as neuroblastoma, the second histopathological examination revealed PNET. In spite of the advanced stage of disease (IIIrd or IVth) surgical excision was not performed but chemotherapy (8 courses of VADRAC and 8 courses of VP16 + CDDP) and radiotherapy (40 Gy) was administered. After 4 initial cycles all symptoms of the disease disappeared. The child remains in CCR for 60 months, including 40 months of therapy.
HISTORY: A 44-year-old man presented to his general practitioner with increasing exertional dyspnoea. After a syncope he was admitted to hospital. INVESTIGATIONS: Echocardiography on admission demonstrated a large pericardial effusion (45 mm over the right and 57 mm over the left ventricle) which, in view of its haemodynamic relevance, had to be removed by pericardiocentesis. Cytological examination of the fluid showed various blood constituents but no atypical cells. Computed tomography (CT) of the thorax revealed a homogeneous hyperdense structure in the area of the left atrium. After several more pericardiocenteses echocardiography showed a pericardial tumour between the left atrium and ventricle. Gastroscopy, coloscopy, abdominal CT, an octreotide scan and positron-emission tomography did not indicate an extracardiac tumour. Coronary angiography and video-assisted thoracoscopy were performed. They confirmed an epicardial tumour at the level of the left atrium. TREATMENT AND COURSE: The entire round and solid tumour of about 3 cm in diameter, at the tip of the left atrial appendage was removed under extracorporeal circulation. No adjuvant treatment was given. Histological and immunohistological tests of the resected specimen (CD-99 and NSE-positive) provided the diagnosis of malignant peripheral primitive neuroectodermal tumour (pPNET). CONCLUSION: There are at present no adequate data on optimal treatment of pPNET in the heart. This case demonstrates that even with a large such tumour long remission is possible after complete removal without any adjuvant treatment.
We have evaluated the relationship between the neuronal myc gene (NMYC) and class I major histocompatibility complex (MHC) expression in human neuroblastoma (NB) tumor cell lines. Class I MHC surface Ag expression in NB cell lines varied from nearly undetectable to levels nearly as high as in a lymphoblastoid cell line. Class I MHC mRNA levels in NMYC-amplified NB cell lines were lower than levels observed in single copy NMYC NB cell lines. However, considerable variation in class I MHC surface Ag and mRNA expression was evident in NMYC-amplified cell lines. To determine directly whether NMYC might modulate class I MHC expression in NB, we transfected a plasmid containing a recombinant NMYC gene into two tumor cell lines derived from a NB and a related neuroepithelioma tumor. Constitutive overexpression of the recombinant NMYC gene produced no consistent change in class I MHC surface Ag or mRNA levels. To determine whether class I MHC expression might be developmentally regulated in adrenal medullary cells, the precursor cells of adrenal NB tumors, beta 2-microglobulin expression was measured in fetal and adult adrenal glands. beta 2-Microglobulin expression was not evident in the neuroblasts of a 24-wk-old fetal adrenal gland, whereas beta 2-microglobulin expression was present in the adult adrenal medulla. These data suggest that variation in class I MHC expression among NB cells may reflect the developmental stage at which neuroblasts were arrested during tumorigenesis.
In week 12 of the EICESS 92 protocol a 12-year-old boy with pelvic PNET developed acquired von Willebrand disease: bleeding time was prolonged (> 15 min) and von Willebrand factor antigen (54%) and ristocetin cofactor activity (50) were reduced. Platelet aggregations with thrombin and collagen and the number of major platelet glycoproteins/per platelet did not differ from the controls. After Haemate P (Behring Werke, Marburg, Germany) bleeding time normalized and surgery could be performed without occurrence of bleeding episodes. Three weeks after surgery bleeding time, ristocetin cofactor activity, and von Willebrand factor antigen increased to normal paediatric values. Without occurrence of further bleeding episodes the patient received another 10 courses of polychemotherapy (EICESS 92).
Peripheral neuroblastic tumors in childhood present unique problems in terms of diagnosis, classification, and histologic determinants of prognosis. The proper specimen handling of these neoplasms requires integration of gross and microscopic pathologic examination along with cytogenetic, immunohistochemical, and electron microscopy studies. The appropriate gross examination and processing of these tumors are described with particular emphasis on ancillary studies. Important special studies such as immunohistochemistry, flow cytometry, and genetic and molecular oncologic investigation are stressed, and the appropriate methods of processing materials for these studies are discussed. The handling of small biopsy specimens, fine-needle aspirates, or both is also addressed. The staging of neuroblastoma varies according to Pediatric Oncology Group and Children's Cancer Study Group systems, and the importance of obtaining appropriate information to satisfy either system is noted. Ancillary information for classification of neuroblastoma and related neoplasms is also presented.
Melanotic neutroectodermal tumor of infancy (MNTI) is a rare, usually benign tumor commonly occurring in the maxilla. MNTIs at unusual sites like the cranium clinically mimic malignant small round cell tumors. Consequently, a correct preoperative cytologic diagnosis of MNTI at these sites helps in the surgical management of the patient. We report on a cytologically diagnosed case of MNTI in the frontotemporal region of the skull in an infant. Aspirates from the lesion were cellular, with a bimodal population mainly of small neuroblast-like cells admixed with a few large epithelioid cells with melanin granules. In the present case, following the cytologic diagnosis a wide local excision was carried out, and the histologic examination confirmed the cytologic diagnosis. Diagn. Cytopathol. 1999;21:280-283.
The PNET is an extremely malignant soft tissue neoplasm resulting from a balanced reciprocal translocation t (11; 22) (q24; q12). Treatment of the undifferentiated small cell tumor is carried out in compliance with the protocol of the soft tissue trail (CWS) from the German Society of Pediatric Oncology. Biopsy-proven diagnosis is followed by primary chemotherapy which leads in 95% of cases to remission. After excision of the remainder of the malignancy, an irradiation of the tumor site and two further sequences of chemotherapy are performed. Between 1986 and 1994, in cooperation with our pediatric and radiotherapeutical colleagues, we treated ten patients. In four patients (median age, 14 years) the PNET originated from the chest wall, in six patients from the paravertebral and retroperitoneal region. Five patients died after 20 months on average, while the remaining five patients are in full remission after 22, 37, 41, 42 and 82 months, respectively.
In the past two decades, chemotherapy has proven to be an increasingly more effective modality in the treatment of medulloblastoma. Current evidence suggests that chemotherapy be included as part of standard treatment for all patients with high-risk medulloblastoma. Ongoing multi-centre trials are determining whether chemotherapy should be added to reduced dose radiotherapy as a substitute therapy for standard-dose radiotherapy. The major randomized and non-randomized chemotherapy trials for newly diagnosed patients with medulloblastoma or for patients at recurrence are presented. It is hoped that the addition of chemotherapy will eventually lead to improved survival rates as well as the reduction in the craniospinal radiotherapy dose for patients with medulloblastoma.
A search of TP53 mutations was undertaken in a series of 51 pediatric brain tumors. The only germ-line mutation was detected in a 9-year-old girl with a PNET. Her family history was unremarkable for neoplastic disease, except for the paternal grandfather, who died of a gallbladder carcinoma at an advanced age. The mutation was a thymine deletion at the first base of codon 241, leading to termination codon at position 246 that has not previously been reported. This mutation was found to be inherited from the proband's father, who was healthy at age 40. In the tumoral sample, loss of heterozygosity in several 17p markers was found, the only TP53 allele preserved in the tumor was the mutated one. The presence of two short tandem repeats and two different palindromic sequences spanning the deletion lead us to propose the predisposition of this region to forming a complex secondary structure during replication. Consequently, it could have facilitated the present deletion. Furthermore, six other short deletions affecting--partially or totally--the region implicated in the folding model that we propose have been described in the literature. These findings confirm that this sequence represents a hotspot of deletion in the TP53 gene.
BACKGROUND: Primitive neurocetodermal tumors (PNETs) constitute a family of neoplasms of presumed neuroectrodermal origin most often presenting as bone or soft tissue masses. There are very few reported cases of PNET of the kidney and none diagnosed by fine needle aspiration cytology (FNAC), to the best of our knowledge, in the world literature. We present two cases of renal PNET diagnosed on cytology. CASES: Two patients with renal masses were diagnosed as having PNET on FNAC. Cytologically the tumors showed a dispersed population of malignant small round cells with focal rosette formation and perivascular arrangement of tumor cells. Immunohistochemistry on the cell blocks in both cases showed strong membrane positivity for CD99 (MIC2). Cytogenetic studies in both cases showed the characteristic t(11;22)(q24;q12) translocation, with additional chromosomal abnormalities in case 2. CONCLUSION: PNET of the kidney is a distinct entity and can be diagnosed on fine needle aspiration smears and confirmed with immunohistochemistry and cytogenetic studies. A diagnosis of PNET must be included in the differential diagnosis of renal masses in adolescents and young adults.
CONCLUSION: Although PNETs are rare malignancies, they should be considered in the differential diagnosis of submucosal gastric tumours in adolescents with clinical alarm symptoms.NET was confirmed by detection of the characteristic EWS/FLI-1 fusion gene, resulting in a reciprocal translocation t(11;22)(q24;q12). Three distinct liver metastases were detected by CT, MRI, and PET. The tumour failed to respond to neoadjuvant polychemotherapy with vincristine, etoposide, doxorubicin, and ifosfamide. Subtotal gastrectomy was performed and, surprisingly, we found diffuse metastatic infiltration of the liver that had not been detected by preoperative staging. Due to the diffuse metastatic disease the young patient's prognosis has to be considered very poor. Because of the tumour's intense expression of CD117 (c-kit), the patient is now treated with the tyrosine kinase inhibitor imatinib (STI571).
AWe report on two siblings (brother and sister) who developed cerebral PNETs at the age of 5 years and 6 months, respectively. Both children were treated by operation followed by polychemotherapy. The brother also received cranio-spinal irradiation. Nevertheless, the children died about 12 months and 24 months post-operatively due to extensive cerebral tumor recurrences. Shortly after having lost both of her children, the mother developed an intra-abdominal tumor, which was resected and histologically diagnosed as ovarian carcinoma. Because of this unusual familial clustering of tumors and a positive history of brain tumors and other cancers in several maternal relatives, we analyzed DNA isolated from both PNETs and the ovarian carcinoma as well as constitutional (leukocyte) DNA from the whole family for mutation of the TP53 tumor suppressor gene. This analysis revealed that all tumors were homozygous for a missense mutation at codon 213 (CGA => TGG) resulting in an amino acid exchange from arginine to tryptophane. The same mutation was present in one TP53 allele in the constitutional DNA of the mother and the children, indicating that the mother had transmitted a TP53 germline mutation to both of her children. Analysis of loss of heterozygosity at microsatellite markers from 17p confirmed deletion of the paternal (wild-type) allele in both PNETs. Further investigation of the PNETs by comparative genomic hybridization revealed multiple chromosomal abnormalities. Interestingly, some genomic changes were common to both PNETs, while many others were not, a finding suggesting substantial genomic instability, probably as a consequence of p53 inactivation.
Medulloblastomas represent about 25% of all pediatric intracranial neoplasms. These highly malignant tumors arise from the cerebellum, affecting mainly children between ages 5 and 15. Although the etiology of medulloblastomas has not yet been elucidated, several reports suggest that both the cellular protein insulin-like growth factor I (IGF-I) and the early protein of the human polyomavirus JC (JCV T antigen) may contribute to the development of these tumors. The results of this study show a potential functional cooperation between these two proteins in the process of malignant transformation. Both medulloblastoma cell lines and medulloblastoma biopsies are characterized by the abundant presence of the IGF-I receptor (IGF-IR) and its major signaling molecule, insulin receptor substrate 1 (IRS-1). Importantly, IRS-1 is translocated to the nucleus in the presence of the JCV T antigen. Nuclear IRS-1 was detected in T antigen-positive cell lines and in T antigen-positive biopsies from patients diagnosed with medulloblastoma. The IRS-1 domain responsible for a direct JCV T antigen binding was localized within the N-terminal portion of IRS-1 molecule and the competition for IRS-1 T antigen binding by a dominant-negative mutant of IRS-1 inhibited growth and survival of JCV T antigen-transformed cells in anchorage-independent culture condition.
Recent studies have suggested that formalin-fixed paraffin-embedded (FFPE) tissues can be used for molecular analyses by fluorescence in situ hybridization (FISH) and RT-PCR. We analyzed 18 cases of ES/PNET for the t(11;22)(q24;q12) and t(21;22)(q22;q12) fusion transcripts by RT-PCR and analyzed for EWS translocation by interphase FISH with a dual color fusion probe to compare these two approaches directly. RT-PCR detected 13 (72%) EWS-FLI-1 fusions (type I=10, type II=3) and 2 (11%) EWS-ERG fusions. Three cases could not be evaluated because the housekeeping gene phosphoglycerate kinase (internal mRNA control) was not amplified. FISH was diagnostic in 15 of 18 cases (83%). There were three discordant cases between RT-PCR and FISH (concordance of 83%). Using a combination of RT-PCR and FISH, the results were complementary. One advantage of RT-PCR analysis was that subtypes of EWS translocation could be determined specifically (type I, type II and ERG). These findings indicate that because of the difficulties and limitations associated with the molecular analysis of FFPE tissues, a combination of RT-PCR and FISH may be a better approach to enhance the sensitivity and accuracy of detecting ES/PNET translocations in FFPE tissues with suboptimally preserved nucleic acids.