Volume 1, Issue 1 , Pages 27-32, March 2006
Maxillar localization of a congenital peripheral primitive neuroectodermal tumor:
A case report
Article Outline
Summary
Peripheral primitive neuroectodermal tumor is very rare in children and congenital forms are exceptional. This tumor belongs to the Ewing's sarcoma (ES) family and the difficulty of diagnosis lies in the confusion with rhabdomyosarcoma, neuroblastoma, ES and lymphoma. Diagnosis is only performed by immunohistochemistry and RNA analysis. Congenital peripheral primitive neuroectodermal tumor seems to be more aggressive and refractory to treatment than non-congenital forms. In literature, most of the patients die within 6 months of diagnosis despite therapy. We report the first case of congenital peripheral primitive neuroectodermal tumor localized in the left maxillary bone of a full-term female infant.
Keywords: Peripheral primitive neuroectodermal tumor, Neural crest, Congenital, Ewing's sarcoma, EWS/FLI-1 fusion gene
1. Introduction
Peripheral primitive neuroectodermal tumor (pPNET) starts in the embryonal cells of the neural crest, which differentiate into neuronal, glial or epithelial lineage. During the early embryonic period, these cells migrate laterally and dorsally to participate in the genesis of the peripheral nervous and endocrine systems [1].
pPNET commonly arises in soft tissue or bone outside cerebral or sympathetic nervous system. Before the age of 18 years, the most common location of pPNET is the thoracopulmonary region (46%) followed by the head and neck region (42%) [2]. pPNET occurs particularly in childhood from the newborn to the second decade, but rare cases in adult are described.
pPNET and Ewing's sarcoma (ES) belong to the same tumor family but pPNET follows a more aggressive course. For some authors, classic ES and pPNET are the same tumor with variable cellular differentiation because of the same cytogenetic modification each one induces [1]. Actually, pPNET and ES have the characteristic translocation t(11;22) or t(21;22) in more than 90% of cases. Moreover, MIC2, a pseudoautosomal gene located on the short arm of the sexual chromosome is a specific marker of both the tumors. Compared with ES, pPNET presents a neuronal differentiation that appears clearly with immunostainings, which help specific diagnosis [3].
There are no clinical or radiological criteria to differentiate pPNET from other tumors. Usual confusion is done with rhabdosarcoma, ES, neuroblastoma or lymphoblastoma. Diagnosis is uneasy and based on immunohistochemistry and RNA analysis [4].
The concept of PNET was introduced in 1973 [5] to classify an unusual group of undifferentiated brain tumors, defined as an independent entity by Jaffe et al. [6] in 1984. Dehner et al. [7] have proposed a differentiation between central PNET, which is found in the brain or the spinal cord, and peripheral PNET found outside the central nervous system. The first description of pPNET was made by Stout [8] in 1918, who described a tumor of the forearm of peripheral nerve origin. Since, pPNET has been named after various terms including Askin's tumor, peripheral neuroepithelioma, extraskeletal ES or peripheral medulloepithelioma [3]. After the advances made by molecular biology and cytogenetics, pPNET, ES and Askin's tumor have been definitely grouped under the name of primitive neuroectodermal tumor or PNET [3], [4].
The incidence of pPNET in pediatric population is difficult to assess. Congenital and neonatal tumors represent 2% of all childhood malignancies [9]. Two cases of congenital pPNET were mentioned by the International Society of Pediatric Oncology in 2002 [9]. Nine cases of neonatal pPNET have been reported by Sebire et al. [10] in 2003.
The purpose of this article is to report the different cases of pediatric pPNET found in English literature and to highlight the features of congenital forms, their prognosis factors and the difficulty of diagnosis.
The clinical, radiological, histological and immunohistochemical findings are presented and the relevant literature is reviewed.
2. Case report
We report the first case of pPNET localized in the left maxillary bone of a full-term female infant. This primary maxillar localization has never been reported in a congenital form.
The first child of healthy parents was born by normal delivery at 39 weeks and 2 days after an uncomplicated pregnancy. Antenatal obstetrical ultrasonographies had neither shown any anatomic anomaly nor hydramnios.
At birth, the girl presented a congenital soft tissue mass measuring 4
cm×4cm, localized in the mouth and the left nasal cavity (Fig. 1). The tumor appeared with hemorrhagic and necrotic features and bled easily. General physical examination including neurological and cutaneous examination was unremarkable. No obstructive respiratory insufficiency was found. Computed tomography (CT) enhanced by intravenous contrast confirmed the tissular nature, the volume of the tumoral mass and its dependence from the left maxillary bone (Fig. 2, Fig. 3). The nasal septum and the orbital floor were respected but the periostic reaction was important.
Fig. 1.
Clinical photograph showing the congenital mass localized in the mouth and the left nasal cavity. The tumor appeared hemorrhagic and necrotic.
Fig. 2.
Computed Tomography (CT) scan with axial imaging showing a tumoral mass dependant of the maxillary bone invading the left nasal cavity with an important periostic reaction (white arrow).
Fig. 3.
Computed Tomography (CT) scan with axial and coronal imaging showing the recurrence of the tumoral process invading the ethmoïdal bone and the orbit roof (white arrow).
Cerebral and thoraco-abdominal CT scan, bone marrow biopsy and bone scintigraphy showed no other tumoral localization. The blood counts, serum biochemistry, alphafoetoprotein and catecholamins dosage were within normal limits for her age.
A first biopsy was realized in her third day of life. Initial histological assessment suggested an alveolar rhabdomyosarcoma.
Following the histological results, a first course of chemotherapy according to MMT 95 protocol was started (Actinomycine (90μg/day at D1 and D15) and Vincristine (90μg/day at D8)).
Tumor was partially resected by a purely oral approach at the end of the MMT 95 protocol. The lesion was of a soft consistency and bled easily.
Histological examination revealed small malignant blue cells (Fig. 4). Mitotic figures were frequent and the complete characteristic rosette aspect was not found in sections but only a starting aspect (Fig. 4).
Fig. 4.
(A) Photomicrographs showing that the tumor is composed of densely packed cells with hyperchromatic nuclei (black arrow) (hematoxylin and eosin at 200× magnification); (B) mitosis are shown. An aspect of rosette is visible (black arrow)) (hematoxylin and eosin at 400× magnification).
Immunohistochemical studies demonstrated positive immunoreactivity (Fig. 5) for S100, CD56, synaptophysin, CK22, HMB45, AE1, AE2 and MIC II. Stains for desmin and CD17 were negative. A reverse transcriptase–polymerase chain reaction was used to detect the fusion gene EWS/FLI-1 considered specific for pPNET and ES group. Specific translocations like PAX 3/7/FKHR for alveolar rhabdomyosarcoma, or SYT/SSX2 for synoviosarcoma were not highlighted.
Fig. 5.
Immunohistochemical stainings shown by black arrows for (A) synaptophysin; (B) HMB45; and (C) AE1-AE3. Peripheral tumoral cells are positive for HMB45 and AE1-AE3 stainings (B and C; magnification ×400). Central tumoral cells are positive for synaptophysin (A; magnification ×400).
With respect of these findings, this tumor was considered to be a pPNET. This diagnosis was only performed 1 month after birth. The patient then received a second course of chemotherapy (Cyclophosphamide (3mg/kg/day during 7 days) and Adriamycine (0.75mg/kg/day at D8)).
Inspite of chemotherapy, signs of tumor relapse and progression during chemotherapy were observed with a rapid growth towards orbit, ethmoïd sinus, infratemporalis fossa and controlateral maxillary sinus without evidence of metastasis.
Five days after the end of the second course of chemotherapy, additional protocol associating Etoposide (14mg/day) and Carboplatine (18mg/day) was performed during 3 days.
Tumor progression was not even slowed. The patient died of respiratory distress 2 months after birth. No autopsy was performed in respect with parental consent.
3. Discussion
pPNET represents less than 1% of all sarcomas [11]. The polymorphism and the lack of clinical specificity are the main characteristics of these tumors.
The basic interest of our case report is to show the difficulty of diagnosis and the essential help brought by immunostainings and cytogenetics.
pPNET originates from the fetal neuroectodermal tissue or neural crest. Primitive neuroectodermal progenitor cells behave as pluripotent stem cells, which have own ability to differentiate along neuronal, glial or epithelial cell lineage. During early embryonic phases, neural crest cells migrate laterally and dorsally, participating in the genesis of organs of the peripheral nervous and endocrine system.
pPNET are encountered very infrequently and congenital cases are exceptional: two cases of congenital pPNET were mentioned by the International Society of Pediatric Oncology in 2002, and 10 cases of neonatal pPNET/ES have been reported in medical literature [9].
Macroscopically, pPNET tend to be well-circumscribed often with cystic hemorrhagic areas and necrosis, but there are no clinical or radiological criteria to differentiate a pPNET from an ES, rhabdomyosarcoma, neuroblastoma or lymphoma [12].
The most common location for pPNETs in Jones’ series [2] that included 26 patients from 9 months to 18 years was the thoracopulmonary region (46%) and the head and neck region (42%) [2]. Other large series including adults have reported a lower incidence of head and neck region (6%) and a higher incidence of abdomen location (26%) and extremities (20%) [11].
Metastases are common at the time of initial diagnosis and most often involve lung (50%), bone (25%), bone marrow (20%), lymph nodes and liver [11].
Light microscopic evaluation of pPNETs reveals small round cells that may form a lobular or pseudorosette pattern or Homer–Wright rosette. Cells have irregular nuclei and scanty cytoplasm; apoptosis and mitosis are both present. Ganglion cells and neurofibrillary structures are suggestive of neural differentiation. Electron microscopic examination reveals electron-dense neurosecretory-like granules, filaments and microtubules.
In our case report, two different cell population were located: an undifferentiated population that outlined a rosette aspect and largest cellular population.
Immunohistochemical analysis allow classification of such undifferentiated tumors according to the markers expressed on the cell surface. Immunostainings look for ectodermal differentiation factors and at least two stainings of neuronal differentiation. Muscular, lymphoïd and adrenergic markers are negative [11].
Different antigenes are usually expressed in pPNET: synaptophysin, glial fibrillary acidic protein (GFAP), neurofilament proteins (NFP), S100 protein, vimentin and neuron-specific enolase (NSE). NSE, NFP and S100 protein are specific markers for neural elements. GFAP is specific for astrocytes and ependymal cells; cytokeratin for epithelial elements.
Several antibodies specifically label pPNET: NSE, S6100, Leu-7, Chromogranine and NFP. However, positive immunostaining for vimentin and CD19 is helpful to differentiate pPNET and ES from other small round cell tumors. CD99 is a marker for the MIC2 protein, sensitive and specific witness of pPNET/ES. The MIC2 gene is a pseudoautosomal gene located on the short arm of human chromosome X and Y [13].
In our case report, immunostainings allowed diagnosis. Cytogenetic analysis showed the fusion gene EWS/FLI-1 considered specific for the pPNET and ES group.
In pPNET, the most common cytogenetic abnormality (80%) is the translocation t(11;22)(q24;q12) that juxtaposes the proximal portion of the gene EWS (22q12) into the distal portion of the gene FLI-1 (11q24).The result of the gene fusion is a chimeric transcript, which acts as an aberrant transcription factor and promotes tumorigenesis [11].This occurs in pPNET and ES and can be detected by reverse transcriptase–polymerase chain reaction.
The second most common translocation is t(21;22)(q22;q12) in 10% of the cases. A third variant is known: t(7;22)(p22;q12) [11].
In front of such genetic modifications, the diagnosis of Ewing family tumor is suggested and secondary confirmed by immunohistochemistry.
The management of these cancers and especially in the neonatal period is difficult because of the balance between cancer treatment and iatrogenic events.
Treatment of localized pPNET is based on neoadjuvant chemotherapy then surgery and/or radiotherapy. For voluminous or disemined tumors, treatment include polychemotherapy and radiotherapy on all metastatic localizations. Surgery on tumoral residual sites can be indicated [1]. Chemotherapy protocols include 6 or 9 months of treatment with VadriaC (Vincristine, Doxorubicine, Cyclophosphamide) or IE (Ifosfamide, Etoposide). After treatment, clinical control is to be performed for years.
The global survival rate is less than 50% after 3 years of evolution and 30–40% after 5 years of evolution. If metastasis are present at the time of diagnosis, this rate drops to 20% after 3 years [11].
Some prognosis factors are now identified. The size of tumor (above 8cm or 100ml), the initial presentation with metastasis, the response after chemotherapy and some fusion genes are pejorative (t(7;22)(p22;q12) is less pejorative) [14].
The interest of such case report is to present the first maxillar localization of a pPNET in a congenital form. Maxillar localization is rare; only two cases have been reported in literature. Filiatrault [15] described in 1993 a pPNET of the maxillar sinus in an adult patient, and Alabid [5] in 2003 the same localization in a 23-year-old female.
Four congenital forms of pPNET are listed in English literature in the temporal area, the hand and the skin. None of the child presenting these congenital forms survived. Some studies show no pronostic differences in pPNET comparing adults and children but prognosis of congenital forms seems to be more aggressive and refractory to treatment.
4. Conclusion
This is the first congenital form of a pPNET localized in the maxillar bone described in English literature. In our case, as in the few cases related, the tumor was aggressive and refractory to treatment. These tumors constitute a challenge for a multidisciplinary approach combining surgery, chemotherapy and irradiation therapy.
The interest of this case report description is to highlight the difficulty of diagnosis, the necessity to realize cytogenetics and immunochemistry.
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PII: S1871-4048(05)00012-2
doi:10.1016/j.pedex.2005.11.006
© 2005 Elsevier Ireland Ltd. All rights reserved.
Volume 1, Issue 1 , Pages 27-32, March 2006
