Primitive Neuroectodermal Tumors
Primitive neuroectodermal tumors (PNETs) are a group of highly malignant tumors composed of small round cells of neuroectodermal origin that affect soft tissue and bone. Primitive neuroectodermal tumors (PNETs) exhibit great diversity in their clinical manifestations and pathologic similarities with other small round cell tumors. This has made classifying this family of tumors challenging and controversial. Batsakis et al (1996) divided the primitive neuroectodermal tumor (PNET) family of tumors into the following three groups based on the tissue of origin  :
Central nervous system (CNS) primitive neuroectodermal tumors (PNETs) – Tumors derived from the CNS 
Neuroblastoma – Tumors derived from the autonomic nervous system
Peripheral primitive neuroectodermal tumors (pPNETs) – Tumors derived from tissues outside the central and autonomic nervous system
Peripheral primitive neuroectodermal tumors (pPNETS) are the focus of this review. See the image below.
Peripheral primitive neuroectodermal tumors (pPNETs) are also classified as part of the Ewing family of tumors (EFTs); peripheral primitive neuroectodermal tumors (pPNETs) and Ewing family of tumors (EFTs) are often referred to interchangeably in the literature.  Generally, Ewing family of tumors (EFTs) and peripheral primitive neuroectodermal tumors (pPNETs) represent different manifestations of the same tumor and have similar genetic alterations. Ewing sarcoma, however, is more common in bone, while peripheral primitive neuroectodermal tumors (pPNETs) are more common in soft tissues. Immunohistochemical and cytogenetic studies suggest that these tumors all have a common origin.
The following tumors are classified as peripheral primitive neuroectodermal tumors (pPNETs):
Malignant peripheral primitive neuroectodermal tumors (pPNETs) or peripheral neuroepithelioma of bone and soft tissues
Askin tumor (peripheral neuroepithelioma of the thoracopulmonary region) 
Other less common tumors (eg, neuroectodermal tumor, ectomesenchymoma, peripheral medulloepithelioma) 
Stout first described PNETs in 1918, and these tumors were thought to arise directly from nerves.  The pathologic and cytogenetic understanding of these tumors has significantly advanced over the last 25 years. Based on molecular cytogenetic analysis, both EFTs and peripheral primitive neuroectodermal tumors (pPNETs) are known to share the same reciprocal translocations, most commonly between chromosomes 11 and 22. Further advances in immunohistochemical analyses have helped further distinguish PNETs and Ewing family of tumors (EFTs) from other small, round, poorly differentiated tumors, including rhabdomyosarcoma, neuroblastoma, and lymphoma. Peripheral primitive neuroectodermal tumors (pPNETs) often exhibit aggressive clinical behavior, with worse outcomes than other small, round cell tumors.
The incidence of peripheral primitive neuroectodermal tumors (pPNETs) is likely underreported in the literature because recent diagnostic advances have allowed these tumors to be distinguished from other small, poorly differentiated, round cell tumors. Although peripheral primitive neuroectodermal tumors (pPNETs) are exceedingly rare, the annual incidence of tumors from the larger Ewing family of tumors (EFTs) from birth to age 20 years is 2.9 per million population. In most large series published to date, peripheral primitive neuroectodermal tumors (pPNETs) usually present in the second decade of life, with a slight male preponderance. They account for 4-17% of all pediatric soft tissue tumors.  Of note, these tumors are rare in African American children and children of Asian descent, with most worldwide cases occurring in white and Hispanic children and adolescents.
Most peripheral primitive neuroectodermal tumors (pPNETs) manifest in the thoracopulmonary region (Askin tumor), pelvis, abdomen, and extremities. In a large series of 26 cases, Jones and McGill reported 11 of 26 patients with disease in the head and neck.  Most other large published series, however, reveal a paucity of cases in the head and neck region. [11, 12, 13] Of the published cases involving the head and neck, the sites of presentation are diverse and include the paranasal sinuses, jugular foramen, oral cavity, nasal cavity, neck, skull, lingual nerve, parotid gland, larynx, retropharyngeal space, maxilla, mandible, masseter, temporal area, pterygomaxillary space, esophagus, and orbit.
Clinical symptoms depend on the site of presentation but invariably include pain and swelling of the surrounding structures due to mass effect. Other reported symptoms and signs are site specific, including individual cranial neuropathies, exophthalmos, epistaxis, nasal obstruction, anosmia, neck masses, and headache (see the image below).
The significant prognostic factors of peripheral primitive neuroectodermal tumors (pPNETs) include site, tumor volume, and the presence of metastasis. Kimber et al, in a review of 26 patients with pPNET who were treated with chemotherapy, reported that patients with head and neck pPNET had an intermediate prognosis when compared with patients with paraspinal and scapular disease (who fared better) and those with abdominopelvic disease (who fared much worse).  Because peripheral primitive neuroectodermal tumors (pPNETs) are highly aggressive, patients may have metastatic disease at presentation.
With reverse transcription polymerase chain reaction (RT-PCR) technology, several groups have demonstrated micrometastatic disease in the bone marrow of up to 30% of patients thought to have a localized disease. The most common sites of pPNET metastases include the lung, bone, and bone marrow. In several large series, the rates of metastases range from 20-31%, with abysmal long-term survival rates (< 25%).
Kushner et al, in a review of Memorial Sloan-Kettering’s experience with pPNET, reported a similarly dismal 25% progression-free survival rate at 2 years in patients with only localized disease.  Other large series, however, reported somewhat better survival rates in patients with localized disease, with 2 large trials showing 2-year and 3-year survival rates of 65% and 56%, respectively. [10, 11]
A study by Jiang et al, using information from the Surveillance, Epidemiology, and End Results (SEER) Program database, indicated via multivariate analysis that age, tumor size, tumor stage, and whether or not the patient has undergone surgery affect cancer-specific survival (CSS) and overall survival (OS) for extraosseous and osseous Ewing sarcoma. Moreover, in osseous Ewing sarcoma specifically, CSS and OS were found to be significantly worse in patients who are non-White, diagnosed at an earlier age, and have an axially located tumor. In addition, multivariate analysis indicated that extraosseous Ewing sarcoma is associated with a worse prognosis than the osseous form. 
Again, with the diagnostic advances made in recent years, more accurate information regarding disease-free and long-term survival will be available in the future.
Differential diagnosis for other small and poorly differentiated round cell tumors of the head and neck should include peripheral primitive neuroectodermal tumors (pPNETs)/Ewing family of tumors (EFTs), malignant lymphoma, poorly differentiated salivary gland tumors, rhabdomyosarcoma, neuroblastoma, and undifferentiated nasopharyngeal carcinoma. 
The information obtained with light microscopy, cytogenetic analysis, and the immunohistochemical profile of tumor cells is essential in diagnosing peripheral primitive neuroectodermal tumors (pPNETs). On light microscopy, peripheral primitive neuroectodermal tumors (pPNETs) appear as a monotonous collection of small, round, darkly stained cells. However, peripheral primitive neuroectodermal tumors (pPNETs) cannot be distinguished from other tumors with small round cells based on histologic studies alone.
Other tumors with a similar appearance on light microscopy include rhabdomyosarcoma, neuroblastoma, and non-Hodgkin lymphoma. In these tumors, Homer-Wright rosettes, in which the tumor cells are arranged about a central space filled with fibrillar extension of the cells, can be found. Examination of peripheral primitive neuroectodermal tumors (pPNETs) with electron microscopy reveals neurosecretory granules with microtubules and microfilaments. In addition, short dendritic processes lie between cells in peripheral primitive neuroectodermal tumors (pPNETs), in contrast to Ewing sarcoma, in which the dendritic processes are absent.
Cytogenetic analyses of peripheral primitive neuroectodermal tumors (pPNETs) reveal the close relationship among tumors in the Ewing family of tumors (EFTs). Approximately 85% of all Ewing family of tumors (EFTs) include a translocation that involves the EWS gene (22q12) and FLI-1 (11q24).  In the other 5-10% of cases, the translocation is found between EWS and ERG (21q22). 
The elucidation of the immunohistochemical profile allows the pathologist to distinguish peripheral primitive neuroectodermal tumors (pPNETs) and EFTs from other small, round cell tumors. Immunohistochemistry can be used to detect antibodies to FLI-1 in the gene fusion product of EWS.  The expression of the MIC2 gene produces an antigen, MIC2, which consistently identifies both Ewing sarcoma and peripheral primitive neuroectodermal tumors (pPNETs). In contrast, CNS PNETs and neuroblastomas uniformly lack the expression of the MIC2.  Furthermore, peripheral primitive neuroectodermal tumors (pPNETs) typically coexpress CD99 (the glycoprotein MIC2) and vimentin.  Other nonspecific markers include S-100, neuron-specific enolase, CD75, and synaptophysin.
Tissue biopsy with cytogenetic and immunohistochemical studies is paramount in diagnosing peripheral primitive neuroectodermal tumors (pPNETs). Radiologic studies such as computed tomography (CT) scanning and magnetic resonance imaging (MRI) are essential in determining the limits of tumor involvement and ruling out metastatic disease.
On CT scans, peripheral primitive neuroectodermal tumors (pPNETs) appear as heterogeneous masses, often invading surrounding tissues, including bone. A study by Ba et al found the masses to be hypodense on CT scans, with osteolytic destruction revealed when the tumors originated in bone. The study also found ill-defined margins demonstrated in all of the bone lesions and more than half of the soft tissue tumors, after contrast administration. 
A study by Xiao et al found that in pediatric patients, the major CT-scan features of pPNETs included poor definition (72.2%), irregular shape (83.3%), heterogeneity (66.7%), and hypodensity (94.4%), again with osteolytic bone destruction demonstrated by pPNETs arising in bone. With contrast administration, all of the soft-tissue masses showed heterogeneous enhancement, with cystic or necrotic areas also seen and with linear enhancement occurring in 71.4% of the soft-tissue lesions. 
According to Ba’s study, the tumors appeared on T1-weighted MRI scans as irregular lesions that were isointense to hypointense to skeletal muscle, while appearing heterogeneously hyperintense on T2-weighted images. As on CT images, bone tumors on MRI scans were seen in association with osteolytic destruction. [21, 23] (See the images below.)
Because of the high incidence of metastatic disease at presentation, a full metastatic workup is indicated in a suspected case of pPNET, including chest radiography, CT scanning of the chest, and a bone marrow biopsy. Furthermore, because pPNET is diagnosed based on biopsy findings, more extensive investigations, such as a technetium 99m bone scan or positron emission tomography (PET) scan, may be indicated. Other adjunctive studies include testing for urinary catecholamines and their metabolites, which are positive in patients with neuroblastoma but negative in patients with PNET and Ewing family of tumors (EFTs).
Obtaining a complete resection of disease with negative margins is paramount in surgically treating primitive neuroectodermal tumors (PNETs) in the head and neck. In some cases, however, the aggressive nature and diffuse spread of these tumors precludes complete surgical excision. Furthermore, complete surgical resection may not be possible when vital structures are involved.
Chemotherapy and radiation are necessary adjuncts in the treatment of primitive neuroectodermal tumors (PNETs). Chemotherapy regimens have significantly improved outcomes in patients with peripheral primitive neuroectodermal tumors (pPNETs). The treatment paradigms differ based on whether the disease is localized or metastatic. As would be expected, the treatments for peripheral primitive neuroectodermal tumors (pPNETs) and Ewing family of tumors (EFTs) are similar in terms of chemotherapeutic regimens.
Current recommendations advocate complete surgical resection whenever possible, adjuvant versus neoadjuvant chemotherapy, and radiotherapy. Multimodality treatment is advocated to prevent metastatic disease, recurrent disease, and to treat residual tumor after resection. Carvajal and Meyers, in a comprehensive review of the chemotherapeutic regimens in the treatment of PNETs and Ewing family of tumors (EFTs), recommend a regimen that includes vincristine, doxorubicin, and cyclophosphamide with ifosfamide and etoposide (IE). 
The treatment of metastatic disease similarly includes neoadjuvant and adjuvant chemotherapy, as well as radiotherapy to all sites of gross disease with surgical excision, where possible. As there is a paucity of head and neck peripheral primitive neuroectodermal tumors (pPNETs) reported in the literature, clinical trials for treatment regimens specific to the head and neck is limited. Current treatment strategies and response rates often include tumors from other subsites. Recommendations for fractionated treatment schedules with higher treatment doses are typically reserved for patients with gross residual disease and microscopic disease.
A mitigating factor in the adjuvant use of radiotherapy is the known complication of a second sarcoma that develops subsequent to treatment with radiation. In addition, treatment-related acute myeloblastic leukemia and myeloblastic syndrome occur in 1-2% of survivors of EFT. In childhood cancer survivors followed through the SEER cancer registries, the greatest risk of subsequent cancers occurred among those previously diagnosed with EFT and PNETs, nearly a 6-fold increase compared to the general population.  The incidence of secondary malignancies increases substantially with radiotherapy treatment doses of more than 60 Gy. Kuttesch et al reported that 20% of patients who receive doses of more than 60 Gy developed secondary malignancies, compared with only 5% in those who receive 48-60 Gy. Those treated with less than 48 Gy had no additional risk of second malignancies. 
While outcomes vary based on disease subsite, patients with metastatic disease uniformly have poor outcome ranging from 0-25% 5-yr survival rates compared to 40-79% for those with localized disease. 
A retrospective study by Jin et al indicated that thyroid dysfunction is common in children with either primitive neuroectodermal tumor (PNET) or pediatric medulloblastoma (a cerebellar PNET). The study group consisted of 56 patients with medulloblastoma and 10 patients with PNET, all children. By a median 3.8 years follow-up, transient hypothyroidism had developed in 12 patients (18%), and permanent hypothyroidism had arisen in 37 (56%). Analysis demonstrated that radiation exposure at age less than 5 years and patient exposure to high-dose chemotherapy are risk factors for hypothyroidism in pediatric patients with medulloblastoma or PNET. 
Peripheral primitive neuroectodermal tumors (pPNETs) are a group of aggressive malignancies that most commonly present in the thoracopulmonary region (Askin tumor), abdomen, pelvis, and, rarely, in the head and neck. The most significant prognostic factor is the presence or absence of metastatic disease, with the former group of patients having a dismal long-term prognosis. Significant advances in the neoadjuvant and adjuvant chemotherapeutic regimens, as well as improved facility in diagnosing these tumors through cytogenetic and immunohistochemical analysis, should improve long-term disease-free survival.
A study by de Blank et al found that in the United States in 2009, among children and adolescents who died of cancer, PNET was the form of cancer responsible for the highest mean years of life lived with disease (4.6 years lived). 
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Primitive Neuroectodermal Tumors
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