Peripheral Primitive Neuroectodermal Tumour of Soft Tissue
Peripheral primitive neuroectodermal tumour of soft tissue is a rare and highly aggressive cancer that develops from embryonic nerve cells in tissues outside the central nervous system, most commonly affecting young people and requiring intensive combined treatment.
Table of contents
- What is peripheral primitive neuroectodermal tumour
- Who is affected
- Where the tumour develops
- Symptoms
- Causes and genetic changes
- Diagnosis
- Treatment approaches
- Prognosis and outcomes
What is peripheral primitive neuroectodermal tumour
Peripheral primitive neuroectodermal tumours, commonly called pPNETs, are a group of highly malignant tumours composed of small round cells of neuroectodermal origin (cells from the embryonic tissue layer that develops into the nervous system) that affect soft tissue and bone[1]. These tumours develop from primitive nerve cells that were left over from the development of the nervous system during gestation[3].
pPNETs are classified as part of the Ewing family of tumors (EFTs), and the terms are often used interchangeably in medical literature[1]. Generally, Ewing family tumours and pPNETs represent different manifestations of the same tumour and have similar genetic alterations. However, Ewing sarcoma is more common in bone, while pPNETs are more common in soft tissues such as muscles, tendons and ligaments[1].
Under a microscope, pPNETs show diffuse sheets, lobules or focal nests of small round cells with deeply stained round, oval, or irregular nuclei. Increased mitotic figures and neural Homer-Wright rosettes (multiple cells that group together around a single cell in the shape of a rose) can be observed[5].
Who is affected
pPNETs are exceedingly rare tumours. The annual incidence is approximately 0.2 to 0.4 per 100,000 people[5]. These tumours most commonly occur in children and young adults[5].
In a study of 89 patients, the median age was 25 years, with a range from 5 to 73 years. The study included 43 males and 46 females, showing that pPNETs can affect both sexes relatively equally[2]. Another large study analyzing 161 patients found a slight male predominance[5].
Where the tumour develops
Because of its embryonic origin, pPNET may arise in any organ[5]. The tumours are derived from tissues outside the central and autonomic nervous system[1].
pPNETs mainly arise in the skeletal system and soft tissues. The predominantly affected regions are the abdomen and pelvis, followed by the thoracopulmonary region (chest and lung area)[2]. Most often, they develop in the area around the chest and lungs, the abdomen, and pelvis[3]. Only around 6% of pPNETs occur outside the bones[3].
pPNETs may also be present in visceral body sites such as heart, lung, genital organs, kidney, pancreas and palate[5]. One specific type, called Askin tumor, is a peripheral neuroepithelioma that occurs in the thoracopulmonary region[1].
Symptoms
pPNETs cause different symptoms depending on where they develop[3]. The symptoms typically arise from the tumour itself or from the effects of the tumour pushing against nearby tissues, known as mass effect[3].
The symptoms of pPNETs in the most common areas may include abdominal pain or swelling, fluid buildup in the abdomen (known as ascites), and mass effect[3].
The mean primary tumour size in one study was 12.6 cm (approximately 5 inches), with a range from 1 to 30 cm[2]. In another series of 89 cases, the mean size of pPNET tumours was 12.9 centimeters (5.07 inches)[3].
Causes and genetic changes
The direct cause of pPNETs is not completely clear. Genetic changes can alter how cells work, divide, and end their life cycles, which can result in cancer[3]. PNETs develop from the external layer of cells surrounding a developing embryo, known as the ectoderm[3].
Based on molecular cytogenetic analysis, both Ewing family tumours and pPNETs are known to share the same reciprocal translocations, most commonly between chromosomes 11 and 22[1]. The most common chromosomal aberration involves a translocation between chromosomes 11 and 22, resulting in the fusion of the EWSR1 and FLI1 genes[17].
Researchers don’t know what triggers the genetic change. However, they have ruled out exposure to carcinogens that cause other types of cancer, because pPNET typically affects children and young adults who don’t experience long-term exposure to substances that can cause cancer[1].
Diagnosis
The diagnosis of pPNET is based on histological and immunohistochemical examination of tissue samples[5].
A doctor may detect a pPNET through imaging tests. During MRI (magnetic resonance imaging), pPNETs usually appear as a single growth but might have fluid-filled lumps called cysts inside the mass, as well as some swelling around the tumour[3]. On unenhanced MRI, most cases showed tissue that was isointense (similar intensity) on T1-weighted images and either isointense or hyperintense on T2-weighted images[6]. Most pPNETs had heterogeneous signal intensity with small necrosis (dead tissue areas) as well as heterogeneous enhancement[6].
CT scans (computed tomography) are also used for diagnosis. The tumours usually had ill-defined borders and irregular shapes on imaging[6].
A surgeon may remove a pPNET and send it for a biopsy. During the biopsy, a neuropathologist (a doctor specializing in diagnosing nervous system diseases) examines the tissue under a microscope[3]. pPNETs have certain features that identify them, including rosettes and the presence of at least two proteins that suggest the involvement of neural cells, known as neural markers[3].
PNETs are usually positive for CD99 (a genetic marker present in 90% to 100% of pPNET cases), neuron-specific enolase (NSE), and CD56. They are negative for markers for epithelia, lymphoid tissue, musculoskeletal tissue and melanoma. At least two of the three markers should be positive to make a diagnosis of PNET[5].
All PNETs are grade 4 cancers, meaning they are aggressive and spread rapidly[3].
Treatment approaches
There are no standard guidelines for management of peripheral PNETs due to the paucity of cases arising in various body sites. The therapeutic approach is derived from Ewing sarcoma family treatment, which currently remains multimodal[5].
Where possible, the main treatment for pPNET is surgery to remove the tumour, combined with chemotherapy and sometimes radiation therapy[3]. A multidisciplinary approach to treat these neoplasms should improve the prognoses[8].
In one study of 89 patients, 46 patients received combined therapy, 35 received mono-therapy, and 8 underwent only biopsy with no further treatment[2]. This highly malignant tumour requires an aggressive combination of radical resection when possible[2].
Analysis of 161 patients showed that surgery, chemotherapy, female sex, small tumour size, no lymph node metastasis, R0 surgical resection (complete removal with no cancer cells at the margins), specific chemotherapy regimens including (vincristine + doxorubicin + cyclophosphamide)/(isophosphamide + etoposide), and more than 10 cycles of chemotherapy were associated with improved overall survival[5].
Surgery, more than 10 cycles of chemotherapy, and small tumour size were independent prognostic factors for higher overall survival[5]. These data indicate that multimodal therapy is the mainstay therapeutic approach for peripheral PNET[5].
Prognosis and outcomes
Peripheral primitive neuroectodermal tumours often exhibit aggressive clinical behavior, with worse outcomes than other small, round cell tumours[1]. The prognosis of pPNET is, overall, poor[2].
In one study, a total of 16 patients (18%) initially presented with metastasis (cancer spread to other parts of the body)[2]. The period of observation ranged from 1 to 232 months. The median overall survival time was 15 months, with 3-year and 5-year overall survival rates of 32% and 25%, respectively[2].
Large tumour size and metastasis at initial presentation were significantly associated with poorer outcomes[2]. Combined modality treatment was significantly associated with improved overall survival[2].
