INTRODUCTION
Primitive neuroectodermal tumors (PNET) are rare tumors of aggressive phenotype with cellular appearance mimicking the differentiation of the central nervous system that can arise from germ cell tumors such as mature and immature teratomas. PNETs are grouped into two distinct morphologic entities, central and peripheral, based on histologic features consistent with CNS neoplasms in central type and small round blue cells in peripheral type tumors mimicking Ewing sarcoma (EWS) [1-4]. Given the overall rarity of PNETs, especially when arising from germ cell tumors, most data regarding their presentation, diagnosis, and treatment exists in several case series and reports. PNET has been demonstrated to primarily occur arising from the paravertebral space in the abdomen, ovaries, and uterus though these tumors do at times arise from both thoracic and abdominal soft tissue [1]. Historically, treatment typically consists of a combination of surgery followed by traditional cytotoxic chemotherapy with or without radiation. Given the rarity of this disease, there is a paucity of genomic data regarding PNETs, leading to difficulty in conducting clinical trials with targeted agents. While peripheral-type PNETs have been associated with t(11;22) translocation resulting in EWS-FLI1 fusion gene typical of EWS-type tumors [5], most PNETs arising from germ cell tumors resemble central-type PNETs which do not have identified genomic variants and lack chromosome 22 rearrangements [4]. In the emerging era of targeted therapies, ongoing identification of molecular targets remains crucial in the treatment of these rare tumors. Currently molecularly targeted therapies remain salvage therapy in many types of malignancy, but the increasing ease of genomic, transcriptomic, and proteomic analysis are opening the door to utilization of targeted therapies. Here we present a case of metastatic PNET which arose from an immature teratoma that was refractory to standard Ewing sarcoma chemotherapy. This PNET was determined to have high levels of ALK protein overexpression in the limited tumor sample which led to utilizing targeted therapy with crizotinib on a palliative basis. This treatment resulted in a sustained partial response.
CASE PRESENTATIONOur patient initially presented in 2015 at the age of 5 with approximately two years of worsening abdominal distension. At the time of presentation, a large right adnexal mass was identified by computed tomography measuring 15cm x 11cm x 13cm with omental involvement and large volume ascites present (Figure 1). Initial imaging likewise revealed multiple soft tissue metastases to both the diaphragm and bilateral lung bases. Urgent resection was undertaken and pathology from the primary tumor revealed high grade immature teratoma with areas of malignant primitive PNET. Tumor excised from the omentum revealed extensive replacement with immature teratoma with PNET features. Biopsies of peritoneal and diaphragmatic implants likewise revealed metastatic PNET with final histology consistent with central type PNET excluding EWS-family features. Bone marrow biopsy at the time of diagnosis did not reveal malignant infiltration and serum biomarkers including alpha-fetal protein (AFP) and beta-human chorionic gonadotropin (β-hCG) were undetectable. Post-operative PET-CT revealed remaining diaphragmatic, splenic, falciform ligament, omental, and peritoneal metastases. Given our institutional experience with high response rates in teratomas transforming to PNETs [6], chemotherapy was initiated with Ewing sarcoma-like therapy with AEWS0031 Regimen B consisting of vincristine, doxorubicin, and cyclophosphamide (VDC) alternating with ifosfamide and etoposide (IE) two weeks after initial presentation and ten days after initial surgical resection. Prior to week 9 of chemotherapy per AEWS0031, her course was complicated by a serious automobile accident leading to right femur and tibia fracture and a small subdural hematoma. These injuries led to a four-week delay in ongoing chemotherapy to allow for recovery. However, a PET scan obtained during this time off therapy revealed significant overall reduction of disease in all areas. Once able to resume therapy, adjuvant abdominal radiation was planned to be given concurrently with week 13 treatment with VDC. However, she suffered multiple further complications with chemotherapy resulting from persistent febrile neutropenia, andstreptococcus pneumoniae bacteremia that led to radiation being delayed until week 15 of therapy. Our patient received a total of 34 fractions to the abdomen, lung, and adrenal gland for a total of 54.8 Gy. Follow-up imaging post radiation and approximately 6 months after diagnosis unfortunately revealed significant disease progression in the abdomen and along the peritoneum with recurrent large volume ascites. Given the rapidity and extent of progression, a care conference was held including the precision genomics team, primary oncology team, and palliative care teams to determine ongoing approach. Non-targeted therapy utilizing irinotecan and temozolomide was offered as palliative chemotherapy, but her parents chose not to pursue this due to its side effect profile. A decision was made to pursue genomic characterization to assess for possible palliative therapeutic targets. Previously obtained tumor sample was sent to Paradigm PCDx for molecular characterization while discussions about hospice enrollment were ongoing. The Paradigm Genomic PCDx testing at that time was limited to NGS analyzing 500 genomic regions of interest including mutation, copy number variation, messenger RNA levels, gene fusions and protein expression via immunohistochemistry (IHC). This test was negative for gene mutations or fusions within the panel. IHC testing was positive for anaplastic lymphoma kinase (ALK) protein (30% staining; see Figure 2) and neurotrophic tyrosine receptor kinase TRK/NTRK (80%), suggesting that either ALK or TRK/NTRK1/2/3 could be a targetable driver in the tumor. Gene sequencing failed to identify any mutations within the ALK coding region. The sample was tested for ALK, ROS1 and NTRK1/2/3 gene rearrangements and found to be negative. Early work has suggested that crizotinib, an oral inhibitor of ALK, has clinical activity in neuroblastoma patients whose tumors over-express ALK protein in the absence of either ALK gene mutations or gene fusions. With few options remaining, crizotinib was selected as a therapeutic/palliative target based on the increased levels of ALK protein expressed in the patient’s tumor (Figure 2). Therapy with oral crizotinib at 215 mg/m2/dose twice a day was initiated approximately seven months after initial diagnosis and led to reduction in volume of multiple metastatic tumors. The patient remained stable for four years on crizotinib monotherapy without disease progression based on follow-up imaging and parents decided to discontinue therapy (Figure 1). The most recent follow-up obtained in July 2022, six years after initiation of crizotinib and 18 months off therapy demonstrated ongoing disease stability without symptoms or evidence of progression (Figure 1).