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).