5. Discussion
Chordomas are low‑to‑intermediate‑grade, midline primary bone tumors,
with dual epithelial-mesenchymal differentiation. The origin is
attributed to embryonal remnants of notochord, with the strongest
evidence being the expression of transcription factor brachyury in
undifferentiated notochord as well as in chordomas9.
Upon reaching 11 mm in embryo development, the notochord undergoes
maturation, leading to its obliteration and displacement from the centre
towards both cranial and caudal ends. Microscopic foci persist within
the vertebral bodies at these locations, which undergo malignant
transformation in the third to fourth decade for spheno-occipital
lesions and in the fifth to sixth decades for sacrococcygeal lesions.
Despite the ectodermal origin, these tumors are usually classified and
approached as sarcomas due to being bony tumors. World Health
Organization (WHO) classification of tumours of soft tissue and bone
2020 classified chordomas histologically into conventional,
dedifferentiated and poorly differentiated, with chondroid chordoma
being a subtype of conventional type. Conventional type has
characteristic physaliphorous cells, with the matrix appearing like
hyaline cartilage in case of chondroid subtype. The latter arise almost
always in the base of skull. Dedifferentiated type has a high-grade
sarcoma component apart from the conventional chordoma component and are
usually diagnosed post RT and in recurrent setting. Role of aberrant p53
inactivation is suggested. Poorly differentiated type is the rarest,
with around 60 reported cases, most commonly affecting children and
young adults. It usually involves skull base and cervical spine, and
rarely the sacrococcygeal region. These tumors usually have loss of INI1
expression, with absence of physaliphorous cells. The prognosis is worse
with poorly differentiated and dedifferentiated
types10. Chordomas are slow-growing tumors and usually
clinically silent till late stages, with pain being the most common
manifestation, followed by location-specific neurological symptoms like
radiculopathy or bowel-bladder dysfunction. There is associated bony
destruction with surrounding soft-tissue mass. Location-wise, sacral
chordomas are usually regarded as the commonest ones, with maximum
involvement of fourth and fifth sacral vertebrae.
National Comprehensive Cancer Network (NCCN) guidelines 2020 recommend
extensive resection of operable chordomas11. Positive
resection margins and soft tissue mass larger than 7 cm mandate
postoperative RT. No response to chemotherapy has been
reported4. Molecular targeted inhibitors and Brachyury
vaccine are upcoming promising options. Complete resection is the
cornerstone of treatment, with the extent of resection largely
determining the recurrence rate. Poor anatomical accessibility, size of
tumor, extent of intraoperative blood loss, and high chances of
sphincteric and sexual dysfunction due to sacral nerve roots sacrifice,
make wide resection feasible in only small number of patients,
culminating in high recurrence risk in sacral
chordomas12. Among 56 chordomas of sacrum and mobile
spine, 33% recurrence rate after extensive resection and 67% after
intracapsular or marginal resection have been
reported13. Similarly, 66% of 48 patients of mobile
spine failed locally in an analysis, with those treated with
intralesional excision or RT alone having 100% recurrence in a period
of 17-20 months, whereas post margin-free en-bloc resection, only 33%
recurred at 56-94 months. Even Intralesional extracapsular resection
followed by RT had 75% recurrence at 30 months5.
These tumors are resistant to conventional radiation doses less than 60
Gy14. Dose escalation upto 78Gy attempted with
image-guided intensity modulated radiation therapy (IG-IMRT) was shown
to decrease five-year local failure rates to 48%, compared to 83% in
patients with surgery alone or low-dose RT15. Various
studies have highlighted the role of higher doses in skull-base
chordomas, especially with particle radiation (alone or in combination
with photons), though the dose-response relationship is not consistent
across all series14. Following resection of spinal
chordoma, adjuvant RT with proton therapy was shown to have 40%
recurrence risk, compared to 88% with photons, though the ratio of
patients in both arms was skewed16. Five-year
local-progression-free survival rate 53%-85% has been reported with
proton RT even in sacral and mobile spine chordomas17.
The median survival as per the analysis of400 patients, published in
2001, is 6.29 years with 5-year, 10-year and 20-year survival rates
decreasing significantly to 67.6%, 39.9%, and 13.1%, respectively,
irrespective of race and sex2. Another review of 682
patients, published in 2017 showed the median survival as 9.5 years,
with 5-year and 10-year rates as 76% and 47% respectively, likely
indicative of the improvement in survival due to advances in treatment
modalities. Their multivariate analyses showed that age less than 18
years increased the likelihood of recurrence as well as death, sacral
origin was negative predictor of progression-free survival (PFS) and the
overall survival (OS) was decreased with recurrence and
metastases3. Local recurrence has been regarded as the
most significant determinant of mortality, other important factor being
distant metastases. A review of 53 cases of poorly differentiated
chordomas revealed the mean age of presentation as 9.7 years, the range
being 3 months to 42 years old. 100% of the patients’ specimen stained
positive for brachyury and panCK, and 96% had INI1 loss. Around 96%
had origin in clivus, skull base or cervical spine, and only 3 cases
(6%) were reported in sacral region. Out of the 41 patients whose
follow-up data was available, only 7 patients (17%) were alive and free
of disease. The median survival was reported as 46 months, much lower
than that by other studies18.
Due to the usually late diagnosis of chordomas, distant metastases are
likely, but less than 5% are detected at presentation, with most being
detected way further in the disease course7.
Metastases to lung, bone, soft tissues and liver have been reported in
upto 43% patients on prolonged follow-up of 16
years6. As per an analysis of 219 patients of chordoma
by Young et al, the median time from initial diagnosis to metastasis was
4.8 years, with the median survival after the detection of metastases
being 1.7 years, varying with the location of the primary and the
metastases8. Others have reported the mean interval
from surgery to metastases as six years, with a mean survival of 0.2
years post detection of metastases19. Young et al also
showed that 17.8% patients developed metastases, out of which 53.8%
did to the lungs. However, 11.8% metastases occurred in the setting of
local recurrence and only 5.9% occurred with locally controlled
disease, showing statistically significant correlation between local
recurrence and metastasis8. Yang et al corroborated
the significant difference in the rate of metastases with (33.7%) and
without (6.7%) local recurrence20.
The mainstay of treatment of such metastatic as well as advanced or
relapsed patients are molecular targeted inhibitors, selected based on
gene mutation screening and IHC21. Tyrosine kinase
inhibitors (TKI) monotherapy can be used as first-line therapy with
Imatinib being the most widely used one22. In case of
drug-resistant chordoma, two TKIs or TKI plus mammalian target of
rapamycin (mTOR) inhibitor is preferred23. Brachyury
vaccine (recombinant Saccharomyces cerevisiae encoding brachyury)
followed by RT could not show any difference in overall response,
compared to placebo arm, yet remains a good target for developmental
therapeutics in chordoma24. Role of Immune checkpoint
inhibitors looks promising as per few case series, and multiple trials
are ongoing regarding the same25. Enrolment of such
patients in clinical trials will pave the way for generation of
evidences regarding these newer modalities. Unfortunately, our patient
could not be given any systemic therapy due to financial constraints.
In our patient, the rapid growth of local and distant disease can hence
be attributed to paediatric age group, sacral origin and the poorly
differentiated histology. The peculiar characteristics of our case
include poorly differentiated histology in sacral disease, presence of
lung metastases upfront, diagnosis of chordoma in paediatric age group
and a chordoma progressing rapidly. Ours is probably the only case
reported till date with these unique features. The diagnosis at an early
age is justified by the poorly differentiated histology, which also
justifies rapid local progression and development of early lung
metastasis. However, association of this histology with sacral chordoma
is very rare. The review of literature shows that paediatric chordomas
with poor differentiation have really bad prognosis, hence such cases
should be started on definitive treatment without any undue delay. The
quest for an effective targeted therapy for INI1 deficient tumors has
remained elusive.