Discussion:
We report a case series of pediatric melanoma adding to the growing data
on the diagnosis and management of this rare malignancy. Sixty-five
percent of the patients in this cohort were diagnosed with melanoma in
adolescence (age ≥ 11 years). Moreover, both patients that progressed
were older than 11 years old at diagnosis, supporting the existing
literature stating that adolescent melanoma has a more aggressive
disease course compared to pre-pubertal melanoma5.
Outcomes were favorable, with event-free and overall survival of 91%
and 100%, respectively. Our data suggest that including nivolumab in
the initial treatment of melanomas diagnosed at Stage III may help avoid
recurrence or progression of melanoma. Four out of the 9 patients
diagnosed at Stage III did have Spitzoid melanoma and 3 of them were
diagnosed in younger childhood (age < 11 years). Multiple
other studies similarly found that Spitzoid melanomas occur more
commonly in pre-pubertal age 5-8. It is generally
thought that patients with Spitzoid melanoma have higher rates of
positive SLN despite an excellent overall prognosis8.
Additionally, we observed no progression or recurrence of melanoma in
the remaining 3 patients diagnosed at Stage III with either melanoma of
unspecified subtype (n=2) or severely atypical spindle cell melanocytic
tumor (n=1). We also observed that among the 19 patients who had an
SLNB, prepubertal patients (< 10 years of age) had a lower
percentage of SLN positivity (57%) when compared to adolescent patients
(75%). This differs from the findings by Moore-Olufemi et al.,Pol-Rodriquez et al. and El Sharouni et al. , but our small
sample size is much smaller7,9,10.
Nivolumab therapy was initiated in 7 patients, and was well tolerated in
most (5/7, 71%). Patients experienced either no adverse events (n=3) or
Grade 1 or 2 toxicities including mild dermatitis (n=1) and chills (n=1)
that improved with steroid administration. Nivolumab treatment was
discontinued in one patient who had a grade 3 lichenoid drug eruption
and withheld in 1 patient who developed hyper-eosinophilia. Although the
safety of nivolumab has not been extensively studied in the pediatric
population, a study by Davis et al. showed that nivolumab is safe
and well-tolerated in children and young adults11. A
small case series (n=10) that included 5 patients with skin melanoma
further supports the safety and efficacy of nivolumab in pediatric
patients. Complete remission was achieved in 3 patients with melanoma
(60%)1. In our cohort, we observed complete remission
in all the patients (100%) treated with nivolumab.
Melanoma in pediatric patients can present differently than in adults:
39% of the pediatric population in this study were diagnosed with Stage
III melanoma which aligns with previous studies suggesting children are
diagnosed at later stages than adults8. This is most
likely due to the relative rarity of melanoma and paucity of research on
the clinical and histopathological features indicative of melanoma in
the pediatric population. Our case series also suggests that ulceration
is less of an adverse prognostic finding in children than it is in
adults as only 3 patients had ulcerated lesions. Of those 3 patients, 2
received nivolumab and all three achieved CR after initial therapy.
Current literature supports these findings with similar reports of lower
frequencies of ulceration histologically12.
While Sharouni et al ., observed that a Breslow thickness
> 4 mm predicted worse survival, in our case series, none
of the patients with a reported Breslow thickness of > 4 mm
had recurrence or progression7. Of the 2 patients that
had a recurrence, 1 was diagnosed with a Breslow thickness of 2 mm,
while the other did not have a reported Breslow thickness. Sharouniet al ., also noted that all 3 children who recurred had melanomas
located on the head or neck. Only 3 of our patients were diagnosed with
head/neck melanomas and of those 1 (33.3%) developed a recurrence.
Another factor influencing the prognosis of pediatric melanoma is its
genomic subtype. Non-spitzoid melanomas typically have evidence of UV
exposure with a large number of C>T transitions at
dipyrimidine sites, BRAF and TERT promoter mutations and
inactivation of PTEN 13. Of the 4 patients
diagnosed with a non-spitzoid type melanoma who underwent genetic
testing, none had these mutations. Instead, 2 patients had negativeBRAF mutations, 1 only underwent a chromosomal microarray andp53 sequencing and deletion/duplication testing and 1 underwent a
diagnostics gene expression profile that did not include BRAF .
These findings are limited by the size of our case series. Additionally,
most of our patients with non-spitzoid melanoma did not undergo genetic
testing (12/18, 67%). All patients diagnosed with melanoma should
undergo genetic testing as taking a combined genomic and
clinicopathologic approach has been shown to optimize diagnosis and
treatment13. Pappo et al. , demonstrated that
the genomic differences between spitzoid melanoma, conventional melanoma
and melanoma arising from a congenital nevus can influence treatment and
thus clinical outcomes13.
Lastly, our findings differ from existing literature suggesting that the
majority of melanomas arise de novo rather than in conjunction with a
pre-existing nevus5,14. While there is no universally
agreed upon histological definition of nevus-associated melanoma,
pathology-based studies have found that 20% to 30% of melanomas
contain nevus cells in histologic continuity with
melanoma15. In our study, only two of the
melanomas had evidence of normal nested melanocytes to support an origin
in an acquired nevus. This is similar to adult melanoma where research
indicates most melanomas develop as new growths and supports the
findings that the lifetime risk for an individual nevus to transform
into melanoma is quite low, particularly in younger
individuals6. However, while nevus-associated
melanomas are not common, they should not be considered incidental
phenomena as incidence is shown to be higher than what would be expected
by chance alone5.