MELANOMA -Diagnosis, Pathology and
Dr. Adrian Pablo Hunis*
Recertified Specialist in Oncology, Maimonides University, Argentina
Submission: August 31, 2020; Published:September 28, 2020
*Corresponding Address:Adrian Pablo Hunis, Associate Professor of Internal Medicine (UBA), Director of the Medical Specialist in Oncology (UBA), Professor of Oncology (Maimonides University), Argentina
How to cite this article:Dr. Adrian Pablo Hunis. MELANOMA -Diagnosis, Pathology and Molecular Biology WHAT HAS ASCO 2020 LEFT US?. Canc Therapy & Oncol Int J. 2020; 17(1): 555952.DOI:10.19080/CTOIJ.2020.17.555952
Melanoma is one of the tumors where diagnosis, monitoring and treatment have been most developed with determinations that include the use of molecular biology. New drugs, new combinations of drugs today result in answers that were unthinkable only five years ago. More patients live longer and many of them with advanced disease achieve survival measured in years when years ago we measured it in weeks. In this review we will see the main articles that were presented at ASCO 2020 and what they have left us, to put them into practice for the benefit of our patients.
Diagnosis should be based on a full thickness excision biopsy with a small lateral margin.
The histological report must include, as a minimum, information on the following:
• Type of melanoma.
• Actinic damage.
• Maximum vertical thickness in millimeters.
• Information on the rate of mitosis.
• Presentation of ulceration.
• Presence and degree of regression and clear surgical margins.
Testing for treatable mutations is mandatory in patients with resectable or unresectable stage III or stage IV melanoma and is highly recommended for high-risk resected stage IIC melanoma, but not for stage I or stage IIA-IIB melanoma. BRAF testing is mandatory.
For circumscribed disease, local excision of primary tumors is recommended, with the following safety margins:
• Melanomas in situ: 0.5 cm.
• Tumors ≤ 2 mm thick: 1 cm.
• Tumors> 2 mm thick: 2 cm.
For locoregional disease, sentinel lymph node biopsy is recommended in all patients with tumors in stage pT1b or more advanced, according to the staging of the American Joint Committee on Cancer, eighth edition .
Complete lymph node dissection is not recommended for patients with positive sentinel node. In the case of isolated metastases to clinically detectable locoregional lymph nodes (macroscopic, no sentinel node), complete lymph node dissection is indicated; it is insufficient to resect only the tumor-bearing lymph node
Patients with resected stage III melanomas should be
evaluated for adjuvant (postsurgical) treatment. Postoperative
radiation therapy for local tumor control can be considered in
cases of inadequate resection margins of lentigo malignant, in R1
resections, or after resection of a bulky tumor.
Preferred treatment options are postsurgical treatment with
an anti PD-L1 or dabrafenib / trametinib.
For advanced disease (stages III and IV not resectable),
surgical resection or stereotactic radiotherapy of locoregional
recurrence or a single distant metastasis should be considered
in suitable patients, as a therapeutic option since it offers the
possibility of controlling the disease to long term. Patients
with metastatic melanoma should be screened for metastasis
(preferably) or the primary tumor for detection of the BRAF V600
mutation. The first- and second-line treatment options consist
of anti-PD-L1 antibodies (pembrolizumab, nivolumab) with or
without ipilimumab for all patients, and the BRAF inhibitor / MEK
inhibitor combination for patients presenting with BRAF-mutated
Inhibition of antiPD-L1 or an antiPD-L1 plus ipilimumab is
now the standard treatment for all patients, regardless of their
BRAF expression, in the first-line setting. For NRAS-mutated
melanoma, first-line immunotherapy options identical to wildtype
melanoma are the first choice, as MEK inhibitors have limited
efficacy. If no clinical studies or new approved drugs are available,
cytotoxic drugs such as dacarbazine or temozolomide may be
administered, with moderate activity expected. For the treatment
of brain metastases, the results of studies seem to indicate that
the combined treatment with ipilimumab plus nivolumab is the
preferred first-line treatment, as well as in asymptomatic patients
with BRAF mutation.
For patients with a small number of asymptomatic metastases
(<5-10) and non-bulky tumors (<3 cm), stereotactic radiosurgery
is initially an option. In other patients, systemic treatment must
be evaluated first, reserving stereotactic radiosurgery for the
treatment of lesions that do not respond to treatment. In the event
that systemic treatment fails, stereotactic radiosurgery could be
considered as rescue treatment if the total number of progressive
lesions is <5-10, and their maximum size is <3 cm .
To the patients with melanoma, they should be instructed to
avoid sunburn and prolonged unprotected exposure to sunlight
or artificial ultraviolet light, as well as regular self-examinations
of the skin and peripheral lymph nodes for life. Patients should
be aware that family members may be at increased risk for
melanoma. During melanoma follow-up, patients are monitored
clinically for relapses and to recognize additional skin tumors,
especially secondary melanomas, as soon as possible. There is no
consensus on the optimal monitoring scheme or the usefulness
of imaging and blood tests for patients with resected melanoma;
Recommendations range from follow-up visits every 3 months
in the first 3 years, and every 6 - 12 months thereafter, to no
organized follow-up. Patients with sentinel nodes should be
followed up with periodic ultrasound examinations. The serum
S100 protein test to monitor increases in concentrations is the
most accurate blood test for monitoring melanoma patients, if any
blood tests are recommended.
EORTC 1325-MG / Keynote-054 is a phase 3 study that
randomized fully resected stage III melanoma patients to receive
200 mg fixed-dose pembrolizumab every 3 weeks for one year or
placebo. In this update at 3 years of follow-up, pembrolizumab
confirmed its benefit in progression-free survival with 63.7%
(95% CI: 59.2 - 67.7) of living patients and without recurrence
compared to 44.1% ( 95% CI: 39.6 - 48.4) of those treated with
placebo (HR: 0.56; 95% CI: 0.47 - 0.68; p <0.001) .
The benefit was independent of PD-L1 status (ligand 1 of
programmed cell death), clinical stage (IIIA vs. IIIB vs. IIIC), and
BRAF status. The most frequent site of recurrence was distant
metastases and the incidence of distant metastases was higher in
the placebo group compared to that of pembrolizumab (HR: 0.55,
95% CI 0.44 - 0.69, p < 0.001). Distant metastasis-free survival
analysis is expected in late 2020 (Figure 1).
The authors of the COMBI-AD study also presented an update
of their study with a 5-year follow-up . This phase 3 clinical
study randomized patients with clinical stage III melanoma and
BRAF V600E / K mutations to receive dabrafenib (150 mg every
12 hours) and trametinib (2 mg every day) or placebo for one
year. At 5 years of follow-up, the median relapse-free survival with
dabrafenib plus trametinib has not been reached (95% CI: 47.9-
not reached), and that of placebo is 16.6 (95% CI: 12, 7 - 22.1)
months (52% of patients alive and without recurrence [95% CI:
48% - 58%] for dabrafenib plus trametinib; 36% [95% CI: 32% -
41%] for placebo: HR: 0.51 [95% CI: 0.42-0.61]). The results were
independent of the type of BRAF mutation and the clinical stage.
The 5-year distant metastasis-free survival is 65% (95% CI: 61%
- 71%) for the dabrafenib plus trametinib group vs. 54% (95%
CI: 49% - 60%) in the group. placebo (HR: 0.55, 95% CI 0.44 -
0.70). The median distance metastasis-free survival has not been
reached for either group.
These studies confirm the utility of both immunotherapy
and target therapies for the adjuvant treatment of patients with
clinical stage III melanoma. Some important questions remain
open, such as the benefit of these treatments in clinical stage IIIA,
which seems to be bordering on both studies. On the other hand,
the question arises as to which is the best therapy for patients
with BRAF mutations; This question remains unanswered, and for
the time being the decision will have to be based on the toxicity
profile and the preference of both the physician and the patient.
Although the results of the PRADO study do not change our
clinical practice at this time, they suggest that there will be a benefit
of immunotherapy in the neoadjuvant field. This phase 2 study
analyzes personalized treatment for patients with clinical stage
IIIB and IIIC melanoma, without transit metastases. Previously,
the results of several studies in this treatment context had been
reported; In particular, the results of the Neo-OPACIN study
demonstrated adequate tolerance and safety for a combination of
ipilimumab at a dose of 1 mg / kg with nivolumab at a dose of 3
mg / kg (ipilimumab plus nivolumab), with high response rates.
In the PRADO study, patients received ipilimumab plus
nivolumab for 2 cycles, and resection of the index adenopathy,
arguing that the pathological response in the largest infiltrated
lymph node represents the state of the entire lymph bed in
question. If after treatment with ipilimumab plus nivolumab the
index adenopathy presented a complete pathological response or
less than or equal to 10% of viable tumor cells, only surveillance
was given. If there was a partial response, between 10% and 50%
of viable tumor cells, it was carried out to lymph node dissection
and then to surveillance. If there was no adequate pathological
response, adjuvant lymph node dissection and nivolumab, or
dabrafenib plus trametinib (in the case of a BRAF mutation) were
The study reported 61% complete pathologic response or
viable tumor cells after 2 cycles of ipilimumab plus nivolumab, and
21% adequate pathologic response. The radiological evaluation,
on the other hand, reported an objective response rate (ORR)
of only 45%, therefore it was concluded that the radiological
response underestimated the pathological evaluation. Grade 3-4
adverse events secondary to ipilimumab plus nivolumab were
22%. There were greater postoperative complications in patients
who underwent lymph node dissection, compared to those who
were led only to index lymph node dissection (81% vs. 41%,
respectively; p <0.001). The patients who only had resection of
index adenopathy also had a better quality of life than those who
had complete resection. The results of recurrence-free survival
and distant metastasis-free survival will be presented at the 2020
European Society for Medical Oncology (ESMO) Congress.
Despite being a small phase 2 study, it brings up various
concepts that we will have to take into account for neoadjuvant
treatment: 1) 2 cycles of ipilimumab plus nivolumab are
probably sufficient to achieve high pathological response rates;
2) Imaging-assessed responses are likely to underestimate
pathologic response rates, and 3) bring to the table the concept
of the index lymph node, which could prevent wide lymph node
dissections that have a detrimental effect on the quality of life of
patients. We will wait impatiently for the results of the outcomes
over time, and of course, phase 3 studies that confirm the value
of immunotherapy in this context of the disease. Palliative land,
one of the greatest needs for the progression of treatment with
A phase 2 study evaluated the efficacy of the combination
of pembrolizmab with ipilimumab at a dose of 1 mg / kg body
weight (ipilimumab plus pembrolizmab) for 4 doses, followed
by maintenance with pembrolizumab in patients with metastatic
melanoma with progression to treatment with an anti- PD1 or a
combination of anti-PD1 with another non-CTLA4 immunotherapy
The RECIST response rates were 27%, with a response
duration of 18.5 months (95% CI: 10.6-undetermined). The
median progression-free survival was 5 months, and the overall
survival 24.7 months. Grade 3-4 adverse effects occurred in
27% of patients. The response was variable between patients
treated with the combo and those with higher response rates
were those with liver or central nervous system disease, elevated
lactic dehydrogenase, and negative PD-L1. In a gene expression
profile analysis, the highest efficacy was observed in non-T-cell
inflamed tumors. This benefit was confirmed in a retrospective
analysis of patients with progression to adjuvant or palliative
immunotherapy, looking at the benefit of using a combination of
ipilimumab monotherapy versus ipilimimumab plus anti-PD1 in
patients previously treated with an anti-PD1.
In this cohort, 88% of the patients had been treated in the
metastatic context; 74% of them were classified as primary
resistances (median progression: 2.7 months), and 26% as
acquired resistances (median progression: 9.5 months). There
were significant differences in the general characteristics of the
patients who were treated with ipilimimumab compared to those
treated with ipilimimumab plus anti-PD1. In general, the patients
who received the combo were younger, had more frequent BRAF
mutations, better ECOG (<1), and more frequent presence of brain
metastases than patients treated with ipilimimumab.
Objective RECIST response rates for patients treated with
ipilimimumab plus anti-PD1 were 27% versus 13% for those
treated with ipilimimumab (p = 0.0021), with a median duration
of response of 11.6 months versus 9 months, respectively (p =
0.04). The progression-free survival at 18 months was 22% for
the patients treated with the combo compared to 18% of those
treated with ipilimimumab (HR: 0.67, 95% CI: 0.53 - 0.85; p = 0
, 0005), and the overall survival of 53% versus 25%, respectively
(HR: 0.51; 95% CI: 0.36 - 0.67; p <= 0.0001). In particular, BRAF
WT patients had better response rates with ipilimimumab plus
anti-PD1, than with ipilimimumab.
Predictive factors associated with longer survival in the
combo-treated cohort were male gender, time to progression
with previous anti-PD1 greater than 3 months, and treatment
with ipilimimumab plus anti-PD1. Negative predictive factors
for overall survival were ECOG less than or equal to 1, presence
of bone metastases and elevated lactic dehydrogenase. Grade
3-4 adverse events occurred in 31% of patients treated with the
combo, and in 33% of those treated with monotherapy. These
data are the first prospective and randomized results that we
have in patients with metastatic melanoma with progression to a
previous anti-PD1. These, plus the results of several retrospective
cohorts, confirm the potential benefit of this strategy in an area
of therapeutic need. Furthermore, a more specific clinical profile
seems to be being defined on the patients who will obtain the
greatest benefit from this combination.