Forum for Nordic Dermato-Venereology Nr 4, 2019 | Page 18

Dissertation
Emilia Hugdahl – Prognostic molecular markers in melanoma
Prognostic Molecular Markers in Melanoma
E milia H ugdahl
Department of Dermatology, Haukeland University Hospital, Bergen, Norway. E-mail: [e-mail]
Emilia Hugdahl, dermatologist at Haukeland University Hospital, defended her thesis in April 20, 2018:
“Prognostic and molecular markers in primary and metastatic cutaneous melanoma” for the degree of PhD
at University of Bergen, Norway. Opponents were Johan Hansson, Stockholm, Silje Fismen, Tromsø, and Leiv
M. Hove, Bergen. Supervisors were Lars Akslen and Rita Grude Ladstein.
The global incidence of cutaneous melanoma has increased
tremendously during the last decades. The course of melano-
ma progression is largely unpredictable, and despite recent
progress in treatment opportunities, many patients with
advanced melanoma do not benefit from these. To improve
prognostication and find new potential treatment targets, a
deeper understanding of molecular alterations, basic tumor and
microenvironment biology and tumor heterogeneity is needed.
In this PhD project, we wanted to explore markers related to
both tumor cell-specific and tumor microenvironment pro­
perties in primary and matched metastatic lesions, in order
to improve our understanding of tumor heterogeneity, prog-
nostication, and possibilities for improved targeted treatment.
In the 3 separate studies, we examined a patient series consist-
ing of 255 consecutive cases of primary nodular cutaneous mel-
anoma diagnosed at the Department of Pathology, Haukeland
University Hospital (Bergen, Norway) during 1998­–2008. In
Paper II and III, 78 paired biopsies from the first appearing
local (skin; n = 26) or regional metastatic tumor (lymph nodes;
n = 52) were examined in addition to the primary tumors (2,
3). In Paper I, BRAF-V600E and total BRAF expression were
assessed by immunohistochemistry using TMAs (n = 248), and
mutation status was assessed by real-time PCR (n = 191) (1).
In Paper II, TERT promoter mutation status was assessed by
Sanger sequencing (194 primary tumors and 72 metastases),
and TERT protein expression by immunohistochemistry using
TMAs (248 primary tumors and metastases) (2). In Paper III,
vascular proliferation index (VPI) was assessed by dual im-
munohistochemistry using Factor-VIII/Ki67 staining (in 242
primary melanomas and 69 metastases (3). Expression of UPAR
and HSP27 was determined by immunohistochemistry using
TMAs (248 primary tumors and 68 metastases), and selected
histopathologic features of the metastases were recorded based
on HE-slides (n = 73) (3).
Positive BRAF-V600E expression was present in 35 of the
cases and was significantly associated with increased tumor
thickness, presence of tumor ulceration and reduced survival.
There was 88% concordance between BRAF-V600E expression
and mutation status (I).
TERT mutations were present in 68% of primary melanomas
and 64% of metastases (2). The mutation status was discord-
ant between primary tumor and metastasis in 24%, among
which 71% did not show a mutation in the metastatic tumor.
TERT mutated tumors showed no significant association with
reduced survival, neither in primary melanoma nor in metas-
tases. TERT protein expression did not correlate with mutation
status, but positive TERT expression in primary melanomas
was significantly associated with increased tumor thickness
and with reduced survival (II).
High VPI and high UPAR expression were associated with each
other, and with aggressive tumor features and reduced surviv-
al in primary melanoma. In loco-regional metastases, high
UPAR expression was significantly associated with increased
MVD, but no prognostic value was found for any marker of
angiogenesis, including UPAR and HSP27. Presence of tumor
necrosis in loco-regional metastases, as a marker of tumor
hypoxia, was associated with increased tumor size, high VPI,
high HSP27 expression and reduced survival. Among paired
primary and metastatic tumors, median MVD was significantly
higher in metastases, while the opposite was found for VPI,
which had significantly lower median value in metastases.
Among discordant VPI cases, most had lower VPI in metastases
compared to primary tumors. The same pattern was seen for
UPAR expression, while among discordant cases for necrosis,
the majority showed a switch from absent in the primary to
present in the metastasis (III).
In conclusion, a prognostic value was found for BRAF-V600E
protein expression, TERT protein expression, VPI and UPAR
expression in primary melanoma, and for tumor necrosis in
loco-regional metastases. Inter-tumoral discordancy of TERT
mutation status was demonstrated.
L ist
of publications
I.
Hugdahl E, Kalvenes MB, Puntervoll HE, Ladstein RL, Akslen LA.
BRAF-V600E expression in primary nodular melanoma is associated
with aggressive tumour features and reduced survival. Br J Cancer
2016; 114: 801–808.
II. Hugdahl E, Kalvenes MB, Mannelqvist M, Ladstein RG, Akslen LA.
Prognostic impact and concordance of TERT promoter mutation
and protein expression in matched primary and metastatic cuta-
neous melanoma. Br J Cancer 2018; 118: 98–105.
III. Hugdahl E, Bachmann IM, Schuster C, Ladstein RG, Akslen LA.
Prognostic value of uPAR expression and angiogenesis in primary
and metastatic melanoma. PLoS One 2019; 14: e0210399.
Fig. 1. From left to right: Johan Hansson (Opponent), Silje Fismen (Opponent), Svein Helland (acting Dean), Emilia Hugdahl (Respondent) and Leiv
M. Hove (Opponent).
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Forum for Nord Derm Ven 2019, Vol. 24, No. 4
Forum for Nord Derm Ven 2019, Vol. 24, No. 4
D issertation
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