Acta Dermato-Venereologica 99-1CompleteContent | Page 22
INVESTIGATIVE REPORT
A Myxoid Fibrotic Reaction Pattern is Associated with Metastatic
Risk in Cutaneous Squamous Cell Carcinoma
Eugenia HERNÁNDEZ-RUIZ 1,2# , Inmaculada HERNÁNDEZ-MUÑOZ 3# , Emili MASFERRER 4 , Carla FERRÁNDIZ-PULIDO 2 , Evelyn
ANDRADES 3 , Javier GIMENO 5 , Xavier DURAN 6 , Vicente GARCÍA-PATOS 2 , Ramon M. PUJOL 1 and Agusti TOLL 1
Departments of 1 Dermatology and 5 Pathology, Hospital del Mar, Parc de Salut Mar, 2 Department of Dermatology, Hospital Universitari Vall
d’Hebron, Universitat Autònoma de Barcelona, 3 Group of Inflammatory and Neoplastic Dermatological Diseases and 6 Methodological and
biostatistical advisory service, IMIM (Hospital del Mar Medical Research Institute), and 4 Department of Dermatology, Hospital Universitari
Mútua de Terrassa, Barcelona, Spain
#
Both authors contributed equally to this work.
Although desmoplasia has been associated with poor
prognoses in cutaneous squamous cell carcinoma, little
attention has been paid to the patterns of fibrosis. This
study aimed to examine the different stromal fibrotic
patterns as markers of metastatic risk. We performed
a multicenter retrospective study that included 102 cu-
taneous squamous cell carcinomas (52 non-metastatic
and 50 metastatic carcinomas). Clinical and histopa
thological data were registered. The fibrotic reaction
pattern was classified as mature, intermediate or im-
mature depending on the presence of keloid-like colla-
gen and myxoid stroma. The immature pattern (areas
characterized by myxoid changes with no inflamma-
tion) was observed in 18 samples and its presence was
significantly associated with immunosuppression, bud-
ding, desmoplasia, perineural invasion, anatomic level,
tumoural depth and metastatic risk in the multivariate
analysis. Our findings suggest that the presence of an
immature myxoid fibrotic pattern, which can be easily
identified by routine hematoxylin-eosin staining, is
strongly associated with metastatic risk.
Key words: metastasis; fibrosis; cutaneous squamous cell car-
cinoma.
Accepted Aug 31, 2018; Epub ahead of print Sep 3, 2018
89
Acta Derm Venereol 2019; 99: 89–94.
Corr: Agustí Toll, Department of Dermatology, Hospital del Mar, Parc de
Salut Mar, Universitat Autònoma de Barcelona, ES-08003 Barcelona,
Spain. E-mail: [email protected], [email protected]
M
etastatic cutaneous squamous cell carcinomas
(MSCCs) usually involve the regional lymph
nodes, and occur in approximately 4–5% of patients (1).
Active research in cutaneous SCC (cSCC) is aimed at the
identification of prognostic markers of clinical value that
could help identify those patients at higher metastatic risk.
Prominent clinical factors linked to an aggressive clinical
behaviour and metastatic risk include tumoural size, im-
munosuppression and certain tumour locations such as the
ears, lips and areas of chronic injury. Some histological
parameters of the primary tumour, including depth, poor
histological differentiation and perineural invasion have
also been associated with poor prognosis (2–4).
Epithelial to mesenchymal transition (EMT), a me-
chanism by which epithelial cells lose adhesion and
SIGNIFICANCE
Cutaneous squamous cell carcinomas are the second most
frequent non-melanoma skin cancers. Despite their gene-
rally good prognosis, approximately 2–5% metastasize,
usually to regional lymph nodes. Recent works have elu-
cidated the relevance of the tumour microenvironment,
consisting of a stromal reaction, a vascular and lymphatic
network and the presence of specific inflammatory cell
subpopulations, in the development of metastases. In this
study we have characterized different types of stromal
reaction patterns in cutaneous squamous cell carcinoma,
including desmoplasia, and have found that the presence
of a myxoid peritumoral infiltration, easily recognisable by
hematoxylin eosin stains, is associated with an increased
metastatic risk.
acquire mesenchymal traits that allow them to invade
and disseminate (5), has been shown to be involved in
the metastasis of a variety of epithelial tumours. Indeed,
we have previously reported that the presence of EMT
markers is associated with an increased metastatic risk in
cSCC (6). Tumour budding, pathologically characterized
by clusters or single tumoural cells that may reflect cells
undergoing EMT, has also been recently linked to nodal
metastasis in cSCC (7, 8).
The EMT process can be induced by the tumoural
microenvironment through the release of cytokines
and extracellular matrix proteins by cancer-associated
fibroblasts (CAFs). In addition to their effect on epi
thelial tumoural cells, CAFs may also generate a fibro-
tic stroma. The role of the fibrotic reaction in cancer
development and progression remains controversial.
While some studies suggest that the host may favour a
desmoplastic response to limit tumour aggressiveness
(9), others have shown that the fibrotic stroma induced
by CAFs might benefit the tumour by inhibiting access
to immune cells (10–13). In this sense, the association
between desmoplastic reaction and poor outcome has
been observed in several cancers such as cholangiocar-
cinoma, breast, pulmonary, pancreatic, tongue, rectal
and colorectal carcinomas (11, 14–18). cSCC with a
desmoplastic phenotype, characterized by strands and
nests of tumour cells surrounded by a prominent fibrous
stromal response, may also pose an increased risk of
This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta
Journal Compilation © 2019 Acta Dermato-Venereologica.
doi: 10.2340/00015555-3025
Acta Derm Venereol 2019; 99: 89–94