Dermatology: Practical and Conceptual


Review | Dermatol Pract Concept. 2022;12(4):e2022193 1

Eruptive Non-melanoma Skin Cancers/Squamous 
Atypia Following Skin Surgery. Report of Two 

New Cases, Concise Review of the Literature With 
Special Emphasis on Treatment Options

Marco Adriano Chessa1,2, Valentino Marino Picciola3, Federica Filippi1,2, Annalisa Patrizi1,2, 
Cosimo Misciali1,2, Bianca Maria Piraccini1,2, Ignazio Stanganelli4, Francesco Savoia4

1 IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy

2 Dermatology Unit, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy

3 University of Bologna, School of Medicine and Surgery, Bologna, Italy

4 Skin Cancer Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy

Key words: Eruptive non-melanoma skin cancers, keratoacanthomas after cutaneous surgery, keratoacanthomas AND split-thickness skin 
graft, cutaneous squamous cell carcinomas AND split-thickness skin graft

Citation: Chessa MA, Marino Picciola V, Filippi F, et al. Eruptive non-melanoma skin cancers/squamous atypia following skin surgery. 
Report of two new cases, concise review of the literature with special emphasis on treatment options. Dermatol Pract Concept. 
2022;12(4):e2022193. DOI: https://doi.org/10.5826/dpc.1204a193

Accepted: March 7, 2022; Published: October 2022

Copyright: ©2022 Chessa et al. This is an open-access article distributed under the terms of the Creative Commons  
Attribution-NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted 
noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited.

Funding: None.

Competing interests: None.

Authorship: All authors have contributed significantly to this publication.

Corresponding author: Federica Filippi, MD, Dermatology, Department of Experimental, Diagnostic and Specialty Medicine, University of 
Bologna, Via Massarenti, 1 – 40138 Bologna, Italy Tel: +39051-2144849; Fax +39-0512144867; E-mail: federicafilippi8@gmail.com

Introduction: Eruptive cutaneous squamous cell carcinomas (ESCC), eruptive squamous atypia (ESA) 
and eruptive keratoacanthomas (EKA) are different terms used to describe the occurrence of multiple 
cutaneous squamous neoplasms after skin surgery, laser treatment, traumas, such as tattoos, and local 
or systemic medical treatments.

ESCC have been reported to arise at the sites of skin surgery, including the area affected by the primary 
tumor and split thickness skin graft (STSG) donor and recipient sites.

Objectives: The aim of this study is to report 2 additional cases of ESCC after skin surgery and make 
a critical revision of the literature, analyzing the clinical, histological features and outcomes of ESCC 
after cutaneous surgery.

Methods: Up to August 2021, according to our systematic review of the literature, we have collected 
19 published articles and a total of 34 patients, including our 2 cases.

Results: The results of this review highlight five red flags that clinicians should consider: (i) lower and 
upper limbs represent the cutaneous site with the highest risk, representing 83,78% of the cases in the 

ABSTRACT



2 Review | Dermatol Pract Concept. 2022;12(4):e2022193

Introduction

Eruptive cutaneous squamous cell carcinomas (ESCC), erup-

tive squamous atypia (ESA) and eruptive keratoacanthomas 

(EKA) are different terms used to describe the occurrence 

of multiple cutaneous squamous neoplasms occurring after 

skin surgery, laser treatment, traumas, such as tattoos, local 

or systemic medical therapies. In this paper, we decided to 

use only the term ESCC.

ESCC have been reported to arise at the sites of skin sur-

gery, including the area affected by the primary tumor and 

split thickness skin graft (STSG) donor and recipient sites 

[1-19]. The best therapeutic option for ESCC after surgery in 

our opinion is still a challenge.

Objectives

The aim of our study is to report 2 additional cases of ESCC 

after skin surgery and make a critical revision of the liter-

ature, analyzing the clinical, histological features and out-

comes of ESCC after cutaneous surgery [18]. An overview of 

this rarely reported condition is provided, in order to raise 

awareness of this clinical entity and of the treatment options.

Methods

We identified studies indexed in PubMed from its inception 

to June 31, 2021. All papers reported in the present study 

involved human clinical studies, including case reports, case 

series and reviews. Search parameters included the terms 

‘‘Keratoacanthomas after cutaneous surgery”, “Keratoacan-

thomas AND STSG”, ‘‘Cutaneous squamous cell carcinomas 

AND STSG”, “Cutaneous squamous cell carcinomas after 

cutaneous surgery’’, “squamous cell carcinoma after Mohs 

Micrographic surgery (MMS)”, “eruptive squamous cell 

carcinoma and surgery”, “eruptive squamous atypia and 

surgery”, “eruptive keratoacanthomas and surgery”, “koeb-

nerized cutaneous squamous cell carcinoma”.

A subsequent review of the relative bibliographies 

aimed to identify any undetected reports. We collected sex, 

age, involved cutaneous area, surgical procedure, medical 

treatment and histopathology findings of primary cutane-

ous skin cancer of all the patients included in this review. 

Furthermore, we reported the time lapse from the primary 

surgery to the onset of ESCC, clinical and histological fea-

tures, management, recurrences and outcome. In addition, 

we describe here our personal experience with two patients 

visited at the Skin Cancer Unit of Bologna between January 

2012 and August 2021, who developed ESCC after cutane-

ous squamous cell carcinoma (CSCC) excision and recon-

struction with STSG.

Results

Up to August 2021, according to our systematic review of 

the literature, we found only 19 published articles (Table 1). 

A total of 34 ascertained patients, including our two 

cases, were included in this study, with a sex ratio F/M = 0.88, 

a mean age = 68.94 years (standard deviation [SD] = 13.6).

The main clinical features of the 34 patients diagnosed 

with ESCC after surgery are reported in Table 2.

The extremities (upper and lower limbs) were the sites 

most frequently involved by primary tumors, representing 

83.78% of cases in our sample. The second most involved 

site was the head, with 13.51% of cases. Regarding our two 

patients, the first had a CSCC of the head and the second a 

cutaneous SCC of the right leg.

Histological examination of the primary skin cancer was 

consistent with a CSSC in 30/37 cases (81.08%), while basal 

cell carcinoma, actinic keratosis, malignant melanoma and 

lentigo maligna were detected in 7 cases (18.92%).

Different surgical techniques were used for the exci-

sion of the primary skin tumors, although classic fusiform 

excision, excision plus STSG, MMS and subsequent recon-

struction with or without STSG were the most commonly 

performed procedures, in 32/37 cases (86.49%).

The main clinical features of the ESCC after skin surgery 

are reported in Table 3. The median time to the onset is ap-

proximately 6 weeks, and in 28/34 of the patients (82.35%) 

it occurred within 16 weeks from the primary surgery.

Surprisingly, ESCC occurred in the area of the skin 

 affected by the primary tumor in 26/37 of the cases 

literature; (ii) the median time to onset of ESCC is approximately 6 weeks; (iii) primary cutaneous 
squamous cell carcinomas were completely excised with free margins on histologic examination in 
the totality of the cases of the literature, and therefore ESCC should not be considered recurrences; 
(iv) any surgical technique involves a risk to promote ESCC; (v) treatment of ESCC includes medical 
treatment, surgery or combined surgical and medical treatment.

Conclusions: This review highlights 5 red flags which could support clinicians in the diagnosis and 
management of ESCC after skin surgery.



Review | Dermatol Pract Concept. 2022;12(4):e2022193 3

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4 Review | Dermatol Pract Concept. 2022;12(4):e2022193

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ST

SG
 

p
ri

m
ar

y 
ex

ci
si

o
n

 
si

te

K
A

E
x

N
o

n
e

N
/A

M
ar

cu
s 

an
d
 

B
ra

d
y,

 2
0
2
1

1
3
9
, F

L
 T

h
ig

h
 

(l
o
w

er
 l
im

b
)

M
M

S 
+
 

ST
SG

N
o
n
e

SC
C

1
2

G
D

S
SC

C
M

M
S

N
o

n
e

N
/A

V
er

ga
ra

  
et

 a
l, 

2
0
0
7

1
8
0
, F

R
 L

eg
 

(l
o
w

er
 l
im

b
)

E
x
 +

 S
T

SG
N

o
n
e

K
A

9
6

G
D

S
K

A
E

x
N

o
n

e
Y

es

L
. K

ea
rn

ey
 

et
 a

l, 
2
0
1
5

1
4
8
, M

R
 C

h
es

t
E

x
 +

 S
T

SG
N

o
n
e

M
M

6
G

D
S

SC
C

E
x

N
o

n
e

N
/A

M
o
rr

it
t 

an
d
 

K
h
an

d
w

al
a,

 
2
0
1
2

1
8
2
, F

L
 L

eg
 (

lo
w

er
 

li
m

b
)

E
x
 +

 S
T

SG
N

o
n
e

SC
C

s
1
1
7

E
x
S 

+
 G

D
S

SC
C

s
E

x
N

o
n

e
Y

es

G
am

b
ic

h
le

r 
2
0
2
1

2
1

4
9
 F

L
eg

 (
lo

w
er

 
li
m

b
)

M
M

S 
+
 

ST
SG

N
o
n
e

SC
C

3
M

M
S

SC
C

E
x

N
o

n
e

Y
es

2
6
0
 M

B
ac

k
 o

f 
th

e 
h
an

d
 (

u
p
p
er

 
li
m

b
)

M
M

S 
+
 

ST
SG

N
o
n
e

SC
C

3
M

M
S

SC
C

E
x

N
o

n
e

Y
es

Ta
b

le
 1

. 
E

ru
p
ti

ve
 n

o
n
-m

el
an

o
m

a 
sk

in
 c

an
ce

rs
 f

o
ll

ow
in

g 
sk

in
 s

u
rg

er
y:

 l
it

er
at

u
re

 r
ev

ie
w

 a
n

d
 o

u
r 

ca
se

s.
 (

co
n

ti
n

u
ed

)



Review | Dermatol Pract Concept. 2022;12(4):e2022193 5

S
tu

d
y
 a

n
d

 
Y

e
a
r

P
a
ti

e
n

ts
Fi

rs
t 

S
k
in

 L
e
si

o
n

E
ru

p
ti

v
e

 N
M

S
C

N
.

C
a
se

A
g

e
, 

S
e
x

A
re

a
 

in
v
o

lv
e
d

S
u

rg
e
ry

 
p

ro
ce

d
u

re
 

p
e
rf

o
rm

e
d

M
e
d

ic
a
l 

Tr
e
a
tm

e
n

t
H

is
to

p
a
th

o
lo

g
y
 

fi
n

d
in

g
s

T
im

e
 

O
n

se
t 

a
ft

e
r 

S
u

R
g

e
ry

 
(W

e
e
k
s)

A
re

a
 

in
v
o

lv
e

d
H

is
to

p
a

th
o

lo
g

y
 

fi
n

d
in

g
s

S
u

rg
ic

a
l 

Tr
e

a
tm

e
n

t
M

e
d

ic
a

l 
Tr

e
a

tm
e

n
t

R
e

cu
rr

e
n

ce

H
ad

le
y 

 
et

 a
l, 

2
0
0
9

3
1

6
7
, M

F
o
re

ar
m

 
(u

p
p
er

 l
im

b
)

M
M

S
N

o
n
e

SC
C

1
6

M
M

S 
si

te
K

A
E

x
N

o
n

e
Y

es

2
7
0
, F

F
o
re

ar
m

 
(u

p
p
er

 l
im

b
)

E
x

N
o
n
e

SC
C

1
2

E
x

S
K

A
M

M
S

N
o

n
e

Y
es

3
8
8
, F

B
 L

eg
s 

(l
o
w

er
 l
im

b
)

S 
+
 C

o
 +

 
E

D
N

o
n
e

K
A

2
T

re
at

m
en

t 
Si

te
K

A
C

o
 +

 E
D

N
o

n
e

Y
es

H
ai

k
 e

t 
al

, 
2
0
0
8

1
6
4
, M

L
ef

t 
B

ig
 T

o
e 

(l
o
w

er
 l
im

b
)

A
 +

 S
T

SG
N

o
n
e

M
M

6
G

D
S

SC
C

E
x

N
o

n
e

N
o

G
o
ld

b
er

g 
 

et
 a

l, 
2
0
0
4

6
1

7
2
, M

L
 L

eg
 a

n
d
 

F
in

ge
r 

(l
o
w

er
 l
im

b
)

M
M

S
N

o
n
e

SS
C

s
6

M
M

S 
si

te
K

A
M

M
S

N
o

n
e

Y
es

2
6
9
, M

L
 F

o
re

ar
m

. 
(u

p
p
er

 l
im

b
)

M
M

S
N

o
n
e

SC
C

4
M

M
S 

si
te

K
A

M
M

S
N

o
n

e
N

o

3
7
4
, F

R
 L

eg
 

(l
o
w

er
 l
im

b
)

M
M

S
Is

o
tr

et
in

o
in

 4
0
 

m
g/

d
 f

o
r 

3
0
 d

ay
s

SC
C

3
M

M
S 

si
te

K
A

C
o

 +
 E

D
Is

o
tr

et
in

o
in

 
4

0
 m

g/
d

Y
es

4
7
9
, M

R
 F

o
re

ar
m

 
(u

p
p
er

 l
im

b
)

M
M

S
N

o
n
e

L
M

4
M

M
S 

si
te

K
A

E
x

N
o

n
e

N
o

5
7
1
, M

R
 T

h
ig

h
 

(l
o
w

er
 l
im

b
)

M
M

S
N

o
n
e

SB
C

C
2

M
M

S 
si

te
K

A
N

o
n

e
Is

o
tr

et
in

o
in

 
(4

0
 m

g/
d

) 
fo

r 
1

 m
o

n
th

.

N
o

6
7
5
, M

R
 F

o
re

h
ea

d
 

(h
ea

d
)

C
o
 +

 E
D

N
o
n
e

SC
C

4
T

re
at

m
en

t 
Si

te
K

A
M

M
S

Is
o

tr
et

in
o

in
 

(4
0

 m
g/

d
) 

fo
r 

1
 m

o
n

th
.

N
o

H
u
ss

ai
n
  

et
 a

l, 
2
0
1
0

1
5
2
, M

R
 H

an
d
 

(u
p
p
er

 l
im

b
)

E
x
 +

 S
T

SG
N

o
n
e

SC
C

8
G

D
S

SC
C

E
x

 +
 

re
co

n
st

ru
ct

ed
 

w
it

h
 a

n
 

is
la

n
d

ed
 V

eY
 

ad
va

n
ce

m
en

t 
fl

ap

N
o

n
e

N
o

P
o
n
n
u
ve

lu
 

et
 a

l, 
2
0
1
1

2
1

5
8
, M

L
ef

t 
p
ar

ie
ta

l 
sc

al
p
 (

h
ea

d
)

E
x
 +

 S
T

SG
N

o
n
e

n
o
d
u
lo

cy
st

ic
 

B
C

C
2

G
D

S
SC

C
E

x
N

o
n

e
N

/A

2
8
8
, F

le
ft

 s
h
in

 
(l

o
w

er
 l
im

b
)

E
x
 +

 S
T

SG
N

o
n
e

K
A

5
G

D
S

SC
C

E
x

 +
 fl

ap
N

o
n

e
N

o

L
ee

 e
t 

al
, 

2
0
1
7

1
9
5
, F

R
 S

h
in

 
(l

o
w

er
 l
im

b
)

E
x
 +

 S
T

SG
N

o
n
e

K
A

2
0

E
x
s 

+
 G

D
S

K
A

C
o

 +
 E

D
Im

iq
u

im
o

d
 

5
%

 c
re

am
 

ap
p

li
ca

ti
o

n

Y
es

Sa
lt

iv
ig

 a
n
d
 

M
at

ze
n
, 

2
0
1
8

1
7
8
, F

L
 K

n
ee

 
(l

o
w

er
 l
im

b
)

E
x
 +

 S
T

SG
N

o
n
e

M
M

9
6
0

ST
SG

 
p
ri

m
ar

y 
ex

ci
si

o
n

 
si

te

M
ar

jo
li

n
 U

lc
er

E
x

N
/A

N
/A

K
im

ya
i-

A
sa

d
i 
et

 a
l, 

2
0
0
4

1
7
6
, M

R
 H

an
d
 

(u
p
p
er

 l
im

b
)

E
x

N
o
n
e

SC
C

8
E

x
S

K
A

E
x

N
o

n
e

N
o

N
eg

as
e 

 
et

 a
l, 

2
0
1
6

1
7
8
, F

N
o
se

 (
h
ea

d
)

F
T

SG
N

o
n
e

A
K

3
ST

SG
 

p
ri

m
ar

y 
ex

ci
si

o
n

 
si

te

K
A

E
x

N
o

n
e

N
/A

M
ar

cu
s 

an
d
 

B
ra

d
y,

 2
0
2
1

1
3
9
, F

L
 T

h
ig

h
 

(l
o
w

er
 l
im

b
)

M
M

S 
+
 

ST
SG

N
o
n
e

SC
C

1
2

G
D

S
SC

C
M

M
S

N
o

n
e

N
/A

V
er

ga
ra

  
et

 a
l, 

2
0
0
7

1
8
0
, F

R
 L

eg
 

(l
o
w

er
 l
im

b
)

E
x
 +

 S
T

SG
N

o
n
e

K
A

9
6

G
D

S
K

A
E

x
N

o
n

e
Y

es

L
. K

ea
rn

ey
 

et
 a

l, 
2
0
1
5

1
4
8
, M

R
 C

h
es

t
E

x
 +

 S
T

SG
N

o
n
e

M
M

6
G

D
S

SC
C

E
x

N
o

n
e

N
/A

M
o
rr

it
t 

an
d
 

K
h
an

d
w

al
a,

 
2
0
1
2

1
8
2
, F

L
 L

eg
 (

lo
w

er
 

li
m

b
)

E
x
 +

 S
T

SG
N

o
n
e

SC
C

s
1
1
7

E
x
S 

+
 G

D
S

SC
C

s
E

x
N

o
n

e
Y

es

G
am

b
ic

h
le

r 
2
0
2
1

2
1

4
9
 F

L
eg

 (
lo

w
er

 
li
m

b
)

M
M

S 
+
 

ST
SG

N
o
n
e

SC
C

3
M

M
S

SC
C

E
x

N
o

n
e

Y
es

2
6
0
 M

B
ac

k
 o

f 
th

e 
h
an

d
 (

u
p
p
er

 
li
m

b
)

M
M

S 
+
 

ST
SG

N
o
n
e

SC
C

3
M

M
S

SC
C

E
x

N
o

n
e

Y
es

T
ab

le
 1

 c
o
n
ti

n
u
es



6 Review | Dermatol Pract Concept. 2022;12(4):e2022193

S
tu

d
y
 a

n
d

 
Y

e
a
r

P
a
ti

e
n

ts
Fi

rs
t 

S
k
in

 L
e
si

o
n

E
ru

p
ti

v
e

 N
M

S
C

N
.

C
a
se

A
g

e
, 

S
e
x

A
re

a
 

in
v
o

lv
e
d

S
u

rg
e
ry

 
p

ro
ce

d
u

re
 

p
e
rf

o
rm

e
d

M
e
d

ic
a
l 

Tr
e
a
tm

e
n

t
H

is
to

p
a
th

o
lo

g
y
 

fi
n

d
in

g
s

T
im

e
 

O
n

se
t 

a
ft

e
r 

S
u

R
g

e
ry

 
(W

e
e
k
s)

A
re

a
 

in
v
o

lv
e

d
H

is
to

p
a

th
o

lo
g

y
 

fi
n

d
in

g
s

S
u

rg
ic

a
l 

Tr
e

a
tm

e
n

t
M

e
d

ic
a

l 
Tr

e
a

tm
e

n
t

R
e

cu
rr

e
n

ce

Q
u
e 

et
 a

l 
2
0
1
9

1
6
2
M

R
 a

n
d
 L

 
le

gs
 (

L
o
w

er
 

li
m

b
s)

E
x

N
o
n
e

3
 S

C
C

N
o
t 

sp
ec

ifi
ed

E
x

s 
si

te
s

Su
sp

ec
te

d
 

er
u

p
ti

ve
 

sq
u

am
o

u
s 

at
yp

ia

N
o

n
e

In
tr

al
es

io
n

al
  

5
-fl

u
o

ro
u

ra
ci

l 
p

lu
s 

ac
it

re
ti

n

N
o

C
h
es

sa
 e

t 
al

, 
2
0
2
1

2
1

6
5
,M

R
 o

cc
ip

it
al

 
ar

ea
 o

f 
th

e 
sc

al
p
 (

h
ea

d
)

E
x
 +

 S
T

SG
N

o
n
e

SC
C

4
ST

SG
 

p
ri

m
ar

y 
ex

ci
si

o
n

 
si

te

SC
C

E
x

A
ci

tr
et

in
 2

5
 

m
g/

d
ie

Y
es

2
8
0
,F

R
 L

eg
 

(l
o
w

er
 l
im

b
)

E
x
 +

 S
T

SG
N

o
n
e

SC
C

6
ST

SG
 

p
ri

m
ar

y 
ex

ci
si

o
n

 
si

te

SC
C

E
x

ac
it

re
ti

n
 2

5
 

m
g/

d
ai

ly
 a

n
d

 
in

tr
al

es
io

n
al

 
m

et
h

o
tr

ex
at

e 
1

0
 m

g/
w

ee
k

ly

N
o

A
K

 =
 A

ct
in

ic
 K

er
at

o
si

s;
 A

 =
 A

m
p
u
ta

ti
o
n
; 

B
 =

 B
il
at

er
al

; 
C

E
M

P
 =

 C
u
ta

n
eo

u
s 

ex
tr

am
ed

u
ll
ar

y 
p
la

sm
ac

yt
o
m

as
; 

C
o
 =

 C
o
u
re

tt
ag

e;
 E

D
 =

 E
le

ct
ro

d
es

ic
ca

ti
o
n
; 

E
x
 =

 E
x
ci

si
o
n
; 

E
x
S 

=
 E

x
ci

si
o
n
 S

it
e;

 F
 =

 F
em

al
e;

  
F

T
SG

 =
 F

u
ll
-T

h
ic

k
n
es

s 
Sk

in
 G

ra
ft

; 
G

D
S 

=
 G

ra
ft

 D
o
n
o
r 

Si
te

; 
; 

K
A

 =
 K

er
at

o
ac

an
th

o
m

a;
 K

A
SP

 =
 K

er
at

o
ac

an
th

o
m

at
o
u
s 

at
yp

ic
al

 s
q

u
am

o
u
s 

p
ro

li
fe

ra
ti

o
n
; 

L
=
 L

ef
t;

 N
/A

=
 d

at
a 

n
o
t 

av
ai

la
b
le

 L
M

 =
 l

en
ti

go
 m

al
ig

n
a;

  
M

 =
 M

al
e;

 M
M

 =
 M

al
ig

n
an

t 
M

el
an

o
m

a;
 M

M
S 

=
 M

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Review | Dermatol Pract Concept. 2022;12(4):e2022193 7

Table 2. Clinical findings of primary tumor in 34 patients diagnosed with eruptive squamous cell 
carcinomas/squamous atypia following skin surgery.

Findings

Number of primary skin cancers excised 37

Patients with one primary skin cancer 32 (94.12%)

Patients with two primary skin cancer 2 (5.88%)

Sex

Male 18 (52.94%)

Female 16 (47.06%)

Mean Age ± SD 68.94± 13.06 (39-95)

Cutaneous site involved

Head and neck 5 (13.51%)

Upper limbs 12 (32.43%)

Lower limbs 19 (51.35%)

Chest 1 (2.70%)

Histopathology

Squamous Cell Carcinoma 25 (67.56%)

Keratoacanthoma 5 (13.51%)

Melanoma 3 (8.12%)

Basal cell carcinoma 2 (5.41%)

Actinic Keratosis 1 (2.70%)

Lentigo maligna 1 (2.70%)

Treatment performed

Excision 6 (16.22%)

Excision plus Split-Thickness Skin Graft 12 (32.43%)

Mohs Micrographic Surgery 10 (27.03%)

Mohs Micrographic Surgery plus Split-Thickness Skin Graft 5 (13.51%)

Courettage plus electrodesiccation 2 (5.41%)

Amputation plus Split-Thickness Skin Graft 1 (2.70%)

Excision plus Full-Thickness Skin Graft 1 (2.70%)

Table 3. Main features of eruptive squamous cell carcinomas/squamous atypia following skin surgery.

Features

Number of primary skin cancers excised 37

Patients with one primary skin cancer 32 (94.12%)

Patients with two primary skin cancers 2 (5.88%)

Time onset after surgery median weeks 6 (2-960)

Cutaneous site involved by eruptive squamous cell carcinomas/squamous atypia

Cutaneous site affected by primary tumor treated with Mohs micrographic surgery 14 (37.84%)

Cutaneous site affected by primary tumor treated with simple excision. 6 (16.22%)

Cutaneous site affected by primary tumor treated with split-thickness skin graft 4 (10.81%)

Cutaneous site affected by primary tumor treated with courettage plus electrodesiccation 2 (5.41%)

Graft donor site 8 (21.61%)

Cutaneous site affected by primary tumor treated with excision and graft donor site 3 (8.11%)

Cutaneous site affected by eruptive squamous cell carcinomas/squamous atypia

Head and neck 3 (8.11%)

Upper limbs 10 (27,03%)

Table 3 continues



8 Review | Dermatol Pract Concept. 2022;12(4):e2022193

(70.27%), the graft donor site (GDS) or both. All primary 

tumors in our series were completely excised, with free 

margins on histological examination. In our sample, cuta-

neous STSG was harvested from the lateral thigh in almost 

all patients and was therefore considered the only cutane-

ous donor site affected.

ESCC were histologically represented by CSCC and ker-

atoacanthomas (KA) in 91.9% of cases while in 3 patients 

was not performed histopathological examination. The same 

histological diagnosis between the primary skin cancer and 

the ESCC was found in 50% of cases and eruptive KAs or 

CSCCs also appeared after excision of lentigo maligna or 

melanoma.

The surgical treatment of ESCC is extremely varied 

( Table 3). However, simple fusiform excision and MMS 

were the most used surgical techniques, comprising 62.16% 

of cases. Medical therapy was associated with surgery in 

7/34 cases while two patients were treated with isotretinoin  

40 mg/die without surgery and 1 patient was treated with in-

tralesional 5-fluorouracil plus acitretin 20 mg daily (Table 3). 

Features

Lower limbs 11 (37.84%)

Donor site affected by eruptive squamous cell carcinomas/squamous atypia

Lower limbs 13 (35.14%)

Histopathology of eruptive squamous cell carcinomas/squamous atypia

Squamous cell carcinoma 18 (48.65%)

Keratoacanthoma 14 (37.84%)

Marjolin Ulcer 1 (2.70%)

Keratoacanthomatous atypical squamous proliferation 1 (2.70%)

Not performed histopathological examination 3 (8.11%)

Concordance between histological diagnosis of primary tumor and and eruptive squamous cell carcinomas/squamous 
atypia

yes 17 (50.00%)

no 17 (50.00%)

Treatment performed

Surgery without medical treatment

Excision 13 (38.24%)

Excision plus flap 2 (5.88%)

Mohs Micrographic Surgery 10 (29.42%)

Courettage plus electrodesiccation 1 (2.94%)

Surgery associated with medical treatment

Excision plus acitretin 25 mg/die 1 (2.94%)

Excision plus acitretin 25 mg/daily and intralesional methotrexate 10 mg/weekly 1 (2.94%)

Excision plus split-thickness skin sraft and acitretin 25 mg/die 1 (2.94%)

Mohs micrographic surgery plus split-thickness skin graft and acitretin 25 mg/die 1 (2.94%)

Mohs micrographic surgery plus isotretinoin 40 mg/die 1 (2.94%)

Courettage plus electrodesiccation plus imiquimod cream application 1 (2.94%)

Courettage plus electrodesiccation isotretinoin 40 mg/die 1 (2.94%)

Medical treatment without surgery

Isotretinoin 40 mg/die without surgery 1 (2.94%)

Intralesional 5-fluorouracil plus acitretin 1 (2.94%)

Recurrences

Yes 15 (40.54%)

No 17 (45.95%)

Not available 5 (13.51%)

Table 3. Main features of eruptive squamous cell carcinomas/squamous atypia following skin 
surgery. (continued)



Review | Dermatol Pract Concept. 2022;12(4):e2022193 9

Of note, the paper from Que et al describe 30 cases of ESCC, 

but only one case is clearly and without doubts associated to 

a previous skin surgery and was added to our review [19].

The treatment was effective without recurrences in 17/37 

cases; these patients were treated with surgery alone in 13 

cases, combined surgical and medical treatment in 2 cases 

and with medical therapy in two cases. Isotretinoin 40 mg/

die resulted effective alone and in combination with Mohs 

surgery [7]. Surgery combined with acitretin (25 mg/daily) 

plus intralesional methotrexate 10 mg/weekly was adminis-

tered to the first our patient, favoring a complete resolution 

without recurrences (Figure 1).

Recurrences of ESCC were reported in 15/37 cases (10 

treated with surgery alone and 5 treated with combined med-

ical and surgical therapy). All 15 cases with recurrences were 

treated with a combination of surgery and medical therapy. 

Patients showed a complete resolution of ESCC recurrences 

at follow-up in 6/15 cases (40%). The following therapies 

proved effective on recurrences: 1 to 2 mL in intralesional 

administration of 50 mg/mL 5-fluorouracil (FU)  [5,19]; 

acitretin (25 mg/day); combined intralesional 5-FU and 

methotrexate to reduce the toxicity of any single agent [5]; 

isotretinoin 40mg/die [7]; oral acitretin (20 to 25 mg/day) 

[10,15]; lastly our second patient was treated with surgery 

plus 25 mg/daily acitretin (Figure 2). In 5/34 cases data on 

recurrences were not available in the papers (Table 1).

Finally, 2/34 patients died, due to lung cancer in one case 

and CSSC metastases in 1 of our patients, who was also af-

fected by chronic lymphatic leukemia [5].

Conclusions

The pathogenesis of ESCC is not clarified and is currently a 

matter of debate [18-23].

Local appearance of ESCC could be referred to residual 

cancer tissue following the excision of the primary tumor 

[21,22]. However, eruptive NMSC in skin graft donor sites 

have no local relation to the original tumor site, even if tu-

mor cells could theoretically spread by direct contact (if the 

same needle was used to infiltrate the tumor and donor site) 

or systemically (via the blood or lymphatic vessels). Moreover, 

ESCC different from primary tumor excised, such as KAs after 

lentigo maligna or melanoma, have been reported [6,7,11,16].

The patient immune system must also be taken into ac-

count. Immunodeficiency induced by drugs or other diseases, 

such as hematologic disorders, may explain the propensity 

for the development of cancer, inducing a generalized ‘field 

of cancerization’ that can induce a Koebner phenomenon 

and the development of new cutaneous cancers in the site of 

surgery [17,21-23].

The presence of a chronic lymphatic leukemia may have 

been a predisposing factor in one of our patients for the 

Figure 1. (A) Six weeks after local excision and repair with an STSG, 

6 x 4.5 cm in diameter, of large squamous cell carcinomas of the 

right leg, three keratotic nodules appeared, two closes to the surgical 

wound and one a few centimeters far from it. (B) Histopathologi-

cal examination eruptive keratotic nodules: proliferation of atypical 

keratinocytes extends into the reticular dermis. The nuclei are large, 

hyperchromatic, and pleomorphic, and the cytoplasm is eosinophilic 

(10 X H&E). (C) Complete healing after surgery and medical therapy 

with oral acitretin 25 mg/daily and intralesional methotrexate 10 mg/

weekly after 8 months of treatment. No recurrences were observed at 

2-year follow-up and regional lymph nodes were free from metastases.

development of ESCC soon after surgery, as well as a neg-

ative prognostic factor for the development of distant me-

tastases, leading to exitus. Interestingly, the only patient that 

developed distant metastases after the development of ESCC 

had the primary CSSC located on the scalp, while none of 

the cases of ESCC reported in the Literature localized both 

on upper or lower extremities had a poor prognosis. This 

distinction can be important and to confirm this statement 

in the paper of Que et al reporting 30 cases of eruptive squa-

mous atypia, without the specification if the onset was spon-

taneous, after surgery or other treatments o traumas, all the 



10 Review | Dermatol Pract Concept. 2022;12(4):e2022193

ESCC after skin surgery. First of all, the extremities (lower 

and upper limbs) represent the cutaneous site with the high-

est risk, representing 82.35% of the cases in the literature.

The second point concerns the time of onset of ESCC, 

which is wide, ranging from 2 to 960 weeks. The median 

time to onset of ESCC is approximately 6 weeks, and in 

28/34 (82.35%) of cases reported in the literature they ap-

peared within 16 weeks from the primary cutaneous surgery.

The third point is that primary CSCC were completely 

excised with free margins on histologic examination in all 

cases of the literature, and therefore the ESCC reported were 

not considered recurrences. This concept has important legal 

implications.

The fourth point is that any surgical technique, includ-

ing classic fusiform excision, excision plus STSG, MMS and 

subsequent reconstruction with or without STSG, involves a 

risk to promote ESCC, which can surprisingly affect both the 

area affected by the primary tumor and the graft donor site. 

patients had a localization on upper or lower extremities or 

both and none developed metastases [19].

According to Nwabudike LC et al, ESCC could also be 

a perfect example of locus minoris resistentae as described 

by Ruocco [20,24]. An immunocompromised district can 

be defined as a regional destabilization of the neuro-immu-

no-cutaneous system, and surgical procedures, as well as 

the scars resulting from them, impair both lymph circula-

tion and neuro-immune crosstalk in the traumatized area 

[24,25]. Gambichler and colleagues demonstrated in two pa-

tients affected by “koebnerized” CSCC that the wound heal-

ing processes can induce a proliferative stimulus and growth 

factors release, which could be able to promote the growth 

of pre-neoplastic keratinocytes and cancer formation, on the 

basis of pre-existing altered epigenetic pathways and cell cy-

cle dysregulation [18].

The results of this review highlight five red flags that cli-

nicians should consider in the diagnosis and management of 

Figure 2. (A) Split thickness skin graft (STSG) on the scalp, 5 x 3.5 cm in diameter, after simple excision 

of ulcerated cutaneous squamous cell carcinomas (SCC) of the right occipital area of the scalp. (B) Thirty 

days after the removal of the stitches, on the site of the STSG, an erythematous firm papule appeared.  

(C) The papule quickly enlarged to form a nodule and then multiple keratoacanthoma-like lesions 

 appeared. (D) Initial good response to surgery and acitretin 25 mg/die therapy, with only 1 residual nod-

ule in the occipital area, which was surgically removed. Three months after the last surgery treatment, 

SCC metastases to the latero-cervical lymph nodes were detected both clinically and with ultrasound 

examination. The patient died 6 months later.



Review | Dermatol Pract Concept. 2022;12(4):e2022193 11

skin cancer excision. J Am Acad Dermatol. 2004;50(5):753-758. 

DOI: 10.1016/j.jaad.2003.11.065. PMID: 15097960.

8. Hussain A, Ekwobi C, Watson S. Metastatic implantation 

squamous cell carcinoma in a split-thickness skin graft donor 

site. J Plast Reconstr Aesthet Surg. 2011;64(5):690-692. DOI: 

10.1016/j.bjps.2010.06.004. PMID: 20584636.

9. Ponnuvelu G, Ng MF, Connolly CM, Hogg FJ, Naasan A. Inflam-

mation to skin malignancy, time to rethink the link: SCC in skin 

graft donor sites. Surgeon. 2011;9(3):168-169. DOI: 10.1016/j.

surge.2010.08.006.

10. Lee S, Coutts I, Ryan A, Stavrakoglou A. Keratoacanthoma for-

mation after skin grafting: A brief report and pathophysiological 

hypothesis. Australas J Dermatol. 2017;58(3):e117-e119. DOI: 

10.1111/ajd.12501. PMID: 27273800.

11. Saltvig I, Matzen SH. Marjolin’s ulcer in a 20 years old split 

thickness skin graft on the knee-A case report. Int J Surg Case 

Rep. 2018;42:102-103. DOI: 10.1016/j.ijscr.2017.11.059. 

PMID: 29241101. PMCID: PMC5730427.

12. Kimyai-Asadi A, Shaffer C, Levine VJ, Jih MH. Keratoacan-

thoma arising from an excisional surgery scar. J Drugs Dermatol. 

2004;3(2):193-194. PMID: 15098978.

13. Nagase K, Suzuki Y, Misago N, Narisawa Y. Acute development 

of keratoacanthoma at a full-thickness skin graft donor site 

shortly after surgery. J Dermatol. 2016;43(10):1232-1233. DOI: 

10.1111/1346-8138.13368. PMID: 27027399.

14. Marous M, Brady K. Cutaneous Squamous Cell Carcinoma 

Arising in a Split Thickness Skin Graft Donor Site in a Pa-

tient With Systemic Lupus Erythematosus. Dermatol Surg. 

2021;47(8):1106-1107. DOI: 10.1097/DSS.0000000000002955. 

PMID: 33731573.

15. Vergara A, Isarría MJ, Domínguez JD, Gamo R, Rodríguez Per-

alto JL, Guerra A. Multiple and relapsing keratoacanthomas 

developing at the edge of the skin grafts site after surgery and 

after radiotherapy. Dermatol Surg. 2007;33(8):994-996. DOI: 

10.1111/j.1524-4725.2007.33207.x.

16. L. Kearney, R.T. Dolan, N.A. Parfrey, E.J. Kelly. Squamous cell 

carcinoma arising in a skin graft donor site following mel-

anoma extirpation at a distant site: A case report and review 

of the literature. JPRAS Open. 2015;3:35-38. DOI: 10.1016/j.

jpra.2015.02.002

17. Morritt, D.G., Khandwala, A.R. The development of squamous 

cell carcinomas in split-thickness skin graft donor sites.  Eur J 

Plast Surg. 32013;6:377–380. DOI:10.1007/s00238-012-0786-z.

18. Gambichler T, Rüddel I, Hessam S, Bechara FG, Stockfleth E, 

Schmitz L. Altered epigenetic pathways and cell cycle dysregu-

lation in healthy appearing skin of patients with koebnerized 

squamous cell carcinomas following skin surgery. J Eur Acad 

Dermatol Venereol. 2018;32(9):1485-1491. DOI: 10.1111/

jdv.14887. PMID: 29478287.

19. Que SKT, Compton LA, Schmults CD. Eruptive squamous 

atypia (also known as eruptive keratoacanthoma): Definition of 

the disease entity and successful management via intralesional 

5-fluorouracil. J Am Acad Dermatol. 2019;81:111-122. DOI: 

10.1016/j.jaad.2018.10.014. PMID: 31103317.

20. Nwabudike LC, Tatu AL. Reply to Gambichler T et al.: Altered 

epigenetic pathways and cell cycle dysregulation in healthy ap-

pearing skin of patients with koebnerized squamous cell carci-

nomas following skin surgery. J Eur Acad Dermatol Venereol. 

2019;33(1):e3-e4. DOI: 10.1111/jdv.15084. PMID: 29797668.

21. Slaughter DP, Southwick HW, Smejkal W. “Field canceri-

sation” in oral stratified epithelium. Clinical implications 

Large longitudinal surgery studies are necessary to evaluate 

the risk assessment of surgical technique and ESCC.

The fifth point is that the treatment of ESCC includes 

medical treatments, surgery or combined surgical and medi-

cal treatments. Que et al reported a 67% resolution rate us-

ing intralesional 5-fluorouracil for eruptive squamous atypia 

of the upper and lower limbs. However, 5-fluorouracil is 

chemotherapeutic agent that can be used only in hospital, it 

is off-label and much more difficult to obtain in Italy than 

intralesional methotrexate or oral acitretin. Moreover, Que 

et al have specified that it can be used only for lesions smaller 

than 15 mm, while over 15 mm of diameter, surgery is still 

considered the best choice. According to our review, ESCC 

recurrences are a medical challenge and have been treated 

combining surgical and medical treatment, with complete 

resolution in about one third of patients [5,7,10,15]. When 

using a nonsurgical treatment modality for ESCC, the con-

cern of missing an aggressive CSSC is an important issue, 

that must be kept in mind, especially in sites different from 

the upper and lower extremities. 

In conclusion, even though the pathogenesis remains 

unclear, this review highlights 5 red flags which could help 

support clinicians in the diagnosis and management of ESCC 

after skin surgery.

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