10.5826/dpc.1204a193
Multiple eruptive cutaneous non-melanoma skin cancers(NMSCs) have been reported to arise at the sites of skin surgery, including the area affected by the primary tumour and split thickness skin graft(STSG) donor and recipient sites. The aim of this study is to make a critical revision of the literature, analysing the clinical, histological features and outcomes of eruptive NMSCs after cutaneous surgery. Up to August 2021, according to our systematic review of the literature, we have collected 18 published articles and a total of 33 patients, including our two cases. 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 82.35% of the cases in the literature; (ii) the median time to onset of eruptive NMSCs that is approximately 6 weeks; (iii) primary NMSCs were completely excised with free margins on histologic examination in all cases of the literature, and therefore the eruptive NMSCs reported could not be considered recurrences; (iv)  any surgical technique involves a risk to promote eruptive NMSCs; (v) treatment of eruptive NMSCs includes surgery or combined surgical and medical treatment. However, eruptive NMSCs recurrences are a real medical challenge and have always been treated combining surgical and medical treatment, with complete resolution in about one third of patients.  In conclusion, even though the pathogenesis remains unclear, this review highlights 5 red flags which could support clinicians in the diagnosis and management of eruptive of NMSCs after skin surgery.
text/xml
2160-9381
2261
en
Francesco Savoia
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
squamous cell carcinoma after Mohs micrographic surgery.
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
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Review
2022-10-31
2021-12-19
2022-10-31
2022-12-02
e2022193
Dermatol Pract Concept
Multiple eruptive cutaneous non-melanoma skin cancers(NMSCs) have been reported to arise at the sites of skin surgery, including the area affected by the primary tumour and split thickness skin graft(STSG) donor and recipient sites. The aim of this study is to make a critical revision of the literature, analysing the clinical, histological features and outcomes of eruptive NMSCs after cutaneous surgery. Up to August 2021, according to our systematic review of the literature, we have collected 18 published articles and a total of 33 patients, including our two cases. 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 82.35% of the cases in the literature; (ii) the median time to onset of eruptive NMSCs that is approximately 6 weeks; (iii) primary NMSCs were completely excised with free margins on histologic examination in all cases of the literature, and therefore the eruptive NMSCs reported could not be considered recurrences; (iv)  any surgical technique involves a risk to promote eruptive NMSCs; (v) treatment of eruptive NMSCs includes surgery or combined surgical and medical treatment. However, eruptive NMSCs recurrences are a real medical challenge and have always been treated combining surgical and medical treatment, with complete resolution in about one third of patients.  In conclusion, even though the pathogenesis remains unclear, this review highlights 5 red flags which could support clinicians in the diagnosis and management of eruptive of NMSCs after skin surgery.
Francesco Savoia
2022/10/31
10.5826/dpc.1204a193
e2022193
Skin Cancer Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
2160-9381
squamous cell carcinoma after Mohs micrographic surgery.
en
e2022193
Baroni A, Buommino E, Piccolo V, Chessa MA, Russo T, Cozza V, Ruocco V. Alterations of skin innate immunity in lymphedematous limbs: Correlations with opportunistic diseases. Clin Dermatol. 2014; 32 (5): 592-8. doi: 10.1016/j.clindermatol.2014.04.006. PMID: 25160100.
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
https://dpcj.org/index.php/dpc/article/download/2261/1813
  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




  ABSTRACT             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




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




Introduction                                                      treatment and histopathology findings of primary cutane-
                                                                  ous skin cancer of all the patients included in this review.
Eruptive cutaneous squamous cell carcinomas (ESCC), erup-         Furthermore, we reported the time lapse from the primary
tive squamous atypia (ESA) and eruptive keratoacanthomas          surgery to the onset of ESCC, clinical and histological fea-
(EKA) are different terms used to describe the occurrence         tures, management, recurrences and outcome. In addition,
of multiple cutaneous squamous neoplasms occurring after          we describe here our personal experience with two patients
skin surgery, laser treatment, traumas, such as tattoos, local    visited at the Skin Cancer Unit of Bologna between January
or systemic medical therapies. In this paper, we decided to       2012 and August 2021, who developed ESCC after cutane-
use only the term ESCC.                                           ous squamous cell carcinoma (CSCC) excision and recon-
    ESCC have been reported to arise at the sites of skin sur-    struction with STSG.
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
                                                                  Results
our opinion is still a challenge.                                 Up to August 2021, according to our systematic review of
                                                                  the literature, we found only 19 published articles (Table 1).
Objectives                                                           A total of 34 ascertained patients, including our two
                                                                  cases, were included in this study, with a sex ratio F/M = 0.88,
The aim of our study is to report 2 additional cases of ESCC      a mean age = 68.94 years (standard deviation [SD] = 13.6).
after skin surgery and make a critical revision of the liter-        The main clinical features of the 34 patients diagnosed
ature, analyzing the clinical, histological features and out-     with ESCC after surgery are reported in Table 2.
comes of ESCC after cutaneous surgery [18]. An overview of           The extremities (upper and lower limbs) were the sites
this rarely reported condition is provided, in order to raise     most frequently involved by primary tumors, representing
awareness of this clinical entity and of the treatment options.   83.78% of cases in our sample. The second most involved
                                                                  site was the head, with 13.51% of cases. Regarding our two

Methods                                                           patients, the first had a CSCC of the head and the second a
                                                                  cutaneous SCC of the right leg.
We identified studies indexed in PubMed from its inception           Histological examination of the primary skin cancer was
to June 31, 2021. All papers reported in the present study        consistent with a CSSC in 30/37 cases (81.08%), while basal
involved human clinical studies, including case reports, case     cell carcinoma, actinic keratosis, malignant melanoma and
series and reviews. Search parameters included the terms          lentigo maligna were detected in 7 cases (18.92%).
‘‘Keratoacanthomas after cutaneous surgery”, “Keratoacan-            Different surgical techniques were used for the exci-
thomas AND STSG”, ‘‘Cutaneous squamous cell carcinomas            sion of the primary skin tumors, although classic fusiform
AND STSG”, “Cutaneous squamous cell carcinomas after              excision, excision plus STSG, MMS and subsequent recon-
cutaneous surgery’’, “squamous cell carcinoma after Mohs          struction with or without STSG were the most commonly
Micrographic surgery (MMS)”, “eruptive squamous cell              performed procedures, in 32/37 cases (86.49%).
carcinoma and surgery”, “eruptive squamous atypia and                The main clinical features of the ESCC after skin surgery
surgery”, “eruptive keratoacanthomas and surgery”, “koeb-         are reported in Table 3. The median time to the onset is ap-
nerized cutaneous squamous cell carcinoma”.                       proximately 6 weeks, and in 28/34 of the patients (82.35%)
    A subsequent review of the relative bibliographies            it occurred within 16 weeks from the primary surgery.
aimed to identify any undetected reports. We collected sex,          Surprisingly, ESCC occurred in the area of the skin
age, involved cutaneous area, surgical procedure, medical         affected by the primary tumor in 26/37 of the cases
                                                                  ­



2                                                                            Review | Dermatol Pract Concept. 2022;12(4):e2022193
                                                                                      Table 1. Eruptive non-melanoma skin cancers following skin surgery: literature review and our cases.
                                                                           Patients                               First Skin Lesion                                                       Eruptive NMSC
                                                                                                                                                          Time
                                                                                                                                                          Onset
                                                                                                           Surgery                                        after
                                                       Study and                 Age,       Area          procedure       Medical         Histopathology SuRgery     Area      Histopathology     Surgical    Medical
                                                          Year         N. Case   Sex      involved        performed      Treatment            findings   (Weeks)   involved        findings      Treatment   Treatment       Recurrence
                                                       Neilson         1         59, M     dorsum of      Ex + STSG         None              SCCs         12        GDS            SCC             Ex          None             No
                                                       et al, 1988                       his right ring
                                                       [1]                               finger (upper
                                                                                             limbs)
                                                       Clark et al.,   1         73, F      B Legs    Ex + STSG             None              SCCs         4       ExS + GDS       KASP          Ex + STSG    Acitretin          Yes
                                                       2015                              (lower limb)                                                                                                         25 mg/d
                                                       Juhász and      1         82, F      R Shin         MMS +         3 months of           KA          20      MMS site         KA             MMS          None             No




Review | Dermatol Pract Concept. 2022;12(4):e2022193
                                                       Marmur,                           (lower limb)      STSG       topical mupirocin
                                                       2014                                                              + warm 2%
                                                                                                                       milk compresses
                                                                                                                        for loss of the
                                                                                                                         graft, wound
                                                                                                                          dehiscence,
                                                                                                                        and persistent
                                                                                                                          ulceration
                                                       Bangash         5    1    81, F   L Wrist and        MMS             None              SCC          4       MMS site         SCC            MMS          None             No
                                                       et al, 2009                       Hand (upper
                                                                                            limb)
                                                                            2    63, M     L Hand           MMS             None              SCC          8       MMS site         SCC            MMS          None             No
                                                                                         (upper limb)
                                                                            3    54, M    L occipital        Ex             None              SCC          7         ExS          SCC with         MMS          None             No
                                                                                         Ridge (head)                                                                          features of KA
                                                                            4    58, M Left leg and         MMS             None            SCC; SCC       6       MMS site;     SCC; SCC          MMS          None           Yes, Yes
                                                                                         R Elbow                                                                   MMS site
                                                                                       (upper and
                                                                                       lower limb)
                                                                            5    55, F     L Hand          MMS +            None              SCC          72      MMS site         SCC           MMS +      Acitretin 10        Yes
                                                                                         (upper limb)      STSG                                                                                   STSG         mg/die

                                                                                                                                                                                                                          Table 1 continues




3
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                                                                              Table 1. Eruptive non-melanoma skin cancers following skin surgery: literature review and our cases. (continued)
                                                                         Patients                              First Skin Lesion                                                      Eruptive NMSC
                                                                                                                                                      Time
                                                                                                                                                      Onset
                                                                                                        Surgery                                       after
                                                       Study and                Age,       Area        procedure       Medical        Histopathology SuRgery     Area      Histopathology     Surgical        Medical
                                                          Year       N. Case    Sex      involved      performed      Treatment           findings   (Weeks)   involved        findings      Treatment       Treatment      Recurrence
                                                       Hadley        3    1    67, M      Forearm        MMS             None             SCC          16      MMS site         KA               Ex            None            Yes
                                                       et al, 2009                      (upper limb)
                                                                          2     70, F     Forearm         Ex             None             SCC          12        ExS            KA             MMS             None            Yes
                                                                                        (upper limb)
                                                                          3     88, F      B Legs       S + Co +         None              KA          2       Treatment        KA            Co + ED          None            Yes
                                                                                        (lower limb)       ED                                                     Site
                                                       Haik et al,   1         64, M Left Big Toe      A + STSG          None             MM           6         GDS            SCC              Ex            None            No
                                                       2008                          (lower limb)
                                                       Goldberg      6    1    72, M      L Leg and      MMS             None             SSCs         6       MMS site         KA             MMS             None            Yes
                                                       et al, 2004                          Finger
                                                                                        (lower limb)
                                                                          2    69, M     L Forearm.      MMS             None             SCC          4       MMS site         KA             MMS             None            No
                                                                                        (upper limb)
                                                                          3     74, F      R Leg         MMS        Isotretinoin 40       SCC          3       MMS site         KA            Co + ED       Isotretinoin       Yes
                                                                                        (lower limb)               mg/d for 30 days                                                                           40 mg/d
                                                                          4    79, M     R Forearm       MMS             None              LM          4       MMS site         KA               Ex            None            No
                                                                                        (upper limb)
                                                                          5    71, M       R Thigh       MMS             None             SBCC         2       MMS site         KA             None          Isotretinoin      No
                                                                                        (lower limb)                                                                                                        (40 mg/d) for
                                                                                                                                                                                                               1 month.
                                                                          6    75, M    R Forehead      Co + ED          None             SCC          4       Treatment        KA             MMS           Isotretinoin      No
                                                                                          (head)                                                                  Site                                      (40 mg/d) for
                                                                                                                                                                                                               1 month.
                                                       Hussain       1         52, M      R Hand     Ex + STSG           None             SCC          8         GDS            SCC              Ex +          None            No
                                                       et al, 2010                      (upper limb)                                                                                        reconstructed
                                                                                                                                                                                               with an
                                                                                                                                                                                            islanded VeY
                                                                                                                                                                                            advancement
                                                                                                                                                                                                 flap




Review | Dermatol Pract Concept. 2022;12(4):e2022193
                                                       Ponnuvelu      2   1   58, M Left parietal    Ex + STSG   None   nodulocystic    2      GDS           SCC             Ex         None               N/A
                                                       et al, 2011                  scalp (head)                           BCC
                                                                          2   88, F      left shin Ex + STSG     None       KA          5      GDS           SCC          Ex + flap     None               No
                                                                                      (lower limb)
                                                       Lee et al,     1       95, F      R Shin    Ex + STSG     None       KA         20    Exs + GDS        KA          Co + ED     Imiquimod            Yes
                                                       2017                           (lower limb)                                                                                     5% cream
                                                                                                                                                                                      application
                                                       Saltivig and   1       78, F      L Knee    Ex + STSG     None      MM          960     STSG      Marjolin Ulcer      Ex          N/A               N/A
                                                       Matzen,                        (lower limb)                                            primary
                                                       2018                                                                                   excision
                                                                                                                                                site
                                                       Kimyai-        1       76, M     R Hand          Ex       None      SCC          8       ExS           KA             Ex         None               No
                                                       Asadi et al,                   (upper limb)
                                                       2004




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                                                       Negase         1       78, F   Nose (head)      FTSG      None       AK          3      STSG           KA             Ex         None               N/A
                                                       et al, 2016                                                                            primary
                                                                                                                                              excision
                                                                                                                                                site
                                                       Marcus and     1       39, F      L Thigh      MMS +      None      SCC         12      GDS           SCC           MMS          None               N/A
                                                       Brady, 2021                    (lower limb)    STSG
                                                       Vergara        1       80, F      R Leg     Ex + STSG     None       KA         96      GDS            KA             Ex         None               Yes
                                                       et al, 2007                    (lower limb)
                                                       L. Kearney     1       48, M     R Chest      Ex + STSG   None      MM           6      GDS           SCC             Ex         None               N/A
                                                       et al, 2015
                                                       Morritt and    1       82, F L Leg (lower Ex + STSG       None      SCCs        117   ExS + GDS       SCCs            Ex         None               Yes
                                                       Khandwala,                      limb)
                                                       2012
                                                       Gambichler     2   1   49 F    Leg (lower      MMS +      None      SCC          3      MMS           SCC             Ex         None               Yes
                                                       2021                             limb)         STSG
                                                                          2   60 M    Back of the     MMS +      None      SCC         3       MMS           SCC             Ex         None               Yes
                                                                                      hand (upper     STSG
                                                                                         limb)

                                                                                                                                                                                                    Table 1 continues




5
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                                                                                 Table 1. Eruptive non-melanoma skin cancers following skin surgery: literature review and our cases. (continued)
                                                                           Patients                                First Skin Lesion                                                                 Eruptive NMSC
                                                                                                                                                            Time
                                                                                                                                                            Onset
                                                                                                           Surgery                                          after
                                                        Study and                  Age,       Area        procedure         Medical         Histopathology SuRgery            Area       Histopathology        Surgical        Medical
                                                           Year       N. Case      Sex      involved      performed        Treatment            findings   (Weeks)          involved         findings         Treatment       Treatment      Recurrence
                                                       Que et al       1           62M       R and L          Ex              None                3 SCC           Not        Exs sites      Suspected           None         Intralesional        No
                                                       2019                                legs (Lower                                                          specified                    eruptive                       5-fluorouracil
                                                                                              limbs)                                                                                     squamous atypia                    plus acitretin
                                                       Chessa et al, 2       1     65,M     R occipital   Ex + STSG           None                 SCC              4         STSG             SCC                Ex         Acitretin 25        Yes
                                                       2021                                 area of the                                                                      primary                                           mg/die
                                                                                           scalp (head)                                                                      excision
                                                                                                                                                                               site
                                                                             2     80,F       R Leg     Ex + STSG             None                 SCC              6         STSG             SCC                Ex          acitretin 25        No
                                                                                           (lower limb)                                                                      primary                                        mg/daily and
                                                                                                                                                                             excision                                        intralesional
                                                                                                                                                                               site                                         methotrexate
                                                                                                                                                                                                                            10 mg/weekly

                                                       AK = Actinic Keratosis; A = Amputation; B = Bilateral; CEMP = Cutaneous extramedullary plasmacytomas; Co = Courettage; ED = Electrodesiccation; Ex = Excision; ExS = Excision Site; F = Female;
                                                       FTSG = Full-Thickness Skin Graft; GDS = Graft Donor Site; ; KA = Keratoacanthoma; KASP = Keratoacanthomatous atypical squamous proliferation; L= Left; N/A= data not available LM = lentigo maligna;
                                                       M = Male; MM = Malignant Melanoma; MMS = Mohs Micrographic Surgery; MU = Marjolin Ulcer; N = Number of patients involved;
                                                       SCC = Squamous Cell Carcinoma; SG = Skin Graft; SGS = Skin Graft Site; Sh = Shave; STSG = Split-Thickness Skin Graft.
                                                       R= Right; SBCC = superficial basal cell carcinoma;




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



Review | Dermatol Pract Concept. 2022;12(4):e2022193                                                                       7
       Table 3. Main features of eruptive squamous cell carcinomas/squamous atypia following skin
                                            surgery. (continued)
                                                  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%)




(70.27%), the graft donor site (GDS) or both. All primary           the ESCC was found in 50% of cases and eruptive KAs or
tumors in our series were completely excised, with free             CSCCs also appeared after excision of lentigo maligna or
margins on histological examination. In our sample, cuta-           melanoma.
neous STSG was harvested from the lateral thigh in almost              The surgical treatment of ESCC is extremely varied
all patients and was therefore considered the only cutane-          (­Table 3). However, simple fusiform excision and MMS
ous donor site affected.                                            were the most used surgical techniques, comprising 62.16%
    ESCC were histologically represented by CSCC and ker-           of cases. Medical therapy was associated with surgery in
atoacanthomas (KA) in 91.9% of cases while in 3 patients            7/34 cases while two patients were treated with isotretinoin
was not performed histopathological examination. The same           40 mg/die without surgery and 1 patient was treated with in-
histological diagnosis between the primary skin cancer and          tralesional 5-fluorouracil plus acitretin 20 mg daily (Table 3).



8                                                                               Review | Dermatol Pract Concept. 2022;12(4):e2022193
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].
                                                                  Figure 1. (A) Six weeks after local excision and repair with an STSG,
Conclusions                                                       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
The pathogenesis of ESCC is not clarified and is currently a      wound and one a few centimeters far from it. (B) Histopathologi-
matter of debate [18-23].                                         cal examination eruptive keratotic nodules: proliferation of atypical
                                                                  keratinocytes extends into the reticular dermis. The nuclei are large,
   Local appearance of ESCC could be referred to residual
                                                                  hyperchromatic, and pleomorphic, and the cytoplasm is eosinophilic
cancer tissue following the excision of the primary tumor         (10 X H&E). (C) Complete healing after surgery and medical therapy
[21,22]. However, eruptive NMSC in skin graft donor sites         with oral acitretin 25 mg/daily and intralesional methotrexate 10 mg/
have no local relation to the original tumor site, even if tu-    weekly after 8 months of treatment. No recurrences were observed at
mor cells could theoretically spread by direct contact (if the    2-year follow-up and regional lymph nodes were free from metastases.

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      development of ESCC soon after surgery, as well as a neg-
lentigo maligna or melanoma, have been reported [6,7,11,16].      ative prognostic factor for the development of distant me-
   The patient immune system must also be taken into ac-          tastases, leading to exitus. Interestingly, the only patient that
count. Immunodeficiency induced by drugs or other diseases,       developed distant metastases after the development of ESCC
such as hematologic disorders, may explain the propensity         had the primary CSSC located on the scalp, while none of
for the development of cancer, inducing a generalized ‘field      the cases of ESCC reported in the Literature localized both
of cancerization’ that can induce a Koebner phenomenon            on upper or lower extremities had a poor prognosis. This
and the development of new cutaneous cancers in the site of       distinction can be important and to confirm this statement
surgery [17,21-23].                                               in the paper of Que et al reporting 30 cases of eruptive squa-
   The presence of a chronic lymphatic leukemia may have          mous atypia, without the specification if the onset was spon-
been a predisposing factor in one of our patients for the         taneous, after surgery or other treatments o traumas, all the



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



patients had a localization on upper or lower extremities or             ESCC after skin surgery. First of all, the extremities (lower
both and none developed metastases [19].                                 and upper limbs) represent the cutaneous site with the high-
     According to Nwabudike LC et al, ESCC could also be                 est risk, representing 82.35% of the cases in the literature.
a perfect example of locus minoris resistentae as described                  The second point concerns the time of onset of ESCC,
by Ruocco [20,24]. An immunocompromised district can                     which is wide, ranging from 2 to 960 weeks. The median
be defined as a regional destabilization of the neuro-immu-              time to onset of ESCC is approximately 6 weeks, and in
no-cutaneous system, and surgical procedures, as well as                 28/34 (82.35%) of cases reported in the literature they ap-
the scars resulting from them, impair both lymph circula-                peared within 16 weeks from the primary cutaneous surgery.
tion and neuro-immune crosstalk in the traumatized area                      The third point is that primary CSCC were completely
[24,25]. Gambichler and colleagues demonstrated in two pa-               excised with free margins on histologic examination in all
tients affected by “koebnerized” CSCC that the wound heal-               cases of the literature, and therefore the ESCC reported were
ing processes can induce a proliferative stimulus and growth             not considered recurrences. This concept has important legal
factors release, which could be able to promote the growth               implications.
of pre-neoplastic keratinocytes and cancer formation, on the                 The fourth point is that any surgical technique, includ-
basis of pre-existing altered epigenetic pathways and cell cy-           ing classic fusiform excision, excision plus STSG, MMS and
cle dysregulation [18].                                                  subsequent reconstruction with or without STSG, involves a
     The results of this review highlight five red flags that cli-       risk to promote ESCC, which can surprisingly affect both the
nicians should consider in the diagnosis and management of               area affected by the primary tumor and the graft donor site.


10                                                                                    Review | Dermatol Pract Concept. 2022;12(4):e2022193
Large longitudinal surgery studies are necessary to evaluate                   skin cancer excision. J Am Acad Dermatol. 2004;50(5):753-758.
the risk assessment of surgical technique and ESCC.                            DOI: 10.1016/j.jaad.2003.11.065. PMID: 15097960.
                                                                          8.   Hussain A, Ekwobi C, Watson S. Metastatic implantation
    The fifth point is that the treatment of ESCC includes
                                                                               squamous cell carcinoma in a split-thickness skin graft donor
medical treatments, surgery or combined surgical and medi-
                                                                               site. J Plast Reconstr Aesthet Surg. 2011;64(5):690-692. DOI:
cal treatments. Que et al reported a 67% resolution rate us-                   10.1016/j.bjps.2010.06.004. PMID: 20584636.
ing intralesional 5-fluorouracil for eruptive squamous atypia             9.   Ponnuvelu G, Ng MF, Connolly CM, Hogg FJ, Naasan A. Inflam-
of the upper and lower limbs. However, 5-fluorouracil is                       mation to skin malignancy, time to rethink the link: SCC in skin
chemotherapeutic agent that can be used only in hospital, it                   graft donor sites. Surgeon. 2011;9(3):168-169. DOI: 10.1016/j.
                                                                               surge.2010.08.006.
is off-label and much more difficult to obtain in Italy than
                                                                         10.   Lee S, Coutts I, Ryan A, Stavrakoglou A. Keratoacanthoma for-
intralesional methotrexate or oral acitretin. Moreover, Que
                                                                               mation after skin grafting: A brief report and pathophysiological
et al have specified that it can be used only for lesions smaller              hypothesis. Australas J Dermatol. 2017;58(3):e117-e119. DOI:
than 15 mm, while over 15 mm of diameter, surgery is still                     10.1111/ajd.12501. PMID: 27273800.
considered the best choice. According to our review, ESCC                11.   Saltvig I, Matzen SH. Marjolin’s ulcer in a 20 years old split
recurrences are a medical challenge and have been treated                      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.
combining surgical and medical treatment, with complete
                                                                               PMID: 29241101. PMCID: PMC5730427.
resolution in about one third of patients [5,7,10,15]. When
                                                                         12.   Kimyai-Asadi A, Shaffer C, Levine VJ, Jih MH. Keratoacan-
using a nonsurgical treatment modality for ESCC, the con-                      thoma arising from an excisional surgery scar. J Drugs Dermatol.
cern of missing an aggressive CSSC is an important issue,                      2004;3(2):193-194. PMID: 15098978.
that must be kept in mind, especially in sites different from            13.   Nagase K, Suzuki Y, Misago N, Narisawa Y. Acute development
the upper and lower extremities.                                               of keratoacanthoma at a full-thickness skin graft donor site
                                                                               shortly after surgery. J Dermatol. 2016;43(10):1232-1233. DOI:
    In conclusion, even though the pathogenesis remains
                                                                               10.1111/1346-8138.13368. PMID: 27027399.
unclear, this review highlights 5 red flags which could help
                                                                         14.   Marous M, Brady K. Cutaneous Squamous Cell Carcinoma
support clinicians in the diagnosis and management of ESCC                     Arising in a Split Thickness Skin Graft Donor Site in a Pa-
after skin surgery.                                                            tient With Systemic Lupus Erythematosus. Dermatol Surg.
                                                                               2021;47(8):1106-1107. DOI: 10.1097/DSS.0000000000002955.
                                                                               PMID: 33731573.
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