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.
Keywords : Eruptive non-melanoma skin cancers, keratoacanthomas after cutaneous surgery, keratoacanthomas AND split-thickness skin graft, cutaneous squamous cell carcinomas AND split-thickness skin graft, cutaneous squamous cell carcinomas after cutaneous surgery, squamous cell carcinoma after Mohs micrographic surgery.
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 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 surgery, 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.
The aim of our 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 [ 18 ] . An overview of this rarely reported condition is provided, in order to raise awareness of this clinical entity and of the treatment options.
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”, “Keratoacanthomas 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”, “koebnerized 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 cutaneous 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 features, 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 cutaneous squamous cell carcinoma (CSCC) excision and reconstruction with STSG.
Up to August 2021, according to our systematic review of the literature, we found only 19 published articles ( Table 1 ).
Eruptive non-melanoma skin cancers following skin surgery: literature review and our cases.
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 .
Clinical findings of primary tumor in 34 patients diagnosed with eruptive squamous cell carcinomas/squamous atypia following skin surgery.
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 excision of the primary skin tumors, although classic fusiform excision, excision plus STSG, MMS and subsequent reconstruction 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 approximately 6 weeks, and in 28/34 of the patients (82.35%) it occurred within 16 weeks from the primary surgery.
Main features of eruptive squamous cell carcinomas/squamous atypia following skin surgery.
Surprisingly, ESCC occurred in the area of the skin affected by the primary tumor in 26/37 of the cases (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, cutaneous STSG was harvested from the lateral thigh in almost all patients and was therefore considered the only cutaneous donor site affected.
ESCC were histologically represented by CSCC and keratoacanthomas (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 intralesional 5-fluorouracil plus acitretin 20 mg daily ( Table 3 ). 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 administered to the first our patient, favoring a complete resolution without recurrences ( Figure 1 ).
Figure 1 .
(A) Six weeks after local excision and repair with an STSG, 6 × 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) Histopathological 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.
Recurrences of ESCC were reported in 15/37 cases (10 treated with surgery alone and 5 treated with combined medical 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 ).
Figure 2 .
(A) Split thickness skin graft (STSG) on the scalp, 5 × 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 nodule 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.
Finally, 2/34 patients died, due to lung cancer in one case and CSSC metastases in 1 of our patients, who was also affected by chronic lymphatic leukemia [ 5 ] .
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 tumor 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 account. 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 development of ESCC soon after surgery, as well as a negative prognostic factor for the development of distant metastases, 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 squamous atypia, without the specification if the onset was spontaneous, after surgery or other treatments o traumas, all the 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-immuno-cutaneous system, and surgical procedures, as well as the scars resulting from them, impair both lymph circulation and neuro-immune crosstalk in the traumatized area [ 24 , 25 ] . Gambichler and colleagues demonstrated in two patients affected by “koebnerized” CSCC that the wound healing 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 cycle dysregulation [ 18 ] .
The results of this review highlight five red flags that clinicians should consider in the diagnosis and management of ESCC after skin surgery. First of all, the extremities (lower and upper limbs) represent the cutaneous site with the highest 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 appeared 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, including 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. 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 medical treatments. Que et al reported a 67% resolution rate using 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 concern 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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