There was only one respondent from Denmark, and one from Iceland. We consider the results still relevant as the treatment of eyelid sebaceous carcinoma is centralized to only two centers in Denmark and one center in Iceland. In the other three Nordic countries many centers treat this extremely rare disease. Due to its rarity centralization could be considered in all Nordic countries.
Preoperative work-up
Preoperatively, a comprehensive clinical evaluation including examination of the eye, conjunctiva and caruncle is recommended. All eyelids should be everted and preauricular, submandibular, parotic and cervical lymph nodes should be palpated [
8,
13].
To establish the diagnosis a full thickness eyelid biopsy including skin, tarsus and palpebral conjunctiva is recommended by Shields et al. [
13] This can be done by an incisional biopsy or with a round penetrating trephine. According to Shields et al. [
13] chest x-ray, liver enzyme blood tests and work-up by MRI or CT are not necessary in small lesions. However, if there is a suspicion of orbital invasion or if the risk of nodal metastasis is high, T2b or more (AJCC 7-th edition), a orbital CT or MRI, thorax CT, parotid, submandibular and cervical lymph nodes ultrasonography or CT and possible fine needle aspiration biopsy are needed [
8,
13,
18].
Conjunctival mapping biopsies are recommended to ensure tumour margins as sebaceous carcinoma has a tendency of intraepithelial spread. They are recommended if there is suspicion of conjunctival or caruncular involvement [
1,
13,
19,
20]. Shields et al. [
13] report that routinely four biopsies from the palpebral and six from the bulbar conjunctiva should be taken. If corneal involvement is suspected, 4 additional biopsies close to limbus should be taken. Permanent sections are recommended [
13]. A recent publication by McConnell indicates that the pattern and location of the primary tumour do not correlate to a possible intraepithelial spread and therefore standardized mapping biopsies are always recommended [
21]. Contrary to these recommendations, in our study 27% of respondents never used and 54 % occasionally used conjunctival mapping biopsies.
Muir-Torre syndrome (MTS) is a rare inherited condition characterized by a combination of sebaceous carcinoma, other sebaceous gland tumors and other malignant tumours; colorectal, genitourinary and breast cancer being the most common [
1,
8,
9]. The opinions regarding screening for MTS vary, but it is suggested to rule out visceral malignancies as 6–20% of individuals with periocular sebaceous carcinoma develop visceral tumours [
18,
22]. In one series with eyelid sebaceous cancer, MTS was found in 1 of 34 patients [
1], however, in another series, 10 of 31 patients had MTS as indicated by clinical diagnosis of visceral malignancies [
23]. History of multiple sebaceous neoplasms, other tumours connected to Lynch syndrome (hereditary nonpolyposis colorectal cancer) in the patient or in a relative and age under 60 years are risk factors for MTS [
24]. It is notable that in our study 52% of respondents never screened for MTS, which indicates a need for reconsideration.
Treatment
Full-thickness eyelid tumor resection with posterior lamellar is the golden standard and superior to non posterior lamellar resection [
25,
26]. Mohs surgery has been recommended as treatment of sebaceous carcinoma with excellent results with 11% recurrence rate for primary tumours [
27‐
31]. However, Mohs surgery is resources- and time-demanding and not available everywhere. Good results have also been published using frozen sections and therefore many authors prefer it [
6,
8,
13,
20,
32,
33]. Some prefer multi-stage resection with permanent margins and delayed closure, reporting 12% recurrence rates [
7,
34,
35]. Multicentricity of sebaceous carcinoma makes the securing of clear margins difficult with all methods. There are reports with less favorable results using both Mohs surgery [
12,
36,
37] and frozen section [
12]. In our study 57% used frozen section, 50% multi-stage resection with delayed closure and 18% Mohs surgery, i.e. some respondents had more than one strategy dependent on the case. The technique differed by countries, reflecting, presumably, the facilities available and the surgeon preference.
A 1–3 mm margin is reported to have a recurrence rate of 36% and a 5 mm margin a recurrence rate of 0% [
10]. Good results have been reported using 4 mm [
6,
38‐
40], 5 mm [
13,
41,
42], as well as 5 to 6 mm margins [
43]. It seems reasonable to aim for at least 4 mm margins. The majority of our respondents aimed for 5–6 mm margins.
Sentinel lymph node biopsy (SLNB) was used by 41% of all respondents and more commonly in Finland. Recent reports have recommended the use of SLNB in patients with eyelid sebaceous carcinoma with tumours T2b (AJCC 7-th edition) or worse and in recurrent tumours [
15,
18,
44‐
48]. SLNB has been reported to be beneficial in skin melanoma and Merkel cell carcinoma, but SLNB has not been proven to increase survival in eyelid malignancies [
49]. Pfeiffer et al. [
50] have reported SLNB to identify nodal micrometastasis in 20% of ocular adnexal melanoma cases. However, in tumors, such as sebaceous carcinoma, that spread via the lymphatic system before spreading systematically SLNB is justifiable in tumors with a significant metastatic risk [
30].
Shields et al. [
13] strongly advise to use cryotherapy for every patient, both at time of conjunctival biopsy and final surgery [
13,
14,
19]. However, in Esmaeli’s series of 50 patients, no patient was treated with cryotherapy, with similar outcome [
46].
There are few publications with few patients regarding topical Mitomycin C treatment for sebaceous carcinoma of the conjunctiva. Still most authors recommend it as an alternative in treating residual in situ growth in the conjunctiva [
6,
8,
46]. In cases with extensive conjunctival spread Shields et al. [
51] and Xu et al. [
49] recommend a combination of cryo and Mitomycin C. These options could always be considered as an alternative to large conjunctival resections and exenteration. However, their use was considered by only 27% of respondents, which is surprisingly low.
Postoperative radiation after exenteration in T3 tumors (AJCC 7-th edition) is reported to significantly reduce the risk of recurrent disease [
52]. Radiation has also been recommended for recurrent disease after exenteration [
13] and postoperatively if insufficient margins [
46] or perineural spread [
8,
30,
46] is detected. Xu et al. [
49] recommend radiation therapy for T3 or higher (AJCC 7-th edition), pagetoid spread, nodal metastasis or palliative care.
Radiation as primary therapy for patients who are inoperable or refuse exenteration has shown surprisingly good results when the dose of radiation has been 50–60 Gy. In a series published by Hata [
53], all 5 patients who got radiation as primary treatment, were alive after 5 years. Radiation might be underused in the Nordic countries as only 50% would consider postoperative radiation. However, the risk of radiation induced dry eye, radiation keratopathy, radiation retinopathy, cataract and even a painful blind eye and secondary tumors should be kept in mind.
Few of our respondents have ever performed an exenteration in sebaceous carcinoma patients. In older published series the rate of exenteration was around 10% [
1,
6,
7]. Today it can often be avoided with adjuvant treatments, such as local mitomycin C and cryotherapy in cases with conjunctival spread [
53]. Nevertheless, 60% of our respondents would still consider exenteration in these cases. Exenteration should be considered if there is extensive growth in the orbit or recurrent orbital disease after globe sparing surgery. A very interesting recent study [
54] demonstrated that preoperative chemoterapy reduced tumour size remarkably and spared the patients from exenteration. The follow-up was only 18 months, but chemoreduction seems probably a promising treatment method [
55].
The use of PET/CT was not included in the survey, and none of the respondents reported using PET/CT in the open questions. There is little published data on the role of PET/ CT for staging and treatment of sebaceous eyelid carcinoma, but published data support e.g. selected use of PET/CT for the management of head and neck squamous cell cancer [
56]. Selected use of PET/CT could also be considered in the management of sebaceous eyelid carcinoma.
Follow-up
The length of follow-up is debatable. Many studies report 5 years or longer follow-up. It is noteworthy that local recurrences or metastases have been reported after 60 months [
7], 71 months [
41] and 132 months [
57] in patients who have had free margins. The reported median times from initial treatment to recurrence are 16.5 to 25 months. The reported rates for nodal recurrences are 8–23% and for distant metastasis 2–14% [
6‐
8,
11,
26,
46,
58,
59].
A higher risk for recurrence or metastasis has been reported in patients with symptoms over 6 months, involvement of both upper and lower eyelids, multicentric origin, diffuse or a non-lobular pattern, pagetoid spread, orbital involvement, perineural invasion and stage T2b (AJCC 7th -edition) or worse [
60,
61]. In a chinese study of 238 patients, risk factors for tumor-related death were orbital involvement, the greatest tumor basal diameter, pagetoid spread and lymph node metastasis at initial diagnosis [
62]. From United States Sa et al. [
15] report in study of 100 patients, that T3b or worse (AJCC 8-th edition) and N1 are risk factors for death, Lee et al. [
63] report in study of 940 patients, that older age and greater tumor size correlate with decreased overall survival, whereas surgical treatment or combined surgical and radiation treatment correlate with increased overall survival.
Stage T2b (AJCC 7th-edition) and stage T2c (AJCC 8-th edition) or a more advanced disease is reported to correlate with regional lymph node metastasis and T2b or T3a or worse (AJCC 7th-edition) and stage T2c (AJCC 8-th edition) are reported to correlate with distant metastases [
11,
15,
46,
58]. Kaliki et al. [
61] estimate of lymph node metastasis at 5 and 10 years are 0 and 0% for T1, 11and 11% for T2, 44 and 59% for T3 and 100 and 100% for T4, which would justify a longer than 5 year follow-up for T3 (AJCC 7th- edition) or worse.
Few studies include recommendations for follow-up, but some authors emphasize its importance [
7,
8,
44]. Yin et al. [
8] recommend a minimum of 5 years of follow-up, including clinical examination. Patients with an increased risk of nodal metastases are recommended to have a clinical examination for lymph nodes and a neck ultrasonography. Further, Yin et al. [
8] recommend imaging of the orbit for exenterated patients and possible lung scans in advanced cases. For T2b or worse (AJCC 7-th edition) or T2c or worse (AJCC 8-th edition) a strict regional lymph node surveillance is recommended by Esmaeli et al. [
46], Choi et al. [
58], Lam et al. [
48] and Sa et al. [
15], furthermore a surveillance for distant metastases is recommended by Choi et al. [
58] and Sa et al. [
15].
In our study most respondents used a 5-year follow-up, which in the light of published studies seems a justified minimum follow-up time. However, all respondents did not follow-up their patient, which needs reconsideration.