|Year : 2019 | Volume
| Issue : 3 | Page : 112-122
The incidence rate of metastasis from the primary cutaneous squamous cell carcinoma: A literature review
Badr Mohammed F. Alotaibi1, Mohammed A Kilani2
1 Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The, Netherlands
2 Department of Physiology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
|Date of Web Publication||1-Jul-2019|
Badr Mohammed F. Alotaibi
Ibn Abi Alzhar St. 4313, Riyadh, P.O 14225
Source of Support: None, Conflict of Interest: None
Background: Cutaneous squamous cell carcinomas (cSCCs) are the second highest nonmelanoma skin cancer, commonly targeting the head and neck region. Owing to its rising annual incidence, the actual rate of metastasis from the primary cSCC is needed to be investigated separately to develop more efficient management plans, hence nobly decreasing the incidence rate of metastasis overall. Materials and Methods: We conducted a literature review about the incidence rate of metastasis from the primary (or de novo) cSCC, based on two popular databases (PubMed and Cochrane), excluding different-purpose serving articles, for example, unrelated outcomes, case series, and case reports. Results: The mean incidence rate of metastasis from the primary cSCC is 10% (1.2–16.5). The least mean tumor size reportedly associated with regional and distant metastasis was 1.11 cm, and the least median thickness was 3 mm deep. Most of the metastatic tumors were of T1 stage before metastasis, and all metastases reported in the literature had more than one risk factor at a time. The mean follow-up duration was 4 years. Discussion: About half of the included literature carried a suspicion of selection bias, which threatens both their internal validity by overestimating the actual rate of metastasis and their external validity by seizing the reproducibility of the current evidence. Almost 85% of the metastasis was reported in the regional lymph nodes, while only a few cases involved distant anatomies at the time of diagnosis. This was consistent with other separate literatures. Conclusion: The mean incidence rate of metastasis from the primary cSCC tumors in our literature review is 10%, which is relatively higher than what was reported before in similar reviews. However, a large prospective study needs to be conducted to control and follow the involved prognostic factors, stratify them according to their risk factors, and minimize the risk of the previously reported bias in other reviews.
Keywords: Cutaneous squamous cell carcinoma, de novo cutaneous squamous cell carcinoma, incidence rate, metastasis rate, nonmelanoma skin cancer, primary cutaneous squamous cell carcinoma
|How to cite this article:|
F. Alotaibi BM, Kilani MA. The incidence rate of metastasis from the primary cutaneous squamous cell carcinoma: A literature review. J Nat Sci Med 2019;2:112-22
|How to cite this URL:|
F. Alotaibi BM, Kilani MA. The incidence rate of metastasis from the primary cutaneous squamous cell carcinoma: A literature review. J Nat Sci Med [serial online] 2019 [cited 2021 Oct 19];2:112-22. Available from: https://www.jnsmonline.org/text.asp?2019/2/3/112/251576
| Introduction|| |
Cutaneous squamous cell carcinoma (cSCC) is considered as the second highest nonmelanoma skin cancer (NMSC), commonly affecting the head and neck region of the body., This comes after the basal cell carcinoma, with a rough number of 20%., Furthermore, its incidence has been on the rise in an annual basis., Although it has a rare metastasis potential, not exceeding 9.9%, it has poor prognosis when metastasizes.,, Therefore, preventing the evolvement of this carcinoma from the first scene from a given skin site “or de novo” should be the primary goal. However, the prevention can sometimes be difficult in this type of cancer because its most common underlying cause is cumulative in nature (ultra-violet radiation (UVR). That is, the repeatedly sun-exposed areas of white skin have a cumulative risk of developing cSCC overtime, which also explains why the white-skin elderly are the most affected ethnicity and age group, respectively.,,,
Reasonable amount of data are available regarding the epidemiology of de novo, or primary, cutaneous SCC as a whole. However, the evidence is still lacking about how often this particular disease metastasizes, at least from all the available sources combined. Furthermore, the current incidence rate of metastasis is based on all types of cSCC “e.g., recurrent, primary, in situ etc.” and not solely on the primary one. Most of the published current literature used a well-known staging manual called the American Joint Committee on Cancer (AJCC), however through its older outdated editions, which do not recognize the immunosuppression status as a high-risk factor for the development of metastasis as opposed to the current 8th edition. This is particularly important as poorly differentiating the high- risk from the low-risk factors would end up with patients having a poorer prognosis, overlooking the recognition of early metastasis in such patients and therefore catching it in time.
Therefore, we will review and summarize the existing literature in both databases, PubMed and Cochrane, list all the relevant incidences of the primary cutaneous squamous cell carcinoma, before we finally calculate the average rate of these incidences by getting their mean number. This mean number, will be considered our outcome of interest.
| Methods|| |
A literature review was implemented in all published papers, through PubMed and Cochrane library databases, using the search string: cutaneous squamous cell carcinoma metastasis. Other keywords were used as well for the sake of thoroughness; these include cancer, metastasis, de novo, primary, NMSC, and incidence. The search was conducted in the English language only during October 01, 2017– November 23, 2017. A follow-up search using the same terms and databases was performed during December 11, 2018–December 16, 2018 to see if new studies were published at this new period. However, all the newer relevant studies did not meet our inclusion criteria.
Our inclusion criteria were all cohort studies made solely on primary or de novo SSC tumors. Studies made on humans only were chosen. On the other hand, our exclusion criteria were studies seeking unlrelated outcomes, such as treatments, molecular biology, risk stratifications, imaging, histology, in-transit metastasis, already metastasized tumours, recurrent tumours, or even other types of cutaneous carcinomas, e.g., NMSC, which we are not interested in. Primary tumours arising solely from specific anatomical sites e.g., lips, eyelids, scalp, ears, anogenital, toes, fingers, mucous membranes,. etc., were excluded as well. Likewise, studies that did not distinguish the recurrent, metastatic, or other kind of tumors from the primary ones in their metastasis rates were excluded. The reason we included only the primary tumors is that because we are solely interested in studying the metastasis rates from the primary lesions, while that of excluding lesions of specific locations from our database is because the metastasis rates from these lesions were reportedly higher than the face and parotid region for example, which could exaggerate our estimated average metastasis rate.
There were no restrictions made on sample size while conducting the research; However, we excluded, for example, populations as low as 3 patients as such trivial sample numbers do not reflect the true percentage of the whole population, which could distort our outcome.
We first scanned titles and abstracts only, excluding studies serving different goals as mentioned above. Unfortunately, some of the studies could not be retrieved from their sources; hence, they were excluded as well. Meanwhile, we had been saving articles seeming to carry related papers within their references, for example, review articles, for further search later.
Subsequently, we assessed the full text of the included articles for their eligibility. While keeping on excluding irrelevant articles, we were sparing review articles for reference use later. Of the net included papers, we noted inclusion and exclusion criteria, population characteristics, number and anatomical site of the primary cSCC, size or thickness of the tumor, received treatment, follow-up period, tumor node metastasis (TNM) stage, time to metastasis, location, and the incidence rate by the number of patients. Other potential factors such as immunosuppression status, ethnicity, the site of primary cSCC in metastasis patients, and the possibility of different biases were recorded as well. After the collection of evidence, the separate incidence rates of metastasis by the considered studies were finally averaged to get the mean number. Our primary outcome of interest is the incidence rate of metastasis in the primary cSCC only.
Data were extracted from relevant studies by two independent investigators. The search process and exclusion of irrelevant papers were done by one investigator, and accuracy and completeness of the data extraction were then assessed by another independent investigator.
The risk of bias of the included cohorts was assessed using Newcastle–Ottawa assessment tool for the cohort studies [Table 1]. This is a three-criteria appraisal form focusing on selection, comparability, and outcome; in which every criterion has subquestions beneath, which worth an asterisk if critical enough. A greater number of asterisks means a better quality of evidence of the given criterion, and hence, the overall quality of the paper. These asterisks were then translated into words using the Agency for Healthcare Research and Quality standards as “good, fair, and poor” for easy interpretation. Risk of bias assessment was done by the same two independent investigators, in which the first investigator had done the first assessment and then the second independent investigator went over it again.
|Table 1: Modified Newcastle-Ottawa quality assessment scale for the cohort studiesa|
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We chose this well-known tool for assessing our evidence because it contains the three major arms of a simple cohort (selection, adjusting for confounders, and outcome). That is, we would like to have a tool that it has at minimum the ability to detect possible selection bias, adjust for other confounders, and assure that the minimum follow-up duration in question is sufficient to produce the outcome. These three pillars are considered the most important indicators owing to their direct consequence on the accuracy of the metastasis rate. For the same reason, our minimum follow-up duration was 6 months.
| Results|| |
Starting from the PubMed database, our search yielded 807 hits. First, based on titles and abstracts alone, we excluded 756 publications while saving 15 review articles for references search later. This left us with 27 articles to be assessed in full text for eligibility, of which 15 cohort papers were eligible for the inclusion in our literature review. Two papers by Brantsch et al. and Kyrgidis et al. were prospective,, and the rest were retrospective. Although 147 studies were obtained from the Cochrane library at first, no single article had met our research question to be included [Figure 1].
|Figure 1: Flow diagram of PubMed and Cochrane databases search for the literature review|
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Metastasis rates that were originated from the primary cSCC in the literature varied from 1.2% to 16.5% with a mean of 10%. The least mean tumor size reportedly associated with regional and distant metastasis was 1.11 cm, and the least median thickness was 3 mm deep. Most of the metastatic tumors were T1-staged before metastasis. Moreover, the incidence of metastasis was significant if the primary lesions were located in the cheek, scalp, auricle and periauricle, temple and mastoid, lip and perioral, ocular and periocular, eyelid, forehead, nose, chin, neck, upper and lower extremities, trunk, and anogenital. All reported metastasis had more than one single risk factor at a time.
Most cSCCs were metastasized to the regional lymph nodes, with the parotid and neck being the most frequently affected sites. Although rare, distant metastasis was only reported in 5 studies not exceeding 15% in its highest spectrum.,,,, It was noticeable that whenever the primary tumors involved the upper and lower extremities, and sometimes trunk, there was distant metastasis; except in one study by Kyrgidis et al.
Most patients in the included studies had more than 1 cSCC. Six studies included high-risk patients (immunosuppressed),,,,,, of which one study population were all immunocompromised. Those also included high-risk tumors in the head and neck, with the cheek, scalp, ear, and lip being the most common primarily involved structures. The mean follow-up duration in the studies was 4 years, and the lower duration of follow-ups, the higher it was associated with increased metastasis rates. Increasingly involved immunosuppressed patients were correlated with higher rates of metastasis as well.
One study depended solely on the number of tumors in analyzing its metastasis rate, which was 1.2% [Table 2], while three studies investigated the incidence rate of metastasis by the number of tumors besides that of the patients, being 1.2%, 1.5%, and 2.2%.,, The mean age of all the included populations in our review is 74 years. In two big population studies, after the exclusion of some locations known to produce higher rates of metastasis (e.g., anogenital, nonglabrous lip…), the metastasis rates were noticeably low, being 1.2% and 1.7%, respectively.,
|Table 2: Summary of the incidence of metastasis from the primary cutaneous squamous cell carcinomas from the included literature|
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The least body involvement of head and neck's primary cutaneous SCC was documented in one retrospective study by Schmults et al., which was 37.4%. Most of the primary lesions did not exceed 2 cm in size, but whenever exceeded, it was not associated with higher rates of metastasis in most studies. Three papers neither describe the size of the primary lesions nor describe the thickness.,, Most metastases occurred within the first 2 years of diagnosis of the primary tumor; unfortunately, some papers lacked this essential information by which not counting the time to metastasis [Table 2]. Similarly, not all studies described the TNM staging system, but where mentioned, most of the tumor size fell under T1 stage. The longest duration to metastasis was recorded in only one patient in one study, being 48 months.
We did not recognize a noticeable trend in the metastasis rates to the different treatments received except in one instance, where prophylactic lymphadenectomy on high-risk patients significantly reduced the metastasis rate. All populations were treated surgically, where three studies additionally used neck ultrasound to define the high-risk patients.,, Chemo and radiotherapies were done as well however in fewer studies.
As far as bias assessment was concerned, three papers obtained the best quality,,, while four were relatively poorer, mainly due to the reported selection bias.,,, Nevertheless, all the studies succeeded in the adjustment for other confounders through different statistical analyses. However, it was not possible for a study to get the full four asterisks in the selection criterion owing to the nature of the used tool, as none of them had a control group in the first place [Table 1].
| Discussion|| |
The mean incidence rate of metastasis from the primary cSCC in our review is 10%, which is a little higher than the highest number published thus far, 9.9%, by one literature review. We reported the least number tumor size (1.11 cm) which was associated with the risk of regional and distant metastasis among other relative reviews. For instance, Thompson et al. mentioned that the least tumor diameter associated with metastasis is 2 cm. We did not notice a metastasis in <3 mm-deep tumors. However, one study by Brantsch et al. went even less than our record, in which no metastasis was associated with <2 mm thick lesions despite the bias declared by the author., All the metastases in our literature had more than one concurrent risk factor, which is in keeping with the findings of Vasconcelos et al. and Schmults et al.,
The head and neck are by far the most commonly affected structures by the primary cSCC, especially cheeks, ear, scalp, nasal, and lip regions yet with varying degrees. Therefore, a multivariate analysis is encouraged to quantify the precise contribution of each region. Likewise, Brougham et al. and Hutting et al. reported that most of the primary-involved regions are head and neck., Furthermore, almost 85% of the metastasis was reported in the regional lymph nodes, with only a few cases involved distant anatomies at the time of diagnosis. This is similar to Alam and Ratner results, where distant metastasis was detected in 15% of the cases. Like what Howell JY and Ramsey ML discussed in a separate study, immunosuppression turns out to be always a significant factor for poor prognosis in our review.
The description by Schmitt et al., that the co-occurrence of the primary tumors in the ear or lip together with a lesion more than 2 mm deep permits the stage of T2, was evident in our review. This was reflected by the high number of T1-staged tumors reported in our metastasis rate. We are mainly interested in the tumor size (T-stage) of the TNM system, as it describes the tumor state before metastasis, our outcome of interest. Most studies were conducted in regions known of white populations, which explains the pathophysiology of the disease, although that was not clear in others.
The varying incidence rates of metastasis are highly dependent on the underlying risk factors. Although there is no accurate definition to the high-risk patients according to Schmults et al. in 2013, Krediet et al. in 2017 defined them clearly based on the tumor diameter, site, immunostate of the host, level of differentiation, as well as the thickness. Although a suspected referral bias was reported in the latter due to the increased immunocompromised patients, this is still a promising move of the current evidence toward the stratification of the low- versus high-risk patients and hence more accurate estimates of the metastasis rate from the primary cSCC in the future. In fact, any included paper in the literature which happened to have any of these high-risk factors indeed resulted in a significant risk of metastasis. This was the case as well in other four articles.,,,
Two included studies by Haisma et al. and Košec et al. did not justify the presence of the two exclusion criteria: a unilateral radically dissected-neck tumor and any primary tumor <2 cm. Actually, the exclusion of these criteria resulted in the poorest prognosis among all the fifteen included literature, with metastasis rates of 16.4% and 16.5%, respectively., Otherwise, there was no noticed effect from the inclusion and exclusion criteria on the metastasis rates in the remained papers.
The fact that all the included patients were first approached surgically increases the reliability of our mean metastasis rate. This is because surgical excision gives an accurate assessment of the tumor and assures there is no marginal involvement at the time of primary diagnosis. This will improve the possibility that an individual receives the proper treatment in time, thus reducing the risk of metastasis. Alam and Ratner explained an even more specific type of surgery (Mohs), where all the tumor and its margins are sectioned completely, decreasing the likelihood of incomplete excision. Schmults et al. used the Mohs' surgery in about 20.4% of their patients, ending up with a relatively low rate of metastasis, by tumors (2.2%). However, this is difficult in practice, and this is why it is traditionally reserved for the high-risk primaries only.
Some related external papers described the approach of high-risk patients.,, In another review by Schmitt et al., long follow-up is actually recommended in high-risk patients. Sentinel lymph node biopsy (SLNB) was not discussed in the included articles; one explanation for this could be the known low sensitivity of SLNB in detecting the nodal metastasis. However, according to a review by Navarrete-Dechent et al., this modality is sometimes considered a better option especially when dealing with a high-risk elderly patient who cannot tolerate invasive surgeries, instead of the routine neck ultrasound. Actually, the latter appeared to increase the power of the actual length of follow-up in three included studies. This is in part because detecting metastasis earlier on the course of follow-up decreases the need of more lengthy durations. In fact, three authors recommend close follow-up with ultrasound.,, Unlike what Brougham ND mentioned in another study, we neither observe any effect of the length of follow-up on metastasis rates nor did the type of treatment received deviate the interval to metastasis in either direction.
We consider the minimum durations of follow-up sufficient in all of our literature, owing to the metastatic nature of the disease. That is, the fact that the time to metastasis in most of our included papers is within the first 12 months justifies the follow-up durations. However, not all studies defined the follow-up periods, which could raise the suspicion that not all the recruited sample was followed up until the occurrence of the outcome. For example, <85% follow-up rate was documented in a paper by Brinkman et al., while Krediet et al. did not provide any statement about the transparency of the follow-up process in their patients. On the other hand, Mourouzis et al. failed to provide an explanation about the lost to follow-up patients. Overall, the internal validity is threatened in more than one-third of the selected papers, mainly due to the reported selection and follow-up biases.
As it is clearly seen that only two search databases were used for our literature review, these were PubMed and Cochrane libraries. The reason we mainly used these two libraries is because PubMed in part is considered the most evidence indexed library among other databases. Although no paper was eligible from the Cochrane library, we also used this library to assure that no article already discussed the same objective we have.
There are some limitations to our literature review. First, the search was only conducted in English, which could have missed some other pertinent articles written in different languages. Second, most of the reviewed papers included high-risk factors, such as areas known to be of high metastasis rates (e.g., ear), and immunosuppression, which could have exaggerated the average metastasis rate from the included primary lesions. Third, we reported selection bias in one-third of our included literature, which could affect the power of our data reproducibility. Fourth, only two of the fifteen included studies were of prospective design, while the rest were retrospective. This exposes more data to be underreported.,,,, Last but not least, our average incidence rate is counted by both the patient numbers as well as the tumor cases although the latter is negligible, in which we used only one study to completely retrieve the incidence rate by tumors.
By only implementing a large prospective study,, we can barely overcome the problem of the several selection biases detected in the literature. To the best of our knowledge, this is the first study that investigates the rate of metastasis specifically arising from the primary tumors among several reviews.
| Conclusion|| |
The mean incidence rate of metastasis from the primary cSCC tumors in our literature review is 10%, which is relatively higher than what was reported in similar reviews. This prompts the need of conducting a big-sampled prospective study to stratify the population based on their prognostic factors. Not only will this result in a more accurate and reproducible estimate of the metastasis rate but also will improve how we approach certain patients in terms of screening, treatment, and follow-up before we finally decrease the rate of metastasis overall.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]