Abstract
Patients who are immunosuppressed, such as solid organ transplant recipients (SOTRs), are at a higher risk of developing cutaneous squamous cell carcinoma (cSCC). This population is at a higher risk of metastasis and worse disease-specific survival. The objective of this review is to better characterize the immunosuppressed population with metastatic cSCC. A literature search was conducted to identify reports of lymphatic metastases in immunosuppressed patients with cSCC. Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were followed during creation of a cohort with desired inclusion and exclusion criteria. One hundred and thirty-five articles met the inclusion/exclusion criteria, yielding 1020 total cases. We discovered that the most common forms of immunosuppression within the cohort were solid organ transplantation and hematologic malignancy. White males and cSCC tumors involving the head and neck comprised most cases. Using Brigham and Women’s Hospital and Eighth edition of American Joint Committee on Cancer tumor staging criteria, we observed a trend toward higher stage tumors in SOTR than in patients with hematologic malignancy. This review confirms that known clinical risk factors for metastatic cSCC appear to be similar among the immunosuppressed population and the cSCC population at large. Interestingly, our data suggest that current staging systems may not accurately reflect metastatic risk among patients with hematologic malignancy.
Keywords: Immunodeficiencies, Metastasis, Squamous cell carcinoma
Introduction
Cutaneous squamous cell carcinoma (cSCC) is the second most common nonmelanoma skin carcinoma, with over 1 million cases recorded annually in the United States (Waldman and Schmults, 2019). Many of these cases are reported and treated early; however, certain risk factors can increase cSCC incidence and recurrence and aggressiveness of the tumor. Immunosuppression is a known risk factor for cSCC, and solid organ transplant recipients (SOTRs) have up to a 250-fold increased prevalence of cSCC (Brantsch et al, 2008; Ruiz et al, 2019; Que et al, 2018). The rate of metastasis is also higher in these patients, increasing from 3–5% in immunocompetent patients to 7–13% in SOTRs (Cooper and Brown, 2006; Que et al, 2018; Veness et al, 2006). Immunosuppressive drugs, such as corticosteroids, antimetabolites, and calcineurin inhibitors, are widely used in SOTRs, but treatment of autoimmune diseases such as systemic lupus erythematosus can also include similar types of immunosuppressive medications (Fava and Petri, 2019). Other forms of immunosuppression include chronic lymphocytic leukemia and lymphoma, characterized collectively in this study as hematologic malignancies. Reports have stated that there are significant mortality and poor outcomes among patients with chronic lymphocytic leukemia with cSCC, including those with low T-stage tumors (Velez et al, 2014).
Current staging systems for cSCC include the new eighth edition of American Joint Committee on Cancer (AJCC8) classification system and Brigham and Women’s Hospital (BWH) tumor classification system. The American Joint Committee on Cancer classification system is primarily based on tumor size, but the AJCC8 improves upon the seventh edition by allowing tumors to be upstaged to T3 according to tumor diameter, depth, or perineural invasion (PNI) (Ruiz et al, 2019). This is in contrast to the BWH system where tumors are classified according to how many high-risk features are present. High-risk factors include tumor diameter ≥2 cm, poorly differentiated histology, PNI of a nerve >0.1 mm, and tumor invasion beyond subcutaneous fat (Karia et al, 2013; Ruiz et al, 2019). The BWH and AJCC8 staging systems are useful tools for prognosis for most high-risk cSCC cases. A total of 70% of poor outcomes (nodal metastasis, local recurrence, and disease-specific death [DSD]) occur in AJCC8 T3 and T4 classes, whereas 70% of nodal metastasis and 92% of DSD outcomes occur in BWH T2b and T3 classes (Ruiz et al, 2019). Although both approaches have strengths and weaknesses, immunosuppression is not included as a criterion in either. However, immunosuppression has been shown to be independently associated with DSD in patients with cSCC, with a 2-fold increase in the rate of DSD in immunosuppressed patients compared with that in immunocompetent population (Tam et al, 2020). Consequently, it is important to consider immunosuppression as a prognostic factor in patients with cSCC, especially those with metastatic disease.
The literature lacks a systematic evaluation of published cases of metastatic cSCC in immunosuppressed patients. We searched the literature for reports of such cases published on or before April 11, 2022. After, we characterize this cohort by reporting patient demographics, tumor characteristics, and clinical outcomes.
Results
A total of 135 publications were yielded after examination of each text for correct inclusion and exclusion criteria (Supplementary Material S1). Of these publications, a quality assessment of evidence was performed where a grading of recommendations, assessment, development and evaluation (GRADE) rating of very low was found 16 times, that of low was found 114 times, that of high was found 4 times, and that of very was found high 1 time (Supplementary Material S2). A total of 0.2% of cases were managed from 1970 to 1979, 0.2% of cases were managed from 1980 to 1989, 0.9% of cases were managed from 1990 to 1999, 16% of cases were managed from 2000 to 2009, 71% of cases were managed from 2010 to 2019, and 12% of cases were managed from 2020 to 2022.
We found a total of 1020 cases of metastatic cSCC in immunosuppressed hosts reported in the included literature (Supplementary Tables S1 and S2). Many of these cases lacked individual patient-level data for multiple variables. In this review, we focus on the 107 cases in which both patient sex and age are reported. Among these patients, 55% were males, and 45% were females. The most common age group by decade was 60–69 years (32%) with a median age of 66 years. A total of 55% of cases were found with a primary tumor location of the head and neck. Patient race was reported in a minority of cases, yielding a race breakdown of 17% White, 4% Asian, 1% Black/African American, and 79% of unknown race. Patient ethnicity was not reported. We found the 2 most common forms of immunosuppression to be solid organ transplantation (39%) and hematologic malignancy (38%). Of the cases that reported a solid organ transplantation, 57% were abdominal transplants (Table 1).
Table 1.
Characteristics of Metastatic Squamous Cell Carcinoma in Immunosuppressed Patients
| Characteristic | Number |
|---|---|
| Total number of cases | N = 107 |
| Age, y, n (%) | |
| 0–49 | 15 (14) |
| 50–59 | 16 (15) |
| 60–69 | 34 (32) |
| 70–79 | 30 (28) |
| ≥80 | 12 (11) |
| Sex, n (%) | |
| Male | 59 (55) |
| Race, n (%) | |
| White | 18 (17) |
| Asian | 4 (4) |
| Black/African American | 1 (1) |
| Unknown | 84 (79) |
| Immunosuppression type, n (%) | |
| Solid organ transplant | 42 (39) |
| Hematologic malignancy | 41 (38) |
| Medication induced | 9 (8) |
| Diabetes | 5 (5) |
| Autoimmune disorders | 5 (5) |
| HIV | 4 (4) |
| Unknown | 1 (1) |
| Solid organ transplant type, n (%) | |
| Abdominal | 24 (57) |
| Thoracic | 10 (24) |
| Both | 1 (2) |
| Unknown | 6 (14) |
| Diameter, cm, mean (SD) (n = 50) | 3.6 (2.4) |
| Depth, mm, mean (SD) (n = 16) | 6.1 (4.3) |
| Invasion beyond SQ, n (%) | |
| Yes | 8 (7) |
| No | 15 (14) |
| Unknown | 84 (79) |
| Tumor differentiation, n (%) | |
| Poor | 17 (16) |
| Moderate | 7 (7) |
| Well | 7 (7) |
| Unknown | 76 (71) |
| PNI, n (%) | |
| Yes | 9 (8) |
| No | 5 (5) |
| Unknown | 93 (87) |
| Location, n (%) | |
| Head and neck | 59 (55) |
| Upper extremities | 13 (12) |
| Trunk | 7 (7) |
| Lower extremities | 6 (6) |
| Unknown | 26 (24) |
| Treatment, n (%) | |
| Chemotherapy | 18 (17) |
| Radiation | 14 (13) |
| Chemotherapy + immunotherapy | 8 (7) |
| Immunotherapy | 3 (3) |
| Radiation + chemotherapy + immunotherapy | 3 (3) |
| Radiation + immunotherapy | 2 (2) |
| Other1 | 2 (2) |
| Unknown | 57 (53) |
Abbreviations: PNI, perineural invasion; SQ, subcutaneous fat.
Refused treatment, radiation + chemotherapy.
A primary tumor diameter was reported in 50 cases, with a mean of 3.6 cm (range = 0.3–12.0 cm). Tumor depth was reported in only 16 cases, with a mean depth of 6.1 mm. PNI was reported in 14 cases, of which 8% were positive. The most common form of treatment was chemotherapy (17%), followed by radiation (13%). A majority, 86%, of cases had only nodal metastases. Time to nodal metastasis was reported in 18 cases, with median time to nodal metastasis being 5 months (range = 0.0–24.0 months). The 1-, 3-, and 5-year overall survival rates of immunosuppressed patients with nodal metastasis were 54 (21 of 39), 29 (10 of 35), and 6% (2 of 32), respectively. Nodal and distant metastases were reported in 14% of cases, with median time to distant metastasis of 10.5 months (range = 0.0–24.0 months, n = 8). The lung was the most common site of distant metastasis. The 1-year overall survival of patients with both nodal and distant metastasis was 45% (5 of 11), 3-year overall survival was 18% (2 of 11), and 5-year overall survival was 0 of 10. DSD was reported in 30 patients, with a mean time to death of 13.6 months (Figure 1). Of studies that reported time to DSD and treatment type, mean time to death was 13.9 months for chemotherapy and radiation, followed by 18.7 months for radiation alone. Thoracic SOTRs had a decreased mean time to DSD compared with abdominal SOTRs (Table 2).
Figure 1.
Metastasis and survival in immunosuppressed patients with cSCC. cSCC, cutaneous squamous cell carcinoma.
Table 2.
Outcomes of Metastatic Squamous Cell Carcinoma in Immunosuppressed Patients
| Outcome | Number |
|---|---|
| Total number of cases | N = 107 |
| Type of metastasis, n (%) | |
| Nodal | 92 (86) |
| Nodal and distant metastasis | 15 (14) |
| Organ involved in distant metastasis, n (%) | |
| Lung | 5 (33) |
| Lung, bone | 3 (20) |
| Liver | 2 (13) |
| Esophagus | 2 (13) |
| Other1 | 2 (13) |
| Unknown | 1 (7) |
| Time to nodal metastasis, median (range), mo (n = 18) | 5 (0–24) |
| Time to distant metastasis, median (range), mo (n = 8) | 10.5 (0–24) |
| 1-y survival, n (%) | 27 of 49 (55) |
| 3-y survival, n (%) | 12 of 45 (26) |
| 5-y survival, n (%) | 2 of 41 (5) |
| Disease-specific death, mean (range), mo (n = 30) | 13.9 (2–36) |
| Disease-specific death by treatment type, mean (range), mo (n = 28) | |
| Chemotherapy + immunotherapy | 24 |
| Radiation + immunotherapy | 22 |
| Radiation | 18.7 (2–36) |
| Chemotherapy + radiation | 13.9 (3–24) |
| Disease-specific death by solid organ transplant type, mean (range), mo (n = 9) | |
| Abdominal | 21.9 (10.8–36) |
| Thoracic | 13.8 (6–19) |
| Both | 2 |
Abbreviation: GI, gastrointestinal tract.
Lung, GI, and orbit.
There were 136 cases that reported BWH stage, AJCC8 T stage, or sufficient information for determination of stage. A total of 76% of these reported stage without the inclusion of all tumor characteristics. We recorded 49 cases to be low stage and 87 cases to be high stage. There were the same percentage of tumors located on the head and neck among low T-stage tumors (84%) and high T-stage tumors (84%). Hematologic malignancy was reported in 67% of low-stage tumors, which decreased to 38% in high-stage tumors, whereas the proportion of SOTRs was increased among high-stage tumors compared with that among low-stage tumors (31 vs 19%, respectively) (Table 3).
Table 3.
Characteristics of 136 Metastatic Squamous Cell Carcinoma Cases by T Stage
| Characteristic | T Stage, n (%) |
|
|---|---|---|
| Low stage (n = 21)1 | High stage (n = 45)2 | |
| Immunosuppression type | ||
| Organ transplantation | 4 (19) | 14 (31) |
| Hematologic malignancy | 14 (67) | 17 (38) |
| Multiple | 0 (0) | 3 (7) |
| Other | 3 (14) | 11 (24) |
| Low stage (n = 11)1 | High stage (n = 11)2 | |
| Solid organ transplant type | ||
| Thoracic | 9 | 7 |
| Abdominal | 2 | 4 |
| Low stage (n = 25)1 | High stage (n = 62)2 | |
| Location | ||
| Head and neck | 21 (84) | 52 (84) |
| Other | 4 (16) | 10 (16) |
Abbreviations: AJCC8, Eighth edition American Joint Committee on Cancer; BWH, Brigham and Women’s Hospital.
Low stage = BWH T1/T2a and AJCC8 T1/T2.
High stage = BWH T2b/T3 and AJCC8 T3/T4a/T4b.
Discussion
Immunosuppression is a known risk factor for cSCC and is associated with poor outcomes among patients with cSCC (Feinstein et al, 2019). We reviewed published cases of metastatic cSCC in immunosuppressed patients. In this literature review, we found 1020 cases of metastatic cSCC reported in immunosuppressed patients, of which 107 cases included individual-level data. The data were primarily from patients with history of solid organ transplantation or hematologic malignancy, which does represent the most common at-risk populations treated by dermatologists. Known risk factors for cSCC and metastasis were common in this cohort and confirmed within individual patient-level data, including the majority of patients being of White race, of male sex, and with tumor diameter >2 cm (Wysong, 2023). The mean tumor depth was increased in the individual patient-level data compared with that of immunocompetent cSCC tumors, reflecting the high-risk tumors seen in immunosuppressed patients.
Disease-specific survival has been previously shown to be lower in immunosuppressed patients, and in this study, it was reported to be 13.9 months; however, only 30 cases reported a cause of death. Given the high risk of mortality in this group, immunosuppressed patients should undergo increased screening and surveillance for metastasis and disease progression. We observed that thoracic SOTRs mean time to DSD was shorter owing possibly to differences in immunosuppression regimens between abdominal and thoracic organ transplantations (Karia et al, 2013). Conclusions on mean time to DSD may not be reflective of the population as a whole owing to low sample size. This review spans over a 50-year period; therefore, survival data may not be reflective of current survival rates owing to recent advances in immunosuppressive regimens and improved treatment options for advanced cSCC (Wysong, 2023).
We were only able to report 135 fully staged cases, underscoring the paucity of these data in the literature. Moving forward, those publishing clinicopathological reports of cSCC should be encouraged to include tumor characteristics necessary for staging. Tumor location was highlighted owing to the increased risk of metastasis for tumors located on the head and neck (Veness, 2007). Overall, a majority of metastatic cases in this cohort were found to be of a low T-stage primary tumor, which confirms the importance of immunosuppression as a risk factor for poor outcomes among patients with cSCC. Interestingly, among the cases of metastatic SCC reviewed in this paper, a higher proportion of low-stage tumors were reported to be in patients with hematologic malignancy, whereas the proportion of high-stage tumors that were reported in SOTRs was higher than the proportion of low-stage tumors. However, unfortunately, the study was not powered to determine the significance of these findings. Patients with hematologic malignancy may not be accurately assessed for risk of development of a nodal metastasis owing to standard tumor staging currently not accounting for immunosuppression status. This is consistent with findings that patients with advanced chronic lymphocytic leukemia have a higher risk of poor skin cancer outcomes despite having a low T-stage tumor (Velez et al, 2014). Without knowing the overall incidence of low-stage cSCC in patients with hematologic malignancy, further investigation is needed.
These findings may be a result of differences in patient screening. Although regular full-body skin examinations are recommended for both SOTRs and patients with hematologic malignancy, positron emission tomography (PET) scans are frequently used to monitor hematologic disease progression in the hematologic malignancy population. These scans can reveal early-stage tumors and subclinical metastasis, possibly before they would be detected on examination or other imaging. A possible future study may investigate the frequency of incidental cSCC primary tumor and metastasis detection by PET computed tomography in patients with hematologic malignancy undergoing routine studies. Overall, risk factors associated with metastasis in this patient subset may not be accurately reflected in the BWH or AJCC8 staging systems.
This review reveals a paucity of literature characterizing metastatic cSCC in immunosuppressed patients. Although immunosuppression is known to be associated with higher rates of metastasis, drivers of metastasis within this group are still not well-understood. In practice, even though immunosuppression is not included in BWH or AJCC8 staging systems, patients with a form of immunosuppression, especially SOTRs and patients with hematologic malignancy, should be considered at higher risk for poor outcomes. This dataset provides a glimpse into factors that may allow for improved prognostication and treatment planning; however, additional studies are needed to investigate the underlying biologic factors that drive oncogenesis and poor outcomes in this population.
Limitations
This review has several major limitations. First, only cSCC cases with a nodal metastasis were included, excluding all cases diagnosed with only a distant metastasis. Second, a majority of cases were missing key demographic data points as well as primary tumor information to allow for accurate staging. Consequently, there may be significant bias in the reported patient and tumor characteristics, which influences how the data should be interpreted. This study provides a review of published studies reporting cases of cSCC in immunosuppressed patients with nodal metastasis, most importantly revealing a lack of such data and areas for further study.
Methods
Searches of EMBASE (through embase.com, 1974 till search date), MEDLINE (through EBSCOhost, inception till search date), The Cochrane Library (through Wiley.com, inception till search date), and Scopus (inception till search date) were performed on January 13, 2021 by a research librarian (CMS). Subject headings (when available) and keywords were used to represent the search concepts: (i) cSCC, (ii) lymphatic metastases or evaluation for lymph node metastasis, and (iii) immunosuppression (Supplementary Table S3). Language filters were used to remove records for articles not available in English. Articles indexed as concerning animals that were not also indexed as concerning humans were removed from the results of EMBASE and MEDLINE searches. Conference abstracts were removed from the EMBASE search results. A total of 2110 records were retrieved by the searches (785 EMBASE, 574 MEDLINE, 18 Cochrane Library, and 733 Scopus records). An updated search was performed on April 11, 2022 using the same search concepts. This revealed 280 results (120 EMBASE, 56 MEDLINE, 4 Cochrane Library, and 97 Scopus records). Abstracts and full text were reviewed by 1 researcher for correct inclusion criteria (MW) with conflicts resolved by AW and MJW. Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were used to create a cohort with the correct inclusion criteria (Figure 2). Cases were considered immunosuppressed if they had a solid organ transplantation, hematologic malignancy, HIV/acquired immunodeficiency syndrome, long-term steroid use, long-term immunosuppressive medication use, type II diabetes, sarcoidosis, systemic lupus erythematosus, myelodysplasia, rheumatoid arthritis, or inflammatory bowel disease. Exclusion criteria were cases that did not distinguish between invasive cSCC and squamous cell carcinoma in situ, non-cSCC, mucosal squamous cell carcinoma, cSCC with genital involvement, cSCC data results that could not be distinguished from other skin cancers (ie, melanoma), immunocompetent cases, and reports lacking patient-level clinical data. All articles were assessed for quality of evidence using the GRADE system (Ryan and Hill, 2016). The protocol was not registered with any database; however, Open Science Framework, International Prospective Register of Systematic Reviews, and Cochrane databases were reviewed for similar studies and protocols before submission of this review.
Figure 2.
PRISMA flow diagram.aArticles identified from Cochrane (n = 20), EMBASE (n = 908), MEDLINE (n = 601), and Scopus (n = 756). cSCC, cutaneous squamous cell carcinoma; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.
From these selected publications, we extracted data describing patient and tumor characteristics as well as outcomes. When the data were not available, the case was marked as missing the information. Age, sex, race, type of immunosuppression, history of smoking, treatment of metastatic disease, 1-year survival, 2-year survival, 5-year survival, and cause of death were included. The following tumor characteristics were recorded: diameter (in cm), depth (in mm), invasion beyond the subcutaneous fat, presence of PNI, and tumor differentiation. AJCC8 T stage and BWH stage were recorded when reported in the report. When stage was not explicitly reported, but the tumor characteristics necessary to accurately assign a stage were reported, a stage was assigned for purposes of this study. Low stage was defined as an AJCC8 T1 or T2 or BWH T1 or T2a staged tumor. High stage was defined as an AJCC8 T3, T4a, or T4b or BWH T2b or T3 staged tumor. Cases that did not include data for both sex and age were excluded, and results were analyzed separately.
Ethics Statement
No human or animal studies were conducted for this manuscript.
Data Availability Statement
No datasets were generated or analyzed during this study.
ORCIDs
Megan Wackel: http://orcid.org/0000-0002-9107-0981
Sierra Thomas: http://orcid.org/0009-0009-9229-343X
Cynthia M. Schmidt: http://orcid.org/0000-0003-1657-2671
Cheng Zheng: http://orcid.org/0000-0002-6562-870X
Ashley Wysong: http://orcid.org/0000-0001-5131-1149
Melodi Whitley: http://orcid.org/0000-0002-8163-6881
Conflict Of Interest
AW serves as a research principal investigator for Castle Biosciences. The remaining authors state no conflicts of interest.
Acknowledgments
We thank Elliot Blue for reviewing this manuscript.
Author Contributions
Conceptualization: AW; Data Curation: CMS, MW, ST; Formal Analysis: MW, CZ, MJW; Methodology: MW, MJW, AW; Supervision: MJW, AW; Validation: AW, MJW; Visualization: MW; Writing - Original Draft Preparation: MW; Writing - Review and Editing: MW, MJW, AW, CMS, CZ, ST
Declaration of Generative Artificial Intelligence (AI) or Large Language Models (LLM)
The author(s) did not use AI/LLM in any part of the research process and/or manuscript preparation.
corrected proof published online XXX
Footnotes
Cite this article as: JID Innovations 2024.100294
Supplementary material is linked to the online version of the paper at www.jidonline.org, and at https://doi.org/10.1016/j.xjidi.2024.100294.
Supplementary materials
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Associated Data
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Supplementary Materials
Data Availability Statement
No datasets were generated or analyzed during this study.