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A subset of patients with Lynch Syndrome demonstrates cutaneous manifestations of the disorder. Characterization of these Lynch-related skin lesions could help in early recognition of patients with Lynch Syndrome. A broad search of the literature on OVID Medline and Embase was carried out to capture papers reporting cutaneous manifestations in Lynch Syndrome patients. The results were uploaded into Mendeley reference management software. The PRISMA workflow was used in the literature selection process. In this systematic review, data were collected from 961 cases from 413 studies, including 380 molecularly confirmed Lynch Syndrome cases. The main skin lesions were: Sebaceous adenomas (43%), sebaceous carcino- mas (27%), keratoacanthomas (16%), sebaceomas (13%), squamous cell carcinomas (23%), and basal cell carcinomas (10%). MSH2 variants were the most common underlying genotype (72%). Assessment of mismatch repair by immunohistochemistry, microsatellite instability analysis, or both were performed on 328 skin lesions from 220 (58%) molecularly confirmed cases. In those skin lesions, 95% of Immunohistochemistry and 90% of the microsatellite instability test results were concordant with the underlying genotype. Sebaceous skin lesions are well-recognised phenotypic features of Lynch Syndrome. Our results show that squamous and basal cell carcinomas are relatively common in patients with Lynch syndrome; however, available evidence cannot confirm that Lynch syndrome is causal. Immunohistochemistry and/or microsatellite instability testing of skin tumours in patients with a family history of Lynch Syndrome-associated cancers may be a useful approach in identify- ing patients requiring referral to Clinical Genetics and/or consideration of germline genetic testing for Lynch Syndrome. Keywords Lynch syndrome · Muir-Torre syndrome · Mismatch repair · Sebaceous tumour; squamous cell cancer; basal cell cancer Introduction in one of four mismatch repair (MMR) genes: MLH1, MSH2, MSH6 and PMS2. In approximately 1–3% of families, LS Lynch Syndrome (LS), formerly known as hereditary non- can be caused by constitutional deletions in the 3′ end of polyposis colorectal cancer syndrome, is a common heredi- EPCAM- leading to hypermethylation and transcriptional tary cancer predisposition syndrome with an estimated prev- silencing of MSH2. A small proportion of LS is caused by alence of 1 in 300 . It is an autosomal dominant disorder a de novo or inherited constitutional epimutation of MLH1 most commonly caused by constitutional pathogenic variants [1, 2]. LS is associated with an increased lifetime risk of cancers of the colorectum, endometrium, ovaries, stomach, small bowel, bile duct, pancreas, and upper urinary tract [1, 2]. Cutaneous tumours represent 3–5% of extra-colonic * Shahram Aziz email@example.com; firstname.lastname@example.org malignancies of LS [3–5]. Based on reported population frequencies of constitu- Department of Physiology, University of Sulaymaniyah, tional pathogenic MMR gene variants, it is estimated that Sulaymaniyah, Iraq approximately 175,000 people in the UK have LS, but The Royal Marsden NHS Foundation Trust, London, UK diagnosis has only been confirmed in approximately 5% [1 , Department of Dermatology, Imperial College London & 6]. Confirming a diagnosis of LS in patients with cancer is Chelsea and Westminster Hospital, London, UK important to guide therapeutic decision-making, inform the Komar University of Science andTechnology, Sulaymaniyah, risks of subsequent cancers, facilitate early detection and/or Iraq Vol.:(0123456789) 1 3 S. Aziz et al. cancer prevention, and allow for predictive genetic testing The literature search was performed on January 15th, of at-risk relatives [1, 6]. Cancers occurring within the con- 2022, using Ovid to extract articles from the Medline and text of LS typically demonstrate Mismatch repair dec fi iency Embase databases. To fully capture all relevant articles, an (MMRd), with loss of one or more MMR proteins detect- advanced search was conducted using the aforementioned able by immunohistochemistry (IHC), although MMRd is key terms individually (Muir Torre syndrome) or in the fol- more commonly caused by sporadic somatic events [1, 7]. lowing combinations: (Lynch syndrome and skin), (Lynch Mismatch repair deficient tumours, whether due to germline syndrome and cutaneous), (Lynch syndrome and derm*), or somatic events, also typically demonstrate microsatellite (Lynch syndrome and sebaceous), (Lynch Syndrome and instability (MSI) [1, 7]. To help improve identification of sebaceoma), (Lynch Syndrome and keratoacanthoma), patients with LS, guidelines from the National Institute for (Lynch Syndrome and squamous cell), (Lynch Syndrome Health and Care Excellence (NICE) have been issued recom- and SCC), (Lynch Syndrome and basal cell), (Lynch Syn- mending assessment of colorectal and endometrial tumours drome and BCC), (Lynch Syndrome and melanoma), (hered- by IHC or MSI testing, with subsequent germline MMR itary nonpolyposis colorectal cancer and skin), (hereditary gene testing as required [1, 7]. Furthermore, a National LS nonpolyposis colorectal cancer and cutaneous), (hereditary Project has been established through the NHS Genomic nonpolyposis colorectal cancer and derm*), (hereditary Medicine Centres Alliance to help implementation of these nonpolyposis colorectal cancer and sebaceous), (hereditary guidelines, with plans to expand testing to non-colorectal/ nonpolyposis colorectal cancer and sebaceoma), (heredi- non-endometrial LS-associated cancers. tary nonpolyposis colorectal cancer and keratoacanthoma), Sebaceous neoplasms and keratoacanthomas occur as part (hereditary nonpolyposis colorectal cancer and squamous of a well-recognised phenotypic variant of LS, known as cell), (hereditary nonpolyposis colorectal cancer and SCC), Muir-Torre syndrome (MTS) [8, 9]. Other types of reported (hereditary nonpolyposis colorectal cancer and basal cell), cutaneous neoplasia occurring within the context of LS (hereditary nonpolyposis colorectal cancer and BCC), include basal cell carcinomas (BCC) and squamous cell car- (hereditary nonpolyposis colorectal cancer and melanoma), cinomas (SCC) [10–13]. It has not yet been determined if (HNPCC and skin), (HNPCC and cutaneous), (HNPCC the risk of non-sebaceous cutaneous malignancies is attrib- and derm*), (HNPCC and sebaceous), (HNPCC and seba- utable to patients’ underlying genotype. In this systematic ceoma), (HNPCC and keratoacanthoma), (HNPCC and review, we sought to critically evaluate the published litera- squamous cell), (HNPCC and SCC), (HNPCC and basal ture regarding the frequency and characteristics of sebaceous cell), (HNPCC and BCC), and (HNPCC and melanoma). and non-sebaceous cutaneous manifestations in patients with At a later stage, the screened papers’ reference lists were LS. We also aimed to provide data describing the outcomes manually reviewed to identify further relevant articles. of MMR protein immunohistochemistry, MSI testing, and germline genetic testing in such cases. Inclusion criteria All papers reporting studies that provided relevant primary Patients and methods or secondary data were considered for inclusion in this review regardless of date and language of publication. All Search strategy patients with clinically (Amsterdam and/or Bethesda crite- ria) or molecularly (following germline testing) confirmed A systematic review was undertaken following the Pre- LS and skin lesions, and all patients meeting the clinical ferred Reporting Items for Systematic Reviews and Meta- criteria for MTS (sebaceous neoplasms or multiple keratoa- Analyses (PRISMA) workflow. To identify articles relevant canthoma, and visceral malignancies) were included. to the study topic, a broad search of the literature was first conducted, after which, identified papers were manually Data extraction screened using various criteria. The key terms used for the literature search were selected after a preliminary search of To ensure consistency and structure in the extraction of the both medical subject headings and free-text terms performed data from the studies included in this review, a data extrac- on Google and Ovid. This preliminary search produced tion form was used. This form was adapted from the Data fifteen key terms that were deemed relevant to the topic, Extraction and Assessment Form provided by the Cochrane namely “Lynch syndrome”, “skin”, “cutaneous”, “derm*”, good practice data extraction guidelines and was formatted “sebaceous”, “sebaceoma”, “keratoacanthoma”, “Muir Torre for fast and effective extraction of the type of data needed. Syndrome”, “hereditary nonpolyposis colorectal cancer”, The form was first piloted on 20 randomly selected papers, “HNPCC”, “squamous cell”, “SCC”, “basal cell”, “BCC”, further edited, and then standardized. Cases were utilized as and “melanoma”. the unit of measurement to determine the frequency of skin 1 3 Characterization of sebaceous and non‑sebaceous cutaneous manifestations in patients with… lesions. The pathogenicity of reported variants was assessed Results in brief by reviewing reported classifications in ClinVar and InSIGHT databases. Studies published in non-English lan- Study selection guages were translated using Google translate, and through native speakers when necessary. Our literature search produced 4112 papers in the initial screening phase. After duplicate papers were removed, 2636 Data analysis papers remained. We performed title and abstract screening which led to a further 2098 papers being eliminated, leaving The quantitative results are presented using descriptive 538 papers for the full-text screening. These papers were statistics. The Statistical Package for the Social Sciences further reviewed, and data was extracted from 413 papers (SPSS) version 25 and Microsoft Excel were used to produce in this literature review. Figure 1 shows the study selection all the statistics. The distribution of quantitative data was process and the results of the literature search. assessed using the Kolmogorov–Smirnov test, and paramet- ric or non-parametric tests applied as appropriate. P value Summary of included studies of ≤ 0.05 was considered statistically significant. Publications with relevant information were included regard- less of the study type, date, location, and language of pub- lication. 279 (68%) of the papers were case reports and 134 (32%) case series (Online Resource 1). Fig. 1 Flowchart showing the literature selection process fol- lowing PRISMA guidelines 1 3 S. Aziz et al. Table 1 Demographics and characteristics of molecularly confirmed Patient characteristics cases: Four hundred and thirteen papers were included, from which Variable N (%) data was described regarding 961 patients. Among them, Gender 776 patients (81%) fulfilled clinical diagnostic criteria for Male 140 (37%) Muir-Torre Syndrome. Five hundred and eighty-one patients Female 89 (23%) (60%) were included based on: history alone (n = 328) or Unreported 151 (40%) history and tumour IHC and/or MSI results (n = 253). Ger- Ethnicity mline genetic testing was undertaken in 432 patients (44%), Caucasian 27 (7%) of whom 380 (90%) had molecular confirmation of a diag- Asian 7 (2%) nosis of LS. Ashkenazi Jew 4 (1%) Most (202, 65%) of the patients had multiple (≥ three) African 4 (1%) skin lesions, and the majority of patients (321, 85%) had Arab 1 (1%) sebaceous lesions. Non-sebaceous skin lesions were more Unreported 337 (88%) frequently located in sun-exposed areas compared to seba- Type of skin lesion ceous lesions (71%-v- 57%, p = 0.01, X ) (See Table 1). Sebaceous 218 (58%) Non-sebaceous 53 (14%) Germline genetic testing Both 100 (26%) Unreported 9 (2%) Germline testing was performed in 432 patients (Fig. 2). In Number of skin lesions per patient these cases, the tests were prompted by patients’ histories One 84 (22%) alone (n = 144, 33%), history and IHC (93, 22%), or MSI Two 23 (6%) (33, 7%) or both (111, 26%), and undetermined in 51 (12%). > Three 202 (53%) Germline testing provided molecular confirmation of LS in Undetermined 71 (19%) 380 (88%) cases, while 41 (12%) cases had uninformative First type of cancer in patient tests. Pathogenic variants were most commonly identified Cutaneous 76 (20%) in MSH2 (n = 236, 62%), followed by MLH1 (n = 56, 15%), Non-cutaneous 143 (38%) MSH6 (n = 31, 8%), and PMS2 (n = 4, 1%) genes. The name Unreported 161 (42%) of the gene was not reported in 53 (14%) patients. The spe- Family history of cutaneous malignancy cific genetic defects or variants were reported in 235 cases Sebaceous 19 (5%) (62%). The pathogenic variant (NM_000251.3(MSH2):c.9 Non-sebaceous 41 (11%) 42 + 3A > T) was the most commonly reported single vari- No reported family history of cutaneous disease 173 (45%) ant, reported in 18 cases (8%) from 17 families in 9 studies. Unreported 147 (39%) The complete list of reported variants is shown in (Online Median age at diagnosis of cutaneous lesion Resource 2). Among those cases with uninformative test Sebaceous adenoma 55 (28–77) results, the extent of germline genetic testing was variable, Sebaceous carcinoma 56 (31–84) with a one-third having testing of four MMR genes (n = 18, Sebaceoma 56 (41–73) 35%). Testing of MSH2 only was performed in 1 case (2%), Keratoacanthoma 52 (34–70) of MLH1 and MSH2 in 17 cases (33%), and of MLH1, Squamous Cell Cancer 55 (33–75) MSH2, and MSH6 in 10 cases (19%). Extent of testing Basal Cell cancer 53 (29–68) was not specified in 6 cases (11%). The details of the cases with uninformative germline testing are shown in (Online Resource 3). The frequencies of skin lesions according to their genotypes are shown in Table 2. cancers, had evidence of sebaceous hyperplasia from There was a male predominance (Male to Female (M:F) ratio: 1.6:1), which was most pronounced among patients 17 years . The median age at diagnosis of visceral malignancies was 47 (21–72). In a small but substantial with sebaceous (M:F = 1.7:1) compared to non-sebaceous skin lesions (M:F = 1.4:1). The median age for the onset minority (34.7%) of patients, the cutaneous lesion pre- dated the visceral tumours by a median of 1 year (0–19). of skin lesions was 55 years. The median age at diagnosis of sebaceous skin lesions was 55 years (28–84), and of In those patients where LS was not immediately recog- nised, the interval between diagnosis of cutaneous and non-sebaceous skin lesions 53 years (26–75). Notably, one patient with a strong family history of LS-associated visceral tumours was prolonged, up to a median of 7 years (1–19). 1 3 Characterization of sebaceous and non‑sebaceous cutaneous manifestations in patients with… Fig. 2 Flowchart showing the number of cases included in this review, their genotypes, and results of immunohistochemistry and microsatellite instability testing of skin lesions Table 2 Skin lesions according to the underlying genotype of affected patients: Genotype of Total no. of Cases with SA Cases with SC Cases with Cases with KA Cases with SCC Cases with BCC affected cases cases sebaceoma MSH2 236 106 (45%) 62 (26%) 34 (14%) 47 (20%) 55 (23%) 24 (10%) MLH1 56 21 (38%) 18 (32%) 7 (13%) 4 (7%) 13 (23%) 5 (9%) MSH6 31 11 (35%) 8 (26%) 3 (10%) 1 (3%) 6 (19%) 3 (10%) PMS2 4 3 (75%) – – – – – Total 327 141 (43%) 88 (27%) 44 (13%) 52 (16%) 74 (23%) 32 (10%) SA Sebaceous Adenoma, SC Sebaceous Carcinoma, ka Keratoacanthoma, SCC Squamous Cell Cancer, BCC Basal Cell Cancer Immunohistochemistry and microsatellite testing Table 3 Skin lesions showing discordance between their IHC and MSI test results: Two hundred and seventy-eight skin lesions from 171 No Case Tumor Genotype IHC MS patients who ultimately had molecularly confirmed LS 1 1 KA MSH2 Intact MSI-High were assessed by IHC and/or MSI testing. In lesions for 2 2 SA MSH6 MSH2/MSH6 loss Stable which IHC (n = 253) was undertaken, 239 (94%) demon- 3 2 SA MSH6 MSH2/MSH6 loss Stable strated MMR protein loss corresponding to their underly- 4 3 SC MSH2 MSH2/MSH6 loss Stable ing germline genetic defects, but a minority of skin lesions 5 4 SCC MSH2 MSH2/MSH6 loss Stable (n = 14, 5%) were found to be MMR proficient, including 5 6 5 SCC MLH1 MLH1/PMS2 loss Stable Sebaceous Adenomas, 2 keratoacanthoma, 2 SCC, 1 Mela- 7 6 SCC MSH2 MSH2/MSH6 loss Stable noma and 4 others. 8 7 SCC MSH2 MSH2/MSH6 loss Stable Of those 114 tumours for which MSI testing was under- 9 8 SCC MSH2 MSH2/MSH6 loss Stable taken, 103 tumours (90%) demonstrated MSI, but 11 skin 10 9 Melanoma MLH1 Intact MSI-High lesions (10%) were MSS, including 6 SCC, 2 Sebaceous Adenomas, 1 Sebaceous Carcinoma, 1 keratoacanthomas, IHC Immunohistochemistry, MSI Microsatellite Instability and 1 intradermal melanocytic nevus. Of 91 skin lesions for which both MMR IHC and MSI determined in the papers. Forty-eight of these sebaceous testing were undertaken, discordance between the two tumour-based tests were noted in 10 tumours (11%) from tumours were reported to show MMRd (96%). In the majority of sebaceous adenomas, sebaceous carci- 9 cases (13%) (Table 3). There were additional 50 sebaceous tumours from 49 nomas, and sebaceomas, the patterns of MMR protein loss were consistent with their underlying germline defect: [111 molecularly confirmed LS patients in which the names of the genes and the details of the IHC testing were not (96%), 44 (100%), and 22 (100%), respectively]. Further- more, most of them were MSI [32 (95%), 19 (95%), and 18 1 3 S. Aziz et al. (100%), respectively]. On the other hand, 12 (86%) of the including BCC, SCC, and to a lesser extent melanoma, are keratoacanthomas were reported to show consistent MMR among the most common types of cancer in the general protein loss, and 4 (80%) were MSI. population, with estimated incidences of 158,934, 47,977, Seventy-four patients with molecularly confirmed LS 15,332, respectively in 2019 in the UK . developed SCC. Twenty-two SCCs were assessed for MMR Many authors postulate that the risk of squamous and deficiency by IHC, of which 20 (91%) were reported to other cutaneous malignancies in LS is under-recognised have MMR protein loss consistent with their underlying [10, 11]. Accordingly, in this systematic review, the most genotype. Sixteen SCCs in patients with LS were tested commonly reported lesions in the molecularly confirmed for MSI, of which 10 (63%) were reported to demonstrate cases were sebaceous adenoma (43%), sebaceous carcinoma MSI. Tumour-based testing of BCCs in patients with LS was (27%), sebaceoma (13%), and keratoacanthoma (16%). How- rarely undertaken, with 3 (9%) assessed by IHC; all of which ever, in addition to those skin lesions, which have already were reported to demonstrate a consistent MMR protein loss been linked to LS, there were high frequencies of SCC (100%), and only one case (3%) was tested for MSI, and it (23%) and BCC (10%). was also found to be MSI (100%). The male to female ratio in the cases, similar to skin can- Another notable skin lesion reported in molecularly cers in the general population, was higher in males compared confirmed cases was melanoma (N = 14) with median age to females. However, the age of onset of the skin tumours of diagnosis at 57 (Range: 26–68). IHC and MSI testing was much lower compared to their sporadic counterparts. was undertaken on melanomas from only two patients with The median age of onset of sebaceous carcinomas, SCC, and molecularly confirmed LS, both of which were found to be BCC in the patients were 56, 55, 53 years, compared to 73, MSI-High, and one was MMRd. The details of IHC and MSI 75, 68 years, respectively, in the general population [22, 23]. testing of the lesions from molecularly confirmed cases are This gap in their ages of onset suggests a potential role for shown in (Online Resource 4). Lynch Syndrome in the pathogenesis of these skin tumours. Non-sebaceous cutaneous malignancies are common, with risk increased by sun exposure, particularly among Discussion patients with Fitzpatrick Type I/II skin types. A number of hereditary disorders associated with melanoma and non- Prevention and/or early detection of cancer in patients with melanoma skin cancers have been identified. Many of the Lynch Syndrome is associated with increased survival . heritable conditions associated with an increased risk of The link between LS and sebaceous skin manifestations squamous and/or basal cell skin cancers are rare, recessive is well established . The total number of MTS cases or X-linked disorders associated with DNA repair defects— reported in the literature (n = 604) has increased by at least such disorders include Xeroderma Pigmentosum, Fanconi 200% in the last two decades compared to its total number Anaemia, Bloom Syndrome, Rothmund Thomson Syn- in 1999, reflecting an increased awareness of MTS and LS, drome, Werner Syndrome or Dyskeratosis Congenita . as well as an increase in the access to genetic testing . Other rare causes of basal cell skin cancer include auto- In the general populations, non-sebaceous skin lesions, somal dominant Gorlin Syndrome, Bazex-Dupré-Christol including SCC, BCC, melanomas, are widely studied Syndrome or Rombo Syndrome . These syndromic and characterized. However, frequency and characteris- disorders are typically associated with other non-malignant tics of sebaceous tumours, particularly benign sebaceous features; and some, particularly those recessive disorders neoplasms, are poorly defined. On the contrary, in Lynch associated with DNA repair defects, will be evident from Syndrome patients, sebaceous tumours have been widely early childhood . Lynch Syndrome, in contrast, has few investigated for the last 50 years, whereas little attention non-malignant manifestations, and is easily missed—with a has been given to non-sebaceous skin lesions. As a result, reported 95% of affected individuals unaware of their genetic the exact incidence of different sebaceous tumours in the diagnosis [1, 6]. Diagnosis of LS therefore relies on clini- general population is not known, and according to available cians being alert to family history and tumour features con- resources, they are considered rare. In a 9-year-retrospective sistent with this autosomal dominant disorder. study, Manonukul et al. found sebaceous tumours in only In this cohort, although SCC and BCC were noted in 2.34% of all skin lesion biopsies . In a population-based patients with molecularly confirmed LS, few of the tumours study, Dores et al., using the (Surveillance, Epidemiology, were assessed by IHC or MSI, and attribution of skin can- and End Results) data, indicated an incidence rate of seba- cer risk to the underlying genotype cannot be confirmed. ceous carcinoma in the order of 0.11/100,000 person-years Furthermore, compared to sebaceous skin lesions, higher . A more recent study by Sargen et al., using the same numbers of SCC (64%) and BCC (86%) were occurring in data, suggested an overall incidence of 2.4 cases per mil- sun exposed areas, suggesting an environmental risk factor. lion [19, 20]. Non-sebaceous tumours, on the other side, Melanomas have been linked to LS to a much lesser extent 1 3 Characterization of sebaceous and non‑sebaceous cutaneous manifestations in patients with… compared to SCC and BCC in the literature. However, 8 of origin . In 2017, the Food and Drug Administration the molecularly confirmed LS cases in this review had his- (FDA) approved pembrolizumab for advanced MSI-H/ tories of melanoma. Family history of melanoma was also MMRd malignancies, this was the first tissue-agnostic drug reported in 6 other molecularly confirmed cases. In addition approval for cancer by the FDA . to cutaneous melanomas, there are reports of ocular melano- More recently, the anti PD-1 agent cemiplimab has shown mas in LS patients in the literature [25, 26]. efficacy in both advanced cutaneous SCC and BCC [32, 33]. Of those cutaneous tumours that were assessed by MMR This has led to drug approval by the European Medicines IHC and/or MSI in molecularly confirmed cases, the major - Agency and FDA for both indications, meaning patients ity were MMRd or MSI-high, or both. However, the sensi- can access immunotherapy irrespective of MMR/MSI sta- tivity of MMR IHC was higher compared to MSI testing, tus [34–36]. particularly among keratoacanthoma and SCC. This does not appear to be limited to LS—in a small case series of unselected apparently sporadic cutaneous SCC, microsatel- lite instability was rare (1 of 22), but MMR deficiency as Limitations defined by loss of one or more proteins detected by IHC, more common (4 of 22) . It is well-recognised that the Few of the papers in this review provided comprehensive relative sensitivity of microsatellite testing in tumours of detail of the tumour and/or germline testing undertaken. In patients with LS is variable across tissue types, and greatly order to capture as wide a breadth of published literature influenced by neoplastic cell content in the sample, such that as possible, we included all published literature, such that IHC may be preferable in assessment of extracolonic malig- there is variability in the type of study and nature of data nancies, or in tumours of low cellularity [10, 28]. Recently, collection in the studies included in this review, precluding Ykema et al. reported ten SCCs in seven molecularly con- meaningful meta-analysis of data. The significant majority firmed Lynch Syndrome cases, all of which were IHC defi- of published literature relates to single case reports. Further- cient (100%), but only three of 9 assessed for microsatellite more, determining the frequency of skin lesions and their instability (33%) demonstrated MSI . Sowter et al., in characteristics were limited to the molecularly confirmed his response to Ykema et al. study, strengthened this link by Lynch Syndrome cases. As a result, there could be other skin testing nine SCCs from seven other molecularly confirmed lesions that are associated with Lynch Syndrome and have cases (data outside of the timeframe of this review), and not been described in this paper. found that eight tumours were MSI-H (89%) . Although in both studies the total number of SCCs and patients were small, the findings of immunohistochemically demonstrated MMR deficiency and/or MSI suggests that the underlying Conclusion diagnosis of Lynch Syndrome is clinically relevant to the pathogenesis of such cancers. The discordance between Skin lesions reported in patients with Lynch syndrome MMR immunohistochemistry and MSI testing in LS-asso- include SCC and BCC as well as sebaceous adenoma, seba- ciated non-colorectal samples reflects discordance observed ceous carcinoma, sebaceoma and keratoacanthoma, but by other authors. further large-scale prospective studies, with robust paired Basal and squamous cell cancers are much more common tumour and germline assessments, are required to confirm in the general population than sebaceous neoplasms/keratoa- causal association between non-sebaceous malignancy and canthoma, limiting the feasibility of universal screening by Lynch Syndrome. In the meantime, patients should be pro- MMR IHC/MSI for non-sebaceous malignancy. Universal vided with general advice to manage the risk of cutaneous screening of sebaceous malignancies may be more readily malignancies—taking care to avoid sunburn or exposure achievable, but the likelihood of MMRd or MSI being attrib- to excess UV irradiation (sunbeds), using high factor sun utable to underlying LS in isolated cases without personal/ cream, and seeking prompt advice when they develop any family history of other LS cases is very low . Rather than new skin lesions. They should also be provided with advice universal screening, judicious application of MMR IHC and/ regarding vitamin D replacement as necessary. Dermatolo- or MSI testing in patients with any type of skin cancers and gists should be alert to the relevance of a family history of suspicious family histories and/or earlier than expected age colorectal, endometrial or other Lynch Syndrome associ- at diagnosis and absence of other relevant risk factors, may ated cancers in individuals presenting with non-sebaceous facilitate detection of LS, and in some, may predate and help as well as sebaceous neoplasms, with assessment of MMR manage risk of visceral malignancy. by immunohistochemistry and/or MSI testing, and onward Immune checkpoint inhibitors have been shown to have germline testing or referral to Clinical Genetics undertaken activity in MSI-H/ MMRd cancers regardless of site of as required. 1 3 S. Aziz et al. Supplementary Information The online version contains supplemen- cancer. NICE Diagnostics Guidance. h t t p s : // w w w . n i c e . o rg. u k / tary material available at https://doi. or g/10. 1007/ s10689- 022- 00319-8 .guida nce/ dg42/ chapt er/1- Recom menda tions 8. Schwartz RA, Torre DP (1995) The Muir-Torre syndrome: a Author contributions All the authors have participated in writing, pre- 25-year retrospect. J Am Acad Dermatol 33(1):90–104. https:// paring the tables/figures, and reviewing this manuscript.doi. org/ 10. 1016/ 0190- 9622(95) 90017-9 9. John AM, Schwartz RA (2016) Muir-Torre syndrome (MTS): an Funding No funds, grants, or other support was received. update and approach to diagnosis and management. J Am Acad Dermatol. Elsevier 74(3):558–566. https://doi. or g/10. 1016/j. jaad. Data availability The datasets generated during and/or analysed dur-2015. 09. 074 ing the current study are available from the corresponding author on 10. 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Familial Cancer – Springer Journals
Published: Apr 1, 2023
Keywords: Lynch syndrome; Muir-Torre syndrome; Mismatch repair; Sebaceous tumour; squamous cell cancer; basal cell cancer
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