Mismatch Repair
Mismatch Repair
Mismatch Repair
12958
ORIGINAL RESEARCH
ratio for subgroups, defined by gender, age at diagnosis, Table 1 Descriptive characteristics for individuals with seba-
subtype of sebaceous neoplasia and anatomic location, for ceous neoplasia
predicting MMR deficiency. By definition, sensitivity is the
Characteristic Individuals (N = 882)
probability of a value above a threshold among those with
disease (i.e. MMR-deficient), while specificity is the proba- Gender, n (%)
Male 597 (67.7)
bility of a value below a threshold among those without
Female 285 (32.3)
disease (i.e. MMR-proficient). The positive predictive value Age at diagnosis (years)
is the probability that a lesion above a threshold is truly Mean (SD) 68.4 (13.3)
MMR-deficient, while the negative predictive value is the Range 16.1–100.1
probability that a lesion below a threshold is truly MMR- Total number of sebaceous 928
proficient. The likelihood ratio compares the probability of skin lesions
getting a value above a threshold if the lesion was MMR- Number of individuals 31 (3.5)
with >1 sebaceous skin lesion, n (%)
deficient with the corresponding probability if the lesion
Type of sebaceous skin lesion, n (%)
was MMR-proficient [=sensitivity/(1–specificity)]. Confi- Sebaceous adenoma 566 (64.2)
dence intervals (CI) for sensitivities, specificities, predic- Sebaceoma 127 (14.4)
tive values and likelihood ratios were calculated using the Sebaceous carcinoma 147 (16.7)
binomial formula. The receiver operating characteristic BCC + Sebaceous differentiation 18 (2.0)
(ROC) curve, used to discriminate among MMR-deficient SCC + Sebaceous differentiation 13 (1.5)
Miscellaneous/other 11 (1.2)
or MMR-proficient sebaceous neoplasms for subgroups
IEC with sebaceous 3
defined according to combined gender, age, type and ana- differentiation
tomic location, arranged in an ordinal scale (low to high Sebocrine adenoma 3
risk), was plotted as 1 minus the specificity (i.e. the false- Adnexal tumour with 1
positive rate) vs sensitivity.18 The area under the ROC sebaceous differentiation
curve (AUC) is equivalent to the probability that the pre- Appendageal carcinoma 1
Mixed appendageal tumour 1
dicted risk is higher for a MMR-deficient lesion than for a
Sebaceous carcinoma (metastatic) 1
MMR-proficient lesion.18 All analyses were two-sided, and Sebaceous trichoepithelioma 1
significance was set at a P value of 0.05. All statistical anal- Location, n (%)
yses were performed using Stata 15.0 (StataCorp, College Head/neck 728 (82.6)
Station, TX, USA). Trunk 108 (12.2)
Limbs 40 (4.5)
Unknown 6 (0.7)
RESULTS
BCC, basal cell carcinoma; IEC, intra-epithelial carcinoma; SCC,
Within the audit period, MMR IHC was performed on 928 squamous cell carcinoma; SD, standard deviation.
lesions obtained from 882 individuals, with a mean age at
first diagnosis of sebaceous neoplasia of 68.4 years
SD = 13.3 years and over two-thirds from males deficiency (89.5%) compared with only 14% in the head/
(Table 1). Nearly two-thirds of the lesions were sebaceous neck location (further stratification of the sebaceous
adenomas and 82.6% occurred in the head and neck lesion type according to anatomical subtype is provided
regions (Table 1). Thirty-one individuals had multiple in Table S3). There were no statistical differences
lesions tested during the ascertainment period (Tables 1 observed in the distribution of all lesions by MMR status
and S1). Rare lesions with regions of sebaceous differentia- for gender or mean age at diagnosis. Considering age at
tion were also included (Tables 1 and S2). diagnosis in 10-year age brackets, the highest frequency
Sebaceous neoplasia was further characterised for dif- of MMR deficiency for sebaceous adenomas, sebaceomas
ferences in gender, age at diagnosis, lesion type and and sebaceous carcinomas was observed in those diag-
anatomic location, stratified by MMR status (Table 2). nosed between 60 and 69 years with 28.1%, 38.2% and
MMR deficiency was reported in 282 of the 919 lesions 26.5%, respectively (Table S4). Early presentation of
tested (30.7%). MMR deficiency was most common in sebaceous lesions was not associated with MMR defi-
sebaceous adenomas (210/594; 35.4%), followed by seba- ciency with 10.4% of the MMR-deficient and 10.1% of
ceoma (34/141; 24.1%) and sebaceous carcinomas (34/ MMR-proficient sebaceous lesions detected in those diag-
150; 22.7%); basal cell carcinoma and squamous cell nosed under 50 years of age (Table S4).
carcinomas with focal sebaceous differentiation exhibited Loss of MSH2 and MSH6 protein expression was the
lower proportions of MMR deficiency (11.1% and 7.7%, most frequent pattern within the MMR-deficient sebaceous
respectively). Approximately two-thirds of the sebaceous lesions (187/281; 66.5%, Table 3). There was evidence that
adenomas, sebaceomas and sebaceous carcinomas com- age at diagnosis differed by pattern of protein loss in the
bined on the trunk or limbs were MMR-deficient com- MMR-deficient sebaceous lesions (P = 0.04) with lesions
pared with only 23.2% of lesions in head or neck with solitary loss of MSH6 (30/281; 10.7%) occurring, on
(P < 0.001; Table 2). This was most pronounced for average, at an older age to those with MLH1/PMS2 or
sebaceomas with all but two of the 19 sebaceomas from MSH2/MSH6 loss (Table 3). Seventy-two per cent of the
the trunk and limb location demonstrating MMR MMR-deficient lesions in the head and neck region
Gender, n (%)
Male 623 (100) 199 (31.9) 424 (68.1) 0.2
Female 296 (100) 83 (28.0) 213 (72.0)
Age at diagnosis (years)
Mean (SD) 68.2 (13.4) 67.7 (13.0) 68.4 (13.6) 0.5
Type of sebaceous skin lesion, n (%)
Sebaceous adenoma 594 (100) 210 (35.4) 384 (64.6) 0.01§
Sebaceoma 141 (100) 34 (24.1) 107 (75.9)
Sebaceous carcinoma 150 (100) 34 (22.7) 116 (77.3)
BCC + Sebaceous differentiation 18 (100) 2 (11.1) 16 (88.9)
SCC + Sebaceous differentiation 13 (100) 1 (7.7) 12 (92.3)
Miscellaneous/other 3 (100) 1 (33.3) 2 (66.7)
Location, n (%)
Head/neck 747 (100) 173 (23.2) 574 (76.8) <0.001¶
Trunk/limbs 167 (100) 108 (64.7) 59 (35.3)
Unknown 5 (100) 1 (20.0) 4 (80.0)
†
n = 9 out of n = 928 sebaceous skin lesions were deemed ineligible for this analysis. ‡v2 tests except for age where t-test was used.
§
Comparing sebaceous adenoma plus sebaceoma vs sebaceous carcinoma by MMR status. ¶Excluding unknown location. BCC, basal cell
carcinoma; MMR, mismatch repair; SCC, squamous cell carcinoma; SD, standard deviation.
Table 3 Comparison of mismatch repair-deficient sebaceous skin lesions by the pattern of immunohistochemistry loss
Gender, n (%)
Male 198 (100) 37 (18.7) 139 (70.2) 20 (10.1) 2 (1.0) 0.1
Female 83 (100) 23 (27.7) 48 (57.8) 10 (12.1) 2 (2.4)
Age at diagnosis (years)
Mean (SD) 67.7 (13.0) 66.3 (14.1) 67.2 (12.8) 73.3 (10.0) 71.8 (17.5) 0.04
Type of sebaceous skin lesion, n (%)
Sebaceous adenoma 209 (100) 46 (22.0) 137 (65.6) 22 (10.5) 4 (1.9) Not calculated
Sebaceoma 34 (100) 7 (20.6) 24 (70.6) 3 (8.8) –
Sebaceous carcinoma 34 (100) 6 (17.6) 25 (73.5) 3 (8.8) –
BCC + Sebaceous 2 (100) – 1 (50.0) 1 (50.0) –
differentiation
SCC + Sebaceous 1 (100) – – 1 (100) –
differentiation
Miscellaneous/other 1 (100) 1 (100) – – –
Location, n (%)
Head/neck 172 (100) 31 (18.0) 124 (72.1) 13 (7.6) 4 (2.3) 0.01§
Trunk/limbs 108 (100) 29 (26.9) 62 (57.4) 17 (15.7) –
Unknown 1 (100) – 1 (100) – –
†
n = 1 out of n = 282 MMR-deficient sebaceous skin lesions was excluded due to unknown pattern of immunohistochemistry loss. ‡v2
tests except for age where ANOVA test was, excluding PMS2. §Excluding unknown location. BCC, basal cell carcinoma; SCC, squamous cell
carcinoma; SD, standard deviation.
showed loss of MSH2/MSH6 protein expression (Table 3). The highest AUC for discriminating MMR-deficient seba-
Of the 31 individuals who had two or more sebaceous ceous lesions from MMR-proficient lesions was observed
lesions (total of 77 lesions) available for analysis for the ROC curve based on subgroups defined by type and
(Table S1), concordance of MMR protein expression was anatomic location of the sebaceous lesion (AUC = 0.6834;
observed for 27 individuals (87%; 14 concordant for MMR- Fig. 1). All other ROC curves and AUCs for subgroups
deficiency and 13 for MMR-proficiency). The remaining defined by gender, age, type and anatomic location are
four individuals with multiple lesions tested demonstrated shown in Figure S1. Sensitivities, specificities, positive and
discordant MMR IHC results; one individual had a MMR- negative predictive values, and likelihood ratios for the
proficient sebaceous adenoma aged 45 years then five sub- prediction of MMR-deficient sebaceous lesions are shown
sequent sebaceous adenomas between 46 and 48 years of in Table 4. The highest sensitivity for identifying a MMR-
age all demonstrating loss of MSH2/MSH6 expression deficient sebaceous lesion was provided by testing males
(Table S1). with sebaceous adenomas or sebaceomas (63.2, 95%
Figure 1 Receiver operating characteristic curve (ROC) for clinical characteristic prediction of mismatch repair-deficient sebaceous skin
lesions – Clinical characteristic were used to define the following subgroups: sebaceous carcinoma in trunk/limbs, sebaceous carcinoma in
head/neck, sebaceous adenoma/sebaceoma in trunk/limbs, sebaceous adenoma/sebaceoma in head/neck. AUC, area under the ROC curve;
SE, standard error.
CI = 57.2–68.9), while the highest specificity was achieved MSH2 and MSH6 protein expression. The ROC curve
by a combination of all features (male with diagnosis age demonstrated only moderate prediction of MMR deficiency
<70 years with sebaceous adenoma/sebaceoma in head/ for the best combination of clinico-pathological features
neck (74.3, 95%CI 70.6–77.7)). Compared with all others, (sebaceous lesion type and anatomical site), with an AUC
the combined clinical characteristics of age at diagnosis of of 0.6834. The combined clinical characteristics of age at
<70 years with sebaceous adenoma or sebaceoma subtype diagnosis of <70 years with sebaceous adenoma or seba-
achieved the highest positive predictive value of 37.3 (95% ceoma subtype achieved the highest positive and negative
CI 32.5–42.3) and highest negative predictive value of 73.2 predictive values with a likelihood ratio for MMR defi-
(95%CI = 69.1–77.1) which resulted in the highest likeli- ciency of 1.30 (95%CI 1.12–1.50).
hood ratio = 1.30 (95%CI 1.12–1.50) with corresponding Previous studies investigating MMR deficiency in seba-
sensitivity of 52.7 (95%CI 46.6–58.7) and specificity of 59.4 ceous neoplasia have reported frequencies ranging from
(95%CI 55.3–63.3). The next best approach resulted from 25% and 66%19 although several studies included patients
the combination of testing males diagnosed <70 years of with a priori high-risk for MTS recruited from genetics
age (Table 4). clinics, likely upwardly biasing the frequency of MMR-defi-
ciency.10,14 Our frequency of MMR deficiency (30.7%) is
similar to that reported by Cesinaro and colleagues9 (18/
DISCUSSION
70; 25.7%), a study cohort comprised of patients with iso-
Muir–Torre syndrome is a subtype of Lynch syndrome lated sebaceous neoplasms and those with both sebaceous
defined by the occurrence of synchronous or metachro- neoplasms and extracutaneous cancer. Across studies, loss
nous sebaceous neoplasia and one Lynch syndrome- of MSH2 protein expression (and its heterodimer partner
related internal cancer, irrespective of family history or MSH6) is the most frequently described pattern of IHC loss
age at onset where, similar to the internal cancers, seba- in sebaceous neoplasia9,16 and was the dominant pattern
ceous lesions are characterised by the presence of tumour of MMR protein loss in our study (66.5%). Further consis-
MMR deficiency. Sebaceous neoplasia may precede the tency in findings between our study and with previous
development of the internal cancers in MTS,14 highlighting studies was observed for lesion type with sebaceous ade-
the importance of screening these lesions for MMR defi- nomas the most frequent sebaceous neoplasm demonstrat-
ciency and the opportunity for internal cancer prevention ing MMR deficiency.16
strategies. In this study, MMR deficiency was observed in We note that a large majority of sebaceous lesions
30.7% of 919 sebaceous lesions tested, with a predomi- (81%) were from the head or neck, consistent with a
nance for lesions on the trunk or limbs to show loss of higher density of sebaceous glands on the upper body,
MMR protein expression, two-thirds of which was loss of especially the face.20 Lesions on the trunk or limbs,
Table 4 Sensitivity, specificity and predictive value of clinical characteristics for prediction of mismatch repair-deficient sebaceous skin lesions
Proportion out of
Proportion out of MMR-deficient skin Positive Negative
all sebaceous skin lesions predictive predictive Likelihood
lesions (N = 880)† (N = 277)† Sensitivity % Specificity % value % value % ratio
n (%) n (%) (95%CI) (95%CI) (95%CI) (95%CI) (95%CI)
Gender
Male (compared with female) 601 (68.3) 196 (70.8) 70.8 (65.0–76.0) 32.8 (29.1–36.7) 32.6 (28.9–36.5) 71.0 (65.3–76.2) 1.05 (0.96–1.16)
Age at diagnosis
<70 years (compared with ≥70 years) 452 (51.4) 159 (57.4) 57.4 (51.3–63.3) 51.4 (47.3–55.5) 35.2 (30.8–39.8) 72.4 (67.9–76.6) 1.18 (1.04–1.35)
Type of sebaceous skin lesion
Sebaceous adenoma/ 732 (83.2) 244 (88.1) 88.1 (83.7–91.7) 19.1 (16.0–22.4) 33.3 (29.9–36.9) 77.7 (70.1–84.1) 1.09 (1.03–1.15)
adenoma/sebaceoma
Male with lesions in head/neck 476 (54.1) 114 (41.2) 41.2 (35.3–47.2) 40.0 (36.0–44.0) 23.9 (20.2–28.0) 59.7 (54.7–64.5) 0.69 (0.59–0.80)
Age <70 with lesions in head/neck 360 (40.9) 93 (33.6) 33.6 (28.0–39.5) 55.7 (51.7–59.7) 25.8 (21.4–30.7) 64.6 (60.3–68.7) 0.76 (0.63–0.92)
Sebaceous adenoma/ 596 (67.7) 149 (53.8) 53.8 (47.7–59.8) 25.9 (22.4–29.6) 25.0 (21.6–28.7) 54.9 (48.9–60.8) 0.73 (0.64–0.82)
sebaceoma in head/neck
Male with sebaceous adenoma/ 412 (46.8) 101 (36.5) 36.5 (30.8–42.4) 48.4 (44.4–52.5) 24.5 (20.4–29.0) 62.4 (57.8–66.8) 0.71 (0.59–0.84)
sebaceoma in head/neck
Age <70 with sebaceous adenoma/ 308 (35.0) 85 (30.7) 30.7 (25.3–36.5) 63.0 (59.0–66.9) 27.6 (22.7–33.0) 66.4 (62.4–70.3) 0.83 (0.68–1.02)
sebaceoma in head/neck
Age <70 male with 213 (24.2) 58 (20.9) 20.9 (16.3–26.2) 74.3 (70.6–77.7) 27.2 (21.4–33.7) 67.2 (63.5–70.7) 0.82 (0.62–1.06)
sebaceous adenoma/
sebaceoma in head/neck
†
Includes eligible sebaceous adenoma, sebaceoma and sebaceous carcinoma only with no missing information on gender, age and location. ‡Compared with all others. CI, confi-
dence interval; MMR, mismatch repair.
Mismatch repair in sebaceous neoplasia 7
compared with the head or neck, were significantly more MMR mutations in only 14/38; 36.8%, of patients, highlight-
likely to exhibit MMR deficiency in our study (64.7% vs ing that MMR protein IHC in sebaceous lesions is not neces-
23.2%; P < 0.001). These results concur with previous sarily diagnostic for Lynch syndrome. In the absence of
studies,15,16 suggesting that the increased UV exposure to further genetic and tumour characterisation, we cannot dis-
head and neck contributes to the development of MMR- criminate between the clinically important subgroups that
proficient sebaceous neoplasia.21 are known to exist within tumours with MMR-deficiency,
The clinical utility of MMR IHC testing in cancer of the namely (i) Lynch syndrome; (ii) MLH1 methylation-positive
colon and rectum (CRC) and endometrial cancer for iden- lesions with corresponding loss of MLH1/PMS2 expression;
tifying Lynch syndrome has led to the recommendation of and (iii) the group referred to as having suspected Lynch
universal or reflex IHC of all newly diagnosed CRCs for syndrome with an absence of both germline MMR gene
MMR protein status, endorsed as the preferred approach to mutation or tumour MLH1 methylation, a group also
identify Lynch syndrome.22–24 By contrast, no guidelines or observed in CRC and endometrial cancer.25
recommendations exist for MMR IHC testing of sebaceous The challenge remains for clinicians and pathologists to
neoplasia for the identification of germline MMR gene determine which sebaceous skin lesions should be tested
mutation carriers (MTS–Lynch syndrome). This is perhaps for MMR deficiency. This study, the largest of its kind,
due to the limitations of studies published to date of small shows that the best combination of measured clinico-
sample sizes, or, like ours, unable to assess germline pathological features achieved only modest positive
mutation status to determine true effectiveness of MMR predictive values, sensitivity and specificity for identifying
IHC for identifying MTS–Lynch. Furthermore, recent stud- MMR-deficient sebaceous skin lesions. Further genotype–
ies have shown that a germline MMR gene mutation is phenotype correlation in sebaceous neoplasia is essential
identified in less than half of the individuals with MMR- to improve decision making for MMR testing and its
deficient sebaceous neoplasia.10,14 This is further compli- clinical consequences.
cated by reports that a small number of individuals have a
pattern of MMR protein loss by IHC that is not consistent
with the MMR gene harbouring the underlying germline ACKNOWLEDGEMENTS
mutation.14,15 Despite these current limitations, MMR IHC We are indebted to Drs Mark Clendenning, Jihoon(Eric)
testing to identify MMR deficiency is currently the only Joo, Bernard Pope, Khalid Mahmood, and Mr Neil O’Cal-
useful screening tool for identifying MTS–Lynch but is not laghan, Ms Sharelle Joseland, Ms Susan Preston and Mr
diagnostic for MMR gene mutation. Thomas Green from the Colorectal Oncogenomics Group
Of interest, 87% of individuals with multiple sebaceous for their support for this manuscript. We are indebted to
lesions in this study demonstrated concordant results for Ms Kirsty Storey and Ms Jessica Taylor from the Genomic
MMR protein expression with roughly equal proportions Medicine and Family Cancer Clinic for their support of this
showing either all lesions with MMR deficiency or all with manuscript.
MMR proficiency. This raises two important points, namely
MMR IHC testing of multiple lesions from an individual
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