Advances in Anatomic Pathology:
Identifying Lynch Syndrome in Patients With Ovarian Carcinoma: The Significance of Tumor Subtype
Chui, Michael Herman MD*; Gilks, C. Blake MD, FRCPC†; Cooper, Kumaresan MD, DPhil, FRCPath‡; Clarke, Blaise A. MBBCh, FRCPC*,§
*Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto
§Department of Pathology, Toronto General Hospital, University Health Network, Toronto, ON
†Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
‡Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA
The authors have no funding or conflicts of interest to disclose.
Reprints: Blaise A. Clarke, MBBCh, FRCPC, Department of Pathology, Toronto General Hospital, University Health Network, 200 Elizabeth Street, Rm 11E404, Toronto, ON, Canada M5G 2C4 (e-mail: firstname.lastname@example.org).
Up to 15% of ovarian cancers are etiologically linked with hereditary susceptibility. Within this group, germline mutations in mismatch repair (MMR) genes, known otherwise as Lynch syndrome (LS), account for the majority of cases that are not associated with mutations in BRCA1 or BRCA2. Clinical schemas specific for gynecologic cancers have been developed to identify patients with LS; however, many of the recommendations are poorly defined. Few case series of germline-confirmed LS-associated ovarian cancers have been reported, limited by small sample size and often lacking central pathology review. Much insight has been gained from studies of unselected cohorts, using immunohistochemical assessment of MMR protein expression or microsatellite instability analysis. In spite of contradictory results, likely reflective of differences in study design, sample size and methodology, a recurring observation is the overrepresentation of “endometriosis-associated tumors,” namely, endometrioid and clear cell subtypes, in the group of ovarian tumors with MMR deficiency. In this review, we summarize the clinical and histomorphologic features of LS-associated/MMR-deficient ovarian epithelial cancers and recommend that reflex testing be performed on the basis of tumor subtype.
Several groups have recommended reflex testing with mismatch repair (MMR) immunohistochemistry (IHC) or microsatellite instability (MSI) testing to identify Lynch syndrome (LS) in patients presenting with colorectal and endometrial cancer.1,2 Such recommendations are predicated on the low genetic counseling referral rates and LS detection rates achieved using clinical and histomorphologic schemas.
In addition to a 40% to 60% lifetime risk of endometrial cancer, women with LS have a 10% to 12% lifetime risk of developing a primary ovarian tumor.3,4 Importantly, in 60% of these women, a gynecologic malignancy will be the sentinel cancer.5,6 Thus, the diagnosis of LS at this opportunity would enable implementation of appropriate colon cancer screening and genetic counseling/testing for the patient’s family members.
Ovarian and endometrial carcinomas are not single disease entities, but encompass multiple distinct subtypes/histotypes. Most studies reviewing endometrial carcinoma subtypes in women with LS have demonstrated a similar distribution to the sporadic population,7–9 though some investigators have suggested a higher incidence of tumors classified as non-endometrioid or mixed.10 There are relatively few clinical studies conducted in this area, with small sample sizes, heterogenous study populations across studies, variable definitions of LS and MSI, and biases introduced through age-based inclusion criteria.3 Another caveat is the moderate level of reproducibility in assigning histotype, which is particularly problematic for high-grade tumors. Currently, any reflex testing strategy would encompass all endometrial carcinoma subtypes, with the inclusion of age as a screening criterion being subject to debate.
Until recently, the WHO classification of epithelial ovarian carcinoma (OC) has been plagued by only moderate interobserver reproducibility (κ statistics of 0.46 to 0.55).11,12 The advent of immunohistochemical and molecular biomarkers has refined the morphologic classification of OC and the contemporary approach to subtype allocation is highly reproducible amongst both subspecialty and general pathologists.13 Each subtype is characterized by distinct risk factors, molecular pathogenesis, prognostic markers, and therapeutic targets. There is growing consensus that germline alterations in BRCA1 or BRCA2 are associated exclusively with high-grade serous histology,14 although some studies suggest other high-grade subtypes may be seen in this setting. Accordingly, cell type can be a key factor in triaging patients for germline mutation testing; in the province of Ontario, all women with invasive pelvic/peritoneal serous carcinoma are eligible for BRCA1 and BRCA2 genetic testing and a recent study confirmed that a histology-based referral system is more effective than family/personal history.15
After BRCA1 and BRCA2, LS is the next most common hereditary OC syndrome, accounting for up to 15% of hereditary cases.16 Women with LS have a lifetime risk of OC of 7% to 15% compared with 1% to 2% in the general population. After colorectal and endometrial cancers, OC has the highest standardized incidence ratio in LS.6 In one study, the estimated prevalence varied depending on the affected gene, with a primary ovarian tumor diagnosed in 5% to 11% of MLH1, 20% to 40% of MSH2, and 33% to 65% of MSH6 families.17 As there is some preliminary evidence to suggest that MMR deficiency in a tumor may be predictive of response to certain chemotherapeutic agents,18,19 identification of this molecular abnormality, whether in syndromic or sporadic form, may be prove to be of clinical significance, as it is for colorectal cancer.
In the present paper, the clinical and histopathologic features of LS-associated OC are reviewed, highlighting the limitations of clinical schemas and age-based criteria for triaging patients for genetic testing. Summarizing the results from studies of confirmed LS-associated OC and of MMR IHC and MSI analyses on unselected cohorts, we propose an evidence-based reflex testing strategy based on tumor subtype and discuss issues that need to be addressed in future research.
The Amsterdam and Bethesda clinical schemas for identification of LS are colon-centric and perform poorly in identifying LS in women with gynecologic malignancies.7,20 Recently the Society of Gynecologic Oncologists (SGO) proposed two new schemas to improve identification of hereditary predisposition in women presenting with gynecologic cancers.21 These have been shown to be more sensitive in identifying LS-associated endometrial cancers.7 In our pilot study comparing the various schemas in a set of 15 OC from confirmed LS families, the SGO20-25% correctly identified 60% of cases and the SGO5-10% identified 93%, whereas the Amsterdam II and revised Bethesda only identified 47% and 33%, respectively.22 Although demonstrating improved sensitivity, the specificity of the SGO criteria is presently unknown. It should also be noted that the recommendations are vague, with considerable leeway left to the clinician’s discretion.
Overall, there is growing consensus that clinical schemas are insufficiently robust, either due to poor implementation in the clinical setting or the variably penetrant nature of the syndrome. As such, several groups have supplanted clinical history with MMR IHC as the primary mechanism to triage patients for LS testing.23,24
REVIEW OF STUDIES
There are only a handful of studies of germline mutation confirmed and/or family pedigree–based LS-associated OC, with sample sizes ranging from 2 to 79 patients and many lacking central pathology review. Without recent central pathology review, the diagnoses in such cohorts can be expected to lack accuracy in subtype assignment, as more refined diagnostic criteria with improved diagnostic reproducibility would not have been uniformly used. Typically, studies have been based on MMR IHC or analysis of MSI markers in unselected OC cohorts, which inherently included both sporadic and syndromic cases. Although variability in testing methodology, data analysis, and completeness of reporting makes comparative analysis between studies difficult, certain clinical and pathologic features have consistently emerged in association with MMR-deficient OC.
STUDIES OF LYNCH SYNDROME–ASSOCIATED OVARIAN CARCINOMA
Age at Diagnosis and Genotype
The age of onset of OC in LS will inform screening and prevention strategies and reflex testing policies. Table 1 presents age-related data from 18 studies of LS-associated OC; these include patients with germline-proven LS, members of known LS families, and patients meeting LS family history criteria. Ages range from 26 to 76 years, with the mean age across studies ranging from 41 to 55 years. Unlike endometrial cancer, the age at diagnosis is similar across genotypes for MLH1, MSH2, and MSH6. The current data is limited by small sample size, with many studies lacking genotype confirmation. On the basis of these few studies, most patients are under 50 years old, and there is no appreciable difference in age of onset between genotypes. However, additional prospective studies are required to adequately inform screening policies.
There are only a handful of reports documenting the histologic subtypes of LS-associated OC (Table 2). Results should be interpreted with caution, as previously discussed, due to limited sample size, lack of central pathology review and usage of outdated diagnostic terminology (including 3-tier tumor grading) in many of these studies. Nevertheless, there seems to be an overrepresentation of non-serous subtypes in LS-associated OC, as previously suggested by Pal et al16 and confirmed in subsequent work.17,36,40
In the largest cohort of LS-associated ovarian tumors, reported by Watson et al,31 71 of 79 tumors with available histology data were OC (89.9%); there was a modest enrichment of the endometrioid subtype in comparison with frequencies typically seen in the general population (18.3% vs. 9.6%). Diagnoses were obtained from medical reports from 14 registries from 11 countries, spanning a 61-year period (1936 to 1997), reported by different pathologists against an evolving and only moderately reproducible classification system. Moreover, with close to one third of cases being unclassified, the specific frequencies should not be considered accurate.
Ketabi et al17 reached a similar conclusion in their retrospective analysis of Swedish and Danish LS patients with documented germline mutations in MLH1, MSH2, or MSH6. Clear cell and endometrioid carcinomas accounted for 36.4% and 20.5% of LS-associated ovarian cancers compared with approximately 14% and 5% of sporadic cases. Serous tumors represented 38.6% of cases and mucinous, 4.5%. Interestingly in the 10 serous carcinomas with stage of disease documented, only 5 (50%) were advanced stage (III or IV), a considerably lower frequency than typically observed for this type of malignancy.43,44 The possibility of some cases being misclassified is therefore likely.
Overall, of the 168 cases of LS-associated OC reported in the literature, 54 (32.1%) were serous, 43 (25.6%) endometrioid, 24 (14.3%) clear cell, 14 (8.3%) mucinous, and 33 (19.6%) were epithelial, not otherwise specified. This contrasts with the relative incidence rates observed in the general population: serous 70%, endometrioid and clear cell, each around 10%, and mucinous 3-4%.44
Stage of Disease
It is clear that the majority of LS-associated OC cases are localized to the pelvis (stage I/II) (Table 3). Although it has been postulated that syndromic cases tend to present at an early stage compared with sporadic OC,17 stage of disease may be a surrogate for a subtype-specific bias in the LS population, with these tumors being predominantly clear cell and endometrioid subtypes.
LOSS OF IMMUNOHISTOCHEMICAL EXPRESSION OF MISMATCH REPAIR PROTEINS IN UNSELECTED COHORTS
Table 4 summarizes 8 studies evaluating MMR protein expression by IHC in OC from general population cohorts. Although some studies included non-epithelial tumors, only data on invasive OC are presented here. For mucinous and serous carcinomas, <5% show loss of MMR staining, whereas frequencies >10% are observed in the endometrioid and clear cell subtypes.
In our series,51 MMR deficiency was significantly more common in the endometriosis-associated carcinomas (including endometrioid, clear cell, undifferentiated/dedifferentiated, and mixed clear cell/endometrioid carcinoma) (7/69; 10%) compared with high-grade serous carcinomas (2/182; 1.1%, P=0.0021). The 2 MMR-deficient high-grade serous carcinomas lost expression of MLH1/PMS2, possibly from sporadic methylation of the MLH1 promoter. All 66 mucinous tumors (32 carcinoma and 34 borderline) retained intact expression of MMR proteins.
Although the diagnosis of mixed carcinoma is poorly reproducible amongst pathologists, the more common types of mixed carcinoma seem to be clear cell/endometrioid (Figs. 1A, B), endometrioid/undifferentiated (ie, dedifferentiated carcinoma), and mixed endometrioid/mucinous carcinoma, the latter perhaps better classified as a variant of endometrioid carcinoma (Figs. 1C, D). We are aware of only 2 studies that have performed MMR IHC on mixed OC. In our study, MMR deficiency was detected in 3 of 5 (60%) mixed tumors (2 mixed clear cell/endometrioid and 1 mixed endometrioid/undifferentiated).51 Rosen et al47 included 73 mixed OC in their tissue microarray, of which only 3 (4.1%) were MMR-deficient (the main components were transitional cell, clear cell, and endometrioid, respectively).
MICROSATELLITE INSTABILITY ANALYSES IN UNSELECTED OVARIAN CARCINOMA COHORTS
Although many studies have examined MSI in ovarian tumors, the variability in testing methodology and reporting of results has made comparisons between studies difficult. To standardize the definition of MSI, the National Cancer Institute (NCI) recommended a panel of 5 microsatellite loci to be tested, including 2 mononucleotide repeats (BAT25 and BAT26) and 3 dinucleotide repeats (D2S123, D5S346, and D17S250). High-frequency MSI (MSI-H) is defined by the presence of ≥2 markers with variations in microsatellite sequence length, whereas low-frequency MSI (MSI-L) is defined by an abnormal result in 1 marker. The frequency of MSI in ovarian cancer has previously been estimated to be around 12% to 20%, with ranges from 0% to 37% reported in the literature.4 In an attempt to draw more meaningful conclusions from the cumulative data, only studies that used markers from the NCI panel and reported proportions of MSI-H, MSI-L, and microsatellite-stable (MSS) tumors by histotype were included in our analysis (Table 5). It is noteworthy that these results, when considered in aggregate, show a marked discordance from the pattern observed in studies of LS-associated OC and studies using MMR IHC. Overall, the frequencies of MSI-H and MMR loss by IHC in serous are 12.9% and 4.8%, in mucinous 18.5% and 3.0%, in endometrioid 18.5% and 11.6%, and in clear cell 15.7% and 13.7%, respectively. Reported rates of MSI-H varied widely across studies (from 0% to 46% in serous, 0% to 27% in mucinous, 0% to 27% in endometrioid, and 0% to 25% in clear cell), reflecting differences in study design, sample size, and marker panel. Indeed, although MMR detection by IHC is straightforward and methodology relatively consistent across studies, the use of different marker panels for MSI, with many studies adding additional markers to the NCI panel, likely contributes to significant interstudy variability.
Of note, the study by Dellas et al,54 which reported the highest rates of MSI-H in serous and mucinous carcinomas, included both high-grade and low-grade serous carcinomas in aggregate, with close to 40% being stage I/II. As close to 90% of high-grade serous carcinomas present as advanced stage disease,43 the high proportion of localized serous carcinomas in this cohort is unusual. There was also a marked discordance between the MSI and MMR IHC data, with an unusually high proportion (65%) of MSI tumors retaining intact expression of MLH1, MSH2, and MSH6.
Future studies should adopt a strict definition for MSI using the standardized NCI panel and central pathology review to ensure rigorous histologic subtyping. Larger sample sizes should also be obtained, particularly for mucinous tumors, with correlation made with MMR IHC and germline mutation status.
SYNCHRONOUS ENDOMETRIAL CARCINOMA
MMR-deficient OC present not uncommonly with synchronous endometrial tumors. In the study by Jensen et al50, of the 4 cases showing MMR deficiency by IHC, 2 were synchronous with endometrial cancers, one of which had discordant histology, with clear cell carcinoma in the ovary and endometrioid carcinoma in the endometrium, both sharing an identical immunoprofile (MSH2 and MSH6 loss). Synchronous endometrial cancers were identified in 18/80 (21.5%) patients in the series by Watson et al31 and in 2/7 (28.6%) patients in the series by Rubin et al.26 In light of these observations, a relationship between synchronous endometrial and ovarian malignancies has been postulated to be associated with MMR deficiency. However, in a pivotal study addressing this issue conducted by the M.D. Anderson group, the finding of synchronous ovarian and endometrial tumors did not predict for loss of MMR expression or MSI, unless there was a family history of LS-associated malignancy.58
OTHER MORPHOLOGIC FEATURES
In colorectal and endometrial cancers, tumor-infiltrating lymphocytes, peritumoral lymphocytes, and de-differentiated morphology are used to screen patients for further LS testing. Aysal et al59 did not find a relationship between these morphologic features and abnormal MMR IHC or MSI in their analysis of 71 endometrioid ovarian carcinomas. At present, the only promising histomorphologic characteristic of MMR-deficient ovarian tumors to allow selection of cases for genetic testing is histotype.
The College of American Pathologists has stated that pathologists should recognize the histologic and clinical features that should prompt at least a recommendation for MMR testing.60 Reflex testing of colorectal cancer with MMR IHC is becoming standard of care and similar recommendations are being made for endometrial cancer. Nevertheless, there is accumulating evidence that there is over-representation of non-serous histologies in LS and MMR-deficient ovarian cancers, analogous to the association between BRCA1 and BRCA2 mutations and high-grade serous carcinoma. This has prompted at least one Canadian health authority, namely Vancouver Coastal Health in British Columbia, to perform reflex testing of all non-serous OC, with 6 of 15 cases tested to date showing loss of MMR expression (C.B.G., unpublished observations). Future studies using rigorous histopathologic review of all cases and standardization of study design and methodology will be essential for precisely defining the frequency of MMR deficiency for different OC subtypes and the morphologic features that should prompt consideration for genetic testing.
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Lynch syndrome; ovarian cancer; reflex testing; mismatch repair; immunohistochemistry
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