Society for Endocrinology
Prevalence and clinical characteristics of Lynch syndrome-associated adrenocortical carcinoma
Avilasha Sinha1, Katherine I Wolf02, Jenae Osborne3, Elizabeth A Hesseltine4, Francis P Worden4, Thomas J Giordano5, Gary D Hammer2 and Tobias Else 02
1Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
2Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, Michigan, USA
3Department of Internal Medicine, Division of Medical Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA 4Department of Internal Medicine, Division of Hematology & Oncology, University of Michigan, Ann Arbor, Michigan, USA
5Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
Correspondence should be addressed to T Else: telse@med.umich.edu
Abstract
Lynch syndrome is the result of pathogenic variants in mismatch repair genes that increase the risk of cancer, including adrenocortical carcinoma. Little is known, however, about the clinical characteristics of patients with Lynch syndrome-associated adrenocortical carcinoma. In order to understand the clinical characteristics and prevalence of Lynch syndrome-associated adrenocortical carcinoma, we conducted a retrospective chart review of patients with adrenocortical carcinoma and germline genetic testing results, indicating pathogenic variants in mismatch repair genes consistent with Lynch syndrome at a single academic tertiary-care institution. In total, 21 patients with Lynch syndrome-associated adrenocortical carcinoma were identified from 2003 to 2024. Three patients met Amsterdam I criteria, and 12 patients met Amsterdam II criteria (including adrenocortical carcinoma as a Lynch syndrome- associated cancer). More than 90% of patients with available histopathology had high-grade tumors, suggesting a more aggressive nature. The prevalence of Lynch syndrome-associated adrenocortical carcinoma is estimated at 2.6%. This study further demonstrates that adrenocortical carcinoma is a Lynch syndrome-associated cancer and may be associated with a high-grade disease. Furthermore, our findings suggest that further research should be pursued to investigate the potential utility of immunotherapy for adrenocortical carcinoma, especially in the presence of microsatellite instability.
Keywords: Lynch syndrome; adrenocortical carcinoma; prevalence; genetic testing
Introduction
First described in 1895 by Dr Aldred Scott Warthin of the University of Michigan (1), Lynch syndrome (LS) is an autosomal dominant hereditary cancer syndrome characterized by loss-of-function germline mutations in the mismatch repair (MMR) genes MSH2, MSH6, MLH1, and PMS2 (2). Patients with LS have an increased risk of colorectal, endometrial, and ovarian cancers with an estimated prevalence of 2.2%, 3%, and 1-2%, respectively (3, 4). While not as common, gastric, upper
urothelial, sebaceous gland (5), and adrenocortical tumors (6) are also associated with LS.
With respect to LS-associated adrenocortical carcinoma (ACC), the association between LS and ACC was first reported in 2013 with an estimated prevalence of LS among ACC of 3.2% (6). Outside of LS-associated tumors, germline TP53 mutations causing Li-Fraumeni syndrome underlie 50-80% of pediatric ACC cases (7, 8, 9). Despite the fact that the majority of ACC cases in adults
| Study name | Authors | Findings |
|---|---|---|
| Characteristics of adrenocortical carcinoma associated with Lynch syndrome (28) | Domènech et al. (28) | · Analysis of 634 patients from 220 families with LS from the years 1999-2018 . During this time period, a total of three patients were diagnosed with ACC and all three of these patients were found to have germline MSH2 mutations |
| Adrenocortical carcinoma is a Lynch syndrome-associated cancer (6) | Raymond et al. (6) | · Analysis of 94 patients diagnosed with ACC who received genetic counseling/screening · Of these 94 patients, three were ultimately found to have mutations in MMR genes consistent with LS, yielding a prevalence of LS in ACC patients of 3.2% |
Abbreviations: ACC, adrenocortical carcinoma; IHC, immunohistochemistry; LS, Lynch syndrome; MMR, mismatch repair; NGS, next-generation sequencing; and PV, pathogenic variant.
*Excluding case reports or case series with less than five patients. Studies were found using a PubMed search utilizing iterations of key words for ‘adrenocortical carcinoma’ and ‘Lynch syndrome’. +Of note, Pozdeyev et al. (29) found that 50/364 patients (13.7%) harbored genomic alterations in MMR genes; however, given that germline DNA was not available for comparison, the study was omitted from the table above.
are thought to be sporadic (10), given the associations of ACC with LS, Li-Fraumeni syndrome (11), multiple endocrine neoplasia type I (12, 13, 14), and familial adenomatous polyposis coli (15, 16, 17), genetic testing for these hereditary syndromes is recommended for patients with adult-onset ACC (18).
Given the rarity of ACC (0.5-2.0 cases per million) (19), prior descriptions are restricted to case reports and only two studies have evaluated the prevalence and/or clinical characteristics of ACC in patients with LS in larger cohorts (Table 1). As such, we conducted a retrospective review to evaluate specific features of LS-associated ACC to ascertain any differences in the course of the disease and disease outcomes, genetic features, and tumor characteristics and to estimate the prevalence of LS in ACC.
Materials and methods
The electronic medical records (EMRs) from a single tertiary-care referral center from January 01, 2003, to December 31, 2024, were searched using a web-based tool for authorized users of the EMR system for patients who had a diagnosis of ACC and features suggestive of a diagnosis of LS in their EMR (e.g., absent MMR staining). Defining keywords (e.g., ‘Lynch syndrome’ and ‘adrenocortical carcinoma’) and provider names from the Endocrine Oncology group were used as search terms. Diagnosis of ACC was confirmed via pathology reports, and 58 patients were identified. Diagnosis of LS was confirmed via documented germline genetic testing showing a pathogenic MMR variant. Twenty-seven patients either did not undergo germline genetic testing or did not have accessible germline genetic testing results and, as such, were excluded, yielding 31 patients who were confirmed to have had germline genetic testing showing a rare MMR gene variant. Ten patients were excluded for benign MMR
variants (BVs) (2) and variants of unknown significance (VUSs) (8). Therefore, a total of 21 patients were confirmed to have both ACC and LS. Transcript variants were classified as a pathogenic variant (PV), a BV, or a VUS using ClinVar. Studies were approved by the local institutional review board (HUM00091004).
Results
Twenty-one patients with ACC and PVs in MMR genes consistent with LS were analyzed. The mean age at diagnosis was 44 years (range 23-76 years) with an approximately equal sex distribution (10 females (47.6%) and 11 males (52.4%)). Pre-operative biochemical status, pathological markers (proliferation index (Ki67) and mitotic rate), stage of disease at diagnosis, and therapies are shown in Table 2.
The majority of patients (17, 81%) were diagnosed prior to stage IV disease progression; however, eight of these 17 patients (47.1%) later developed metastases. Overall, 12 patients (57.1%) had progression of their disease during the studied time period, as shown in Fig. 1. In addition, per the Kaplan-Meier estimate, approximately 65% of patients with LS are expected to have progression of disease within two years. Just over half of the patient cohort (11, 52.4%) had neither lab findings nor clinical signs or symptoms evidencing hormonal excess (of note, four (36.4%) patients did not have a complete biochemical evaluation).
Twenty patients (95.2%) underwent surgical resection of their primary tumors. The mean tumor size (by greatest dimension of the tumor) was 10.9 cm. Pathology reports noted Ki67 indices in only 13 patients (61.9%) and mitotic rates in 16 patients (76.2%). With respect to the available information, 15 patients (93.8%) had high-grade tumors via Ki67 proliferative index ≥10% or mitotic rate ≥20/50 per high-powered field, whereas one patient (6.2%) had a low-grade tumor. Of the eight patients who later
| Number of patients (%) | |
|---|---|
| Mean age at diagnosis (years) | 44.2 |
| Sex | |
| Female | 10 (47.6) |
| Male | 11 (52.4) |
| Stage of diagnosis | |
| Stages I-III | 17 (81.0) |
| Stage IV | 4 (19.0) |
| Tumor mitotic rate* | |
| ≥20/50 per HPF | 13 (81.3) |
| <20/50 per HPF | 3 (18.7) |
| Tumor Ki67%+ | |
| ≥10% | 12 (92.3) |
| <10% | 1 (7.7) |
| Hormone excess | |
| Cortisol | 3 (14.3) |
| Androgen | 2 (9.5) |
| Aldosterone | 1 (4.8) |
| Cortisol and androgen | 3 (14.3) |
| Cortisol and androgen and aldosterone | 1 (4.8) |
| No hormone excess | 11 (52.4) |
| Treatments | |
| Surgical resection | 20 (95.2) |
| Adjuvant mitotane | 14 (66.7) |
| Systemic chemotherapy | 8 (38.1) |
| Immunotherapy | 5 (23.8) |
| Adjuvant radiation | 4 (19.0) |
| Other LS-associated malignancies+ | 7 (33.3) |
Abbreviations: HPF, high-powered field; LS, Lynch syndrome.
*A total of only 16 patients had documented tumor mitotic rates. +A total of only 13 patients had documented tumor Ki67 proliferative indices. * Other LS-associated malignancies include colorectal, ovarian, endometrial, gastric, and renal cancers and sebaceous adenomas.
underwent systemic chemotherapy and/or immunotherapy, all eight underwent surgical resection prior to chemotherapy or immunotherapy. Fourteen patients (66.7%) received adjuvant mitotane.
Four patients (19.0%) received adjuvant radiation to the surgical bed. Eight patients (38.1%) received cytotoxic chemotherapy with an initial regimen of etoposide, doxorubicin, and cisplatin (EDP). Of these eight patients, five had EDP monotherapy, while three were transitioned to alternative chemotherapy regimens following progression, including gemcitabine and docetaxel and cyclophosphamide, vincristine, and dacarbazine (CVD).
Five patients (23.8%) received immunotherapy with the PD-1 inhibitor pembrolizumab. Two patients (40%) received pembrolizumab as second-line therapy, and three patients (60%) received pembrolizumab as third- line therapy. Of these five patients, three patients (60%) had progression of their disease within 12 months of pembrolizumab initiation.
Seven patients (33.3%) had a personal history of other LS- associated malignancies - two patients had upper urothelial tract cancers, two patients had sebaceous adenomas, one patient had colon cancer, one patient had endometrial cancer, and one patient had colon and endometrial cancers.
The genetic characteristics of patients are shown in Table 3. The majority of the patients (12, 57.1%) were found to have a PV in MSH2, while seven (33.3%) and two (9.5%) were found to have PVs in MSH6 and MLH1, respectively. No patients had a PV in PMS2. Only two patients (9.5%) were independently evaluated for microsatellite instability (MSI) - one had MSI and the other had microsatellite stability (MSS). Of these two patients, only the patient who had MSS underwent tumoral mutation testing, which confirmed microsatellite stability with an intermediate (six - 19 mutations/mb) tumor mutational burden (TMB). TMB was also assessed in four additional patients (three were low (<5 mutations/mb) and one was high (>20 mutations/mb)); however, there is no corresponding MSI for comparison. Seventeen patients (81.0%) had
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| Number of patients (%) | |
|---|---|
| Mismatch repair gene | |
| MSH2 | 12 (57.1) |
| MSH6 | 7 (33.3) |
| MLH1 | 2 (9.5) |
| Tumor IHC* | |
| All genes present | 1 (5.9) |
| MSH2 & MSH6 deficient | 10 (58.8) |
| MLH1 & PMS2 deficient | 2 (11.8) |
| MSH6 deficient | 3 (17.6) |
| MSH2 deficient | 1 (5.9) |
| Tumor IHC and germline testing concordance* | 15 (88.2) |
Abbreviations: IHC, immunohistochemistry.
*Only 17 patients had tumor IHC performed.
MMR immunohistochemistry (IHC) analysis of their tumors performed. Of these 17 patients, ten patients (58.8%) had tumors deficient in MSH2 and MSH6, three (17.6%) had tumors deficient in MSH6, two (11.8%) had tumors deficient in MLH1 and PMS2, one (5.9%) had a tumor deficient in MSH2, and one (5.9%) had all MMR genes present. Overall, 15 of these 17 patients (88.2%) had concordance between their tumor IHC analysis and their germline genetic testing results. Two patients with pathogenic MSH6 variants had discordant IHC - one showing the presence of all MMR genes and the other showing deficiency of both MSH2 and MSH6. Review of first- and second-degree relatives in all patients was notable for 15 patients (71.4%) with a family history of LS-associated malignancies (colon 20, gastric 6, endometrial 5, and ovarian 5). No patients had known family members with ACC. Three patients (14.3%) met Amsterdam I criteria, while 12 patients (57.1%) met Amsterdam II criteria (using ACC as a LS-associated malignancy).
The prevalence of LS among patients with ACC was estimated by dividing the number of patients with ACC and pathogenic MMR gene variants consistent with LS who received care at the studied institution’s Endocrine Oncology clinic from January 1, 2016, to December 31, 2024 (16), by the total number of patients with ACC who received care at the studied institution’s Endocrine Oncology clinic from January 1, 2016, to December 31, 2023 (605). This estimated prevalence of LS among patients with ACC was thus calculated to be 2.6%.
Discussion
Our retrospective cohort analysis of 21 patients with ACC and pathogenic MMR gene variants consistent with LS further demonstrates the association between ACC and LS. The estimated prevalence of LS among patients with ACC in the current study was 2.6%. The true prevalence is likely higher as not all ACC patients in the study period
had inclusive genetic testing. The current prevalence estimate is well in line with the prevalence of LS among colorectal, endometrial, and ovarian cancers (3, 4). LS was the most common familial cancer syndrome observed in our cohort over this study’s time frame. Although prior studies had estimated the prevalence of the Li-Fraumeni syndrome to be as high as 3.9-5.8% (11, 20), only 0.5% of ACC patients within the current study’s time frame were found to have pathogenic TP53 variants.
The fact that greater than 90% of patients with a documented tumor Ki67 proliferative index or tumor mitotic rate had a Ki67 proliferative index ≥10% or tumor mitotic rate ≥20/50 per high-powered field is suggestive of differences in biology of LS-associated ACC. However, pathological grade and clinical behavior are not necessarily correlated. Of the six patients with clinically aggressive ACC, as determined by progression- free survival (PFS) of less than one year, just four patients (67%) had pathologically high-grade tumors. Furthermore, 20% (n = 4) of our population lacked Ki67 proliferative indices or mitotic rates, precluding any correlative analysis. That being said, the higher percentage of patients with stage IV disease (19%) in our cohort of LS-associated ACC patients compared to sporadic ACC patients (10%) (10) might suggest a clinically more aggressive behavior of LS-associated ACC compared to sporadic cases.
Immune checkpoint inhibitors are increasingly used for ACC treatment, particularly in patients with progressive metastatic disease despite chemotherapy or those who are unable to tolerate cytotoxic regimens secondary to poor performance status (21). However, given the immunologically cold nature of ACC and the high percentage of either endogenous or exogenous hypercortisolism, immunotherapy has not been as successful in this population compared to other solid tumors, such as melanoma (22, 23, 24). LS-associated ACC might present a valuable indication for checkpoint inhibitor therapy, given the previous success of immunotherapy in MSI-high or MMR-deficient cancers (25). Of the five patients with ACC and LS who were treated with pembrolizumab, two (40%) had a PFS of at least twelve months. While this percentage is promising, the population of patients who received immunotherapy (n = 5, 24%) was limited. Furthermore, just two patients (10%) underwent independent evaluation of MSI, limiting the ability to definitively evaluate the utility and efficacy of immunotherapy for LS-associated, MSI-high ACC. That being said, clinical trial data of immunotherapy in progressive metastatic ACC, regardless of genetic status, have demonstrated overall response rates ranging between 6 and 23% (25). Furthermore, in trials comparing cytotoxic chemotherapy to immunotherapy in MSI-high tumors, each therapy was given as a first- line agent; however, in our cohort, pembrolizumab was a second or even third-line agent. Further evaluation is necessary to determine the impact on the order of therapy in this population and if the current standard
of care, EDP, should be foregone in LS-associated ACC in favor of exploring a trial of immunotherapy.
In our cohort of patients with ACC and PVs consistent with LS, only 14% of patients met Amsterdam I criteria and only 57% met Amsterdam II criteria (even with the inclusion of ACC as a LS-associated malignancy), re- demonstrating the low sensitivity of Amsterdam I and II criteria - other studies have found sensitivities of 14% for Amsterdam I criteria and 27-42% for Amsterdam II criteria (26, 27). The fact that many patients in our study did not meet Amsterdam II criteria and even fewer met Amsterdam I criteria suggests a general recommendation for genetic counseling and germline genetic testing for all patients with ACC, regardless of family history.
LS was the most common familial cancer syndrome in our cohort, and our study confirms a prevalence of LS among ACC patients comparable to those with colon, ovarian, or endometrial cancer, core malignancies of LS. Our findings also suggest that immunotherapy should be explored further as a first-line therapy for LS-associated ACC. Most importantly, we conclude that LS should be considered in all ACC patients, as it provides not only the basis of potential treatment decisions but also the basis of family cascade testing, allowing for the identification of additional at-risk family members who would benefit from individualized cancer screening.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the work reported.
Funding
This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under Award Number T32DK007245 (KIW).
Acknowledgments
We would like to thank the patients and their families for participation in our program.
References
1 Boland CR & Lynch HT. The history of Lynch syndrome. Fam Cancer 2013 12 145-157. (https://doi.org/10.1007/s10689-013-9637-8)
2 Tamura K, Kaneda M, Futagawa M, et al. Genetic and genomic basis of the mismatch repair system involved in Lynch syndrome. Int J Clin Oncol 2019 24 999-1011. (https://doi.org/10.1007/s10147-019-01494-y)
3 Abu-Ghazaleh N, Kaushik V, Gorelik A, et al. Worldwide prevalence of Lynch syndrome in patients with colorectal cancer: systematic review and meta-analysis. Genet Med 2022 24 971-985. (https://doi.org/10.1016/j.gim.2022.01.014)
4 Ryan NA, McMahon RF, Ramchander NC, et al. Lynch syndrome for the gynaecologist. Obstet Gynaeco/ 2021 23 9-20. (https://doi.org/10.1111/tog.12706)
5 Bhattacharya P, Leslie SW & McHugh TW. Lynch syndrome (hereditary nonpolyposis colorectal cancer). In StatPearls. Treasure Island, FL, USA: StatPearls Publishing, 2024. (http://www.ncbi.nlm.nih.gov/books/NBK431096/)
6 Raymond VM, Everett JN, Furtado LV, et al. Adrenocortical carcinoma is a Lynch syndrome-associated cancer. J Clin Oncol 2013 31 3012-3018. (https://doi.org/10.1200/jco.2012.48.0988)
7 Rodriguez-Galindo C, Figueiredo BC, Zambetti GP, et al. Biology, clinical characteristics, and management of adrenocortical tumors in children. Pediatr Blood Cancer 2005 45 265-273. (https://doi.org/10.1002/pbc.20318)
8 Varley JM, McGown G, Thorncroft M, et al. Are there low-penetrance TP53 alleles? Evidence from childhood adrenocortical tumors. Am J Hum Genet 1999 65 995-1006. (https://doi.org/10.1086/302575)
9 Wagner J, Portwine C, Rabin K, et al. High frequency of germline p53 mutations in childhood adrenocortical cancer. J Natl Cancer Inst 1994 86 1707-1710. (https://doi.org/10.1093/jnci/86.22.1707)
10 Scatolini M, Grisanti S, Tomaiuolo P, et al. Germline NGS targeted analysis in adult patients with sporadic adrenocortical carcinoma. Eur J Cancer Oxf Engl 2024 205 114088. (https://doi.org/10.1016/j.ejca.2024.114088)
11 Herrmann LJM, Heinze B, Fassnacht M, et al. TP53 germline mutations in adult patients with adrenocortical carcinoma. J Clin Endocrinol Metab 2012 97 E476-E485. (https://doi.org/10.1210/jc.2011-1982)
12 Waldmann J, Fendrich V, Habbe N, et al. Screening of patients with multiple endocrine neoplasia type 1 (MEN-1): a critical analysis of its value. World J Surg 2009 33 1208-1218. (https://doi.org/10.1007/s00268-009-9983-8)
13 Langer P, Cupisti K, Bartsch DK, et al. Adrenal involvement in multiple endocrine neoplasia type 1. World J Surg 2002 26 891-896. (https://doi.org/10.1007/s00268-002-6492-4)
14 Sørensen SA, Mulvihill JJ & Nielsen A. Long-term follow-up of von Recklinghausen neurofibromatosis. Survival and malignant neoplasms. N Engl J Med 1986 314 1010-1015. (https://doi.org/10.1056/NEJM198604173141603)
15 Marshall WH, Martin FI & Mackay IR. Gardner’s syndrome with adrenal carcinoma. Australas Ann Med 1967 16 242-244. (https://doi.org/10.1111/imj.1967.16.3.242)
16 Wakatsuki S, Sasano H, Matsui T, et al. Adrenocortical tumor in a patient with familial adenomatous polyposis: a case associated with a complete inactivating mutation of the APC gene and unusual histological features. Hum Pathol 1998 29 302-306. (https://doi.org/10.1016/s0046-8177(98)90052-1)
17 Painter TA & Jagelman DG. Adrenal adenomas and adrenal carcinomas in association with hereditary adenomatosis of the colon and rectum. Cancer 1985 55 2001-2004. (https://doi.org/10.1002/1097-0142(19850501)55:9<2001 :: aid- cncr2820550929>3.0.co;2-7)
18 Else T. Association of adrenocortical carcinoma with familial cancer susceptibility syndromes. Mol Cell Endocrino/ 2012 351 66-70. (https://doi.org/10.1016/j.mce.2011.12.008)
19 Torti JF & Correa R. Adrenal cancer. In StatPearls. Treasure Island, FL, USA: StatPearls Publishing, 2023. (http://www.ncbi.nlm.nih.gov/books/NBK546580/)
20 Raymond VM, Else T, Everett JN, et al. Prevalence of germline TP53 mutations in a prospective series of unselected patients with adrenocortical carcinoma. J Clin Endocrinol Metab 2013 98 E119-E125. (https://doi.org/10.1210/jc.2012-2198)
21 Brabo EP, Moraes AB & Neto LV. The role of immune checkpoint inhibitor therapy in advanced adrenocortical carcinoma revisited: review of literature. J Endocrinol Investig 2020 43 1531-1542. (https://doi.org/10.1007/s40618-020-01306-5)
22 Ababneh O, Ghazou A, Alawajneh M, et al. The efficacy and safety of immune checkpoint inhibitors in adrenocortical carcinoma: a systematic review and meta-analysis. Cancers 2024 16 900. (https://doi.org/10.3390/cancers16050900)
23 Fiorentini C, Grisanti S, Cosentini D, et al. Molecular drivers of potential immunotherapy failure in adrenocortical carcinoma. J Onco/ 2019 2019 6072863. (https://doi.org/10.1155/2019/6072863)
24 Tourigny DS, Altieri B, Secener KA, et al. Cellular landscape of adrenocortical carcinoma at single-nuclei resolution. Mol Cell Endocrinol 2024 590 112272. (https://doi.org/10.1016/j.mce.2024.112272)
25 André T, Shiu KK, Kim TW, et al. Pembrolizumab in microsatellite- instability-high advanced colorectal cancer. N Engl J Med 2020 383 2207-2218. (https://doi.org/10.1056/NEJMoa2017699)
26 Moreira L, Balaguer F, Lindor N, et al. Identification of Lynch syndrome among patients with colorectal cancer. JAMA 2012 308 1555-1565. (https://doi.org/10.1001/jama.2012.13088)
27 Barnetson RA, Tenesa A, Farrington SM, et al. Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer. N Engl J Med 2006 354 2751-2763. (https://doi.org/10.1056/nejmoa053493)
28 Domenech M, Grau E, Solanes A, et al. Characteristics of adrenocortical carcinoma associated with Lynch syndrome. J Clin Endocrinol Metab 2021 106 318-325. (https://doi.org/10.1210/clinem/dgaa833)
29 Pozdeyev N, Fishbein L, Gay LM, et al. Targeted genomic analysis of 364 adrenocortical carcinomas. Endocr Relat Cancer 2021 28 671-681. (https://doi.org/10.1530/erc-21-0040)