Characteristics of adrenocortical carcinoma associated with
Lynch Syndrome
Marta Domenech1,2”, Elia Grau1,3, Ares Solanes1,3, Angel Izquierdo 1,4,5, Jesus del Valle1, Cristina Carrato7,, Marta Pineda 1,6, Nuria Dueñas1,6, Magda Pujol 8, Conxi Lázaro 1,6, Gabriel Capellà 1,6, , Joan Brunet 1,3,6, Matilde Navarro1 1,3,6
1 Hereditary Cancer Program, Catalan Institute of Oncology, Insititut d’Investigació Biomedica de Bellvitge (IDIBELL), ONCOBELL Program, Hospitalet de Llobregat, Barcelona.
2 Medical Oncology Department, Catalan Institute of Oncology, ICO-Badalona, Barcelona.
3 Hereditary Cancer Program, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Barcelona.
4 Hereditary Cancer Program, Catalan Institute of Oncology, Hospital Josep Trueta, Girona.
5 Epidemiology Unit and Girona Cancer Registry, Oncology Coordination Plan, Catalan Institute of Oncology, Girona, Spain
6 Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
7 Pathology Department, Hospital Germans Trias i Pujol, Badalona, Barcelona.
8 Pathology Department, Moises Broggi Hospital, Sant Joan Despí, Barcelona
* Correspondence:mdomenechv@iconcologia.net
Author Contributions: Conceptualization, M.D .; E.G and M.N .; methodology, M.D; E.G and M.N; writing-original draft preparation, M.D; E.G; ND and M.N .; writing-review and editing, A.S; A.I; J.V; G.T; C.L; G.C; J.B and M.P; supervision, M.P; M.N; J.B and G.C. All authors have read and agreed to the published version of the manuscript.
Conflicts of Interest: “The authors declare no conflict of interest.”
Abstract
Context: Lynch syndrome (LS) is the most common inherited colorectal and endometrial cancer syndrome, caused by germline mutations in DNA mismatch repair (MMR) genes. It is also characterized by an increased risk of other tumours with lower prevalence, such as adrenal cortical carcinoma (ACC), an endocrine tumour with an incidence of < two cases/million individuals/year. Most ACC developed during childhood are associated with hereditary syndromes. In adults this association is not as well established as in children. Previous studies showed a 3.2% prevalence of LS among patients with ACC. Evidence adquisition: The objective of this study is to determine the prevalence of ACC in a Spanish LS cohort and their molecular and histological characteristics. This retrospective study includes 634 patients from 220 LS families registered between 1999 and 2018. Evidence synthesis: During the follow-up three patients were diagnosed with ACC (0.47%), all were carriers of a MSH2 germline mutation. The three ACC patients presented loss of expression of MSH2 and MSH6 proteins. One tumour analysis showed loss of heterozygosity of the MSH2 wildtype allele. Our findings support previous data which considered ACC as a LS spectrum tumour. Conclusion: MMR protein immunohistochemistry screening could be an efficient strategy to detect LS in patients with ACC.
Keywords: Lynch syndrome, adrenocortical carcinoma, molecular characteristics
Accepted Manterem
Introduction
Adrenocortical carcinoma (ACC) is an uncommon endocrine cancer which has an aggressive course. ACC has an incidence of 0.5-2 cases per million individuals per year1 . According to the Surveillance, Epidemiology and End Results (SEER) database ACC has a bimodal age distribution with a peak representing 1.3% of cancers during childhood and a second peak representing 0.02-0.2% of adult cancers2.
Most ACCs diagnosed during childhood or adolescence are related to hereditary syndromes, mainly Li- Fraumeni syndrome. According to current data, mutations in TP53 would be responsible for 50-80% of childhood ACCs3,4. On the other hand, most adult ACCs are sporadic and their association with hereditary syndromes is less known. In addition to Li-Fraumeni syndrome, other hereditary syndromes have been related with ACC such as Multiple Endocrine Neoplasia type 1 (MEN-1) and Lynch Syndrome (LS), among others. TP53 mutations are responsible for about 3-7% of adult ACCs3,6. In patients diagnosed with MEN-1, most of the adrenal tumours are benign and non-functional, and only a few cases are ACC7.
During the last years, some cases of ACC have been associated with LS 8-15, an autosomal dominant inherited syndrome due to germline mutations and epimutations in DNA mismatch repair genes (MMR), MLH1, MSH2, MSH6, PMS2 and EPCAM. Patients with LS have a 20 to 80% increased lifetime risk of colorectal cancer (CRC) and a 15-70% for endometrial cancer depending on the germline mutated gene16,17.
In addition, LS has an increased risk of other tumours such as ovarian, upper urinary tract, stomach, pancreatic cancer and sebaceous adenomas, among others18.Tumour screening by immunohistochemical analysis of MMR protein expression, with or without microsatellite instability analysis, is currently recommended in all patients diagnosed with colorectal19 and endometrial cancer20 as up to 28% of LS patients would be missed when the study is solely based on clinical criteria 21. Currently, some studies support the routine performance of the immunohistochemical analysis of MMR proteins in other tumour types of the Lynch syndrome spectrum22,23 such as sebaceous adenomas [24] and upper urinary tract tumours25. The identification of MMR- deficiency in tumours from LS patients helps to widen the tumour spectrum of this hereditary syndrome, improving diagnosis and eventually screening strategies for patients and their families.
The low incidence of ACC in adults and its reported association with inherited cancer syndromes prompts the question of whether an ACC tumour is sporadic or related to an inherited cancer syndrome. The objective of this study is to establish the prevalence of adrenocortical carcinoma in a LS cohort as well as their molecular and histological characteristics.
Materials and Methods
This is a retrospective cohort study from the Catalan Institute of Oncology Hereditary Cancer Registry which includes 634 individuals (347 women and 287 men) from 220 families, diagnosed with LS between 1999 and 2018. All individuals included were proven carriers of a pathogenic mutation in one of the MMR genes (286 MLH1, 180 MSH2, 112 MSH6, 41 PMS2 and 15 EPCAM).
Patients referred for MMR mutation analysis were suspected of having LS as they fulfilled LS clinical criteria (Amsterdam or revised Bethesda guidelines) or Jerusalem criteria (MMR-deficiency in tumours diagnosed <70 years, in the absence of BRAF pV600E mutation or MLH1 promoter hypermethylation in tumours showing MLH1 loss of expression, applied since January 2016). Point mutation analyses of MMR genes was performed either by PCR amplification of exonic regions and exon-intron boundaries followed by Sanger sequencing or by next generation sequencing. Classification of the identified genetic variants was performed according to Insight guidelines 26. Genomic rearrangements in MMR genes were analysed by multiplex ligation dependent probe amplification (MRC-Holland). Laboratory reports identifying a pathogenic mutation in any of the MMR genes were required for confirmation. Verification of mutations was lacking in obligate carriers but determined by the inheritance pattern. Once the pathogenic MMR mutation was detected in a family, genetic testing was offered to direct relatives.
All patients in this study met with a genetic counsellor who recorded the pedigree and performed a genetic cancer risk assessment. Appropriate genetic counselling prior to genetic testing was carried out and patients gave informed consent for genetic analysis.
After the LS diagnosis, follow-up recommendations according to LS guidelines were given. Follow-up consisted of colonoscopy every two years starting at 25 years of age and annually after the age of 40 years 16,27,28, except for carriers of mutations in MSH6 or PMS2. These mutation carriers began colonoscopy screening at 30 years
of age, unless an early-onset cancer existed in the family29,30. An annual gynaecologic examination with transvaginal ultrasound was the recommended standard of care as of 30 years of age in women with LS. Prophylactic gynaecologic surgeries were recommended to patients following international guidelines 16,17,31. Follow-up recommendations to prevent other extracolonic tumours such as upper gastrointestinal endoscopy, abdominal examination or urinary analysis were carried out based on family history.
The standardized Incidence Ratio (SIR) and its corresponding 95% confidence interval (95%CI) were estimated. SIR is defined as the comparison between the number of cases observed in the study population with the expected number in the reference population [32]. As a reference population, the incidence rate in the population of Catalonia between 2008 and 2012 was used, which is 0.26 cases per 100,000 men/year and 0.4 per 100,000 women/year33.
Results
The clinical characteristics of our patients are described in Table 1. Two hundred and sixty patients (41%) were diagnosed with CRC, 28 (4.41%) of these presenting multiple CRC tumours (more than two). Ninety-two patients (26.5%) were diagnosed with endometrial cancer. In addition, a total of 24 (6.9%) patients were diagnosed with ovarian cancer, 14 patients (2.2%) were diagnosed with upper urinary tract tumours and 12 patients (1.89%) were diagnosed with gastric cancer.
During follow up, three patients carrying a germline mutation in the MSH2 gene were diagnosed with non- secreting ACCs, corresponding to an incidence of 0.47% of the total of patients included (3/634) and 1.7% of all patients with a MSH2 mutation. Considering a stable incidence rate of ACC in Catalonia for this period of study (1999-2018), the number of ACC in the general population would be of 5.2 cases per 100,000 men and 8 cases per 100,000 women. Extrapolating this data to our LS series, the expected number of ACC would be of 0.0427 cases (0.0149 in men and 0.0277 in women). This represents a standardized incidence ratio (SIR) of 70 (CI 95% 13-172).
Below, we describe the three ACC cases detected in our series:
Patient 1: A 33-year-old woman, with no previous history of cancer, carrier of mutation c.1980_1981delTA in MSH2 gene detected in her family. One year after the genetic diagnosis, she consulted for left rib pain. The abdominal tomography revealed a large left adrenal tumour of 13 cms. The patient did not present any phenotypic feature of excessive hormonal secretion. The catecholamine study performed was negative. There was no further information on the other hormones studied. The histological study of the surgical specimen obtained in the adrenalectomy with nephrectomy described a neoplastic lesion characterized by the proliferation of trabecular and papillary structures, areas of necrosis and cells with a prominent nucleolus compatible with adrenocortical carcinoma which invaded the adrenal vein. The immunophenotype was vimentin, synaptophysin and CD56 positive, chromogranin and Cam5.2 negative. The tumour study showed microsatellite stability and a loss of expression of the MSH2 and MSH6 proteins. In addition, loss of heterozygosity was detected at the mutation site (Figure 1). After surgery, treatment with Mitotane was administered but the patient presented early recurrence in the form of pulmonary, hepatic and peritoneal metastases, dying 6 months after surgery.
Patient 2: A 64-year-old male carrier of mutation c.[2635-3C>T;2635-5T>C] in the MSH2 gene which was detected after diagnosis of stage III transverse colon with loss of expression of the repair proteins MSH2 and MSH6 at 56 years of age. In a follow-up abdominal CT while the patient was asymptomatic, an adrenal mass of 8 cm was identified. The hormonal study performed did not show any excessive hormonal secretion (dehydroepiandrosterone sulphate, cortisol, corticotrophin, gastrin, plasma renin activity, aldosterone, aldosterone/renin activity ratio and cortisol excretion in 24h urine were analyzed). An adrenalectomy with nephrectomy was indicated without post-surgical chemotherapy. Histological study showed undifferentiated cells with signs of necrosis and a marked lymphoid infiltrate. At the immunohistochemical level, cells presented immunonegativity for epithelial, melanic, and hematolymphoid markers, a weak positivity for CD31 and synaptophysin, and marked positivity for vimentin. The tumour study showed high-grade instability of microsatellites and loss of expression of MSH2 and MSH6 (Figure 2). Currently, the patient is free of recurrence 2 years after surgery.
Patient 3: A 78-year-old woman carrier of mutation c.754C>T in the MSH2 gene, detected after the diagnosis of a sebaceous adenoma with loss of immunohistochemical expression of MSH2 and MSH6 protein. Moreover,
the patient presented a personal history of squamous carcinoma of the vulva and two first-degree relatives diagnosed with colorectal cancer. In the first colonoscopy after LS diagnosis, a caecum tumour was detected and in the extension study, a left adrenal mass of 5.5 cms was found. A hormonal study prior to surgery was not performed due to the lack of an endocrine phenotype. A right hemicolectomy and left adrenalectomy were performed as the sole treatment in both tumours. The histological study confirmed a double synchronous neoplasm, stage I colorectal cancer and an adrenocortical carcinoma. ACC histologically presented eosinophilic cytoplasm cells with prominent nucleolus, tumour necrosis and vascular invasion. The immunophenotype of the tumour cells were epithelial membrane antigen (EMA), carcinoembrionary antigen (CEA) and chromogranin negative and inhibin and synaptophysin positive. Tumour analysis showed microsatellite stability and a loss of expression of the MSH2 and MSH6 proteins. The patient was diagnosed with pulmonary metastases 11 months after colon tumour and adrenocortical surgery, which were attributed to the ACC. Chemotherapy was not administered due to the patient’s advanced age, who died due to recurrence of the ACC three years after surgery.
stekt de Manera en,
The clinical, histological and molecular features of the three ACC tumours are described in table 2.
Discussion
Most ACC in childhood are associated with Li-Fraumeni syndrome, an inherited cancer predisposition syndrome due to mutations in the TP53 gene. In adults, ACC had been considered a sporadic tumour. However, current evidence exists of its association with hereditary syndromes. Although ACCs have not been included in the LS diagnostic criteria, our three cases support previous data that consider that this tumour should be considered as within the Lynch syndrome tumour spectrum 8-11.
In LS patients the tumours are mainly located in specific organs and usually show characteristic histological and molecular phenotypes. At the histological level, as for colorectal cancer and endometrial cancer, tumours associated with LS tend to show solid growth with increased lymphocyte infiltration. At the molecular level, both techniques of immunohistochemical detection of DNA MMR proteins and polymerase chain reaction detection of microsatellite instability show enhanced detection of mismatch repair-deficient neoplasms in patients with LS, leading to the identification of tumours not previously included within the tumour spectrum of LS11,23.
In the cases described in the literature, most ACC associated with LS presented germline mutations in the MSH2 gene and, like other rare associated tumours, are microsatellite stable, in contrast to colorectal and endometrial cancers that usually show high levels of microsatellite instability14. At present, the reason why some tumours in LS patients do not show microsatellite instability is unknown. Some authors hypothesize that for some specific variants ATPase activity is not completely eliminated so there is still some repair activity [8]. According to Raymond et al.6, DNA MMR gene deficiency in these tumours is likely to be an event that occurs at a late stage of carcinogenesis. Based on this data, low microsatellite instability does not necessarily exclude the diagnosis of LS in patients with ACC9. The selection and number of markers used in the analysis is also an issue to be considered. In contrast, immunohistochemistry of MMR proteins should be considered as the first molecular screening strategy in patients with ACC, even in the absence of other tumours associated with LS, and a germline study should be carried out in those cases which show absence of repair protein expression. As thenogalts with ACC presented high levels of microsatellite instability in the tumour, whereas three tumours showed loss of expression of the MSH2 protein according to the germline mutation detected previously.
In a retrospective series of patients with ACC Raymond et al.6, showed a prevalence of LS among patients with ACC of 3.2% (3/94), significantly higher than the prevalence of LS in the general population 34 and comparable to the prevalence of LS in colorectal cancer (2-4%)35 .In a retrospective review of 135 LS probands the same authors identified two patients with ACC (2/135, 1.48%), which suggests a higher relative risk than expected in the general population (0.72 cases per million people/year)6. Although the relationship between the cases observed in our series and those expected in our reference general population is high and statistically significant, the wide confidence interval forces us to be cautious and suggest, like Raymond et al., that there is probably an increased risk of ACC in patients with LS.
In our series, the prevalence of ACC in patients carrying a germline mutation in MSH2 was 1.7% (Table 1), similar to other less frequent neoplasms considered to be within the Lynch syndrome spectrum27, which are included in the Amsterdam and Bethesda clinical criteria16. In fact, when patient 1 was diagnosed with ACC we still did not have enough data to indicate that we were facing a tumour of the LS spectrum. The loss of heterozygosity of the MSH2 germline mutation detected in tumour DNA, supported this hypothesis (Figure 1).
As a retrospective study, we acknowledge the limitation of incomplete hormonal, immunohistochemistry data and pathological revision in patient 1 due to the diagnosis and treatment having been performed in
another institution. The information obtained from the image tests, the surgical findings and the review of the histological report by an expert pathologist, supports the diagnosis of a suprarenal carcinoma in this patient.
Currently, there is insufficient evidence to routinely include screening for rare tumours in LS. In LS, follow- up for rare tumours may vary depending on specific circumstances such as the risk of cancer adapted to age, family history, mutated gene or screening tests available with adequate sensitivity and specificity. An important issue to consider in the clinical management of rare MMR-deficient tumours is to know whether their biological behaviour in terms of their development and progression is different compared with sporadic forms. In the same way, given the low incidence of ACC in both the general population and the LS population, routine monitoring is not recommended in MMR-mutation carriers. Considering the difficulties in the diagnosis of ACC, their aggressiveness and limited treatment options in advanced stages, recognizing the association with LS may have clinical implications. An incidental finding of an adrenal tumour or signs and symptoms of adrenal hormone production in a patient with LS could have clinical consequences in diagnosis and treatment. Recently, the efficacy of immunotherapy-based treatments has been demonstrated in patients with solid MMR-deficient-tumours36-38 and LS-associated CRC3, so this could be a future treatment strategy for LS patients with ACC or other advanced rare tumours associated with LS. Since about 10% of patients with ACC will be carriers of a germline mutation responsible for hereditary cancer11, we suggest that patients diagnosed with ACC should be offered genetic counselling in order to perform a correct genetic cancer risk assessment. The genetic evaluation for LS should be considered in all patients with ACC with personal or family history of LS-associated tumours. In addition, our data and that previously published support the indication of performing immunohistochemistry of MMR proteins as molecular screening in all patients diagnosed with ACC. In summary, we provide the description of three cases of ACC detected during follow-up from a large series of LS patients. All of them harboured a germline mutation in the MSH2 gene. These cases support previously published data that advocate including ACC as a tumour within the LS spectrum.
Acknowledgments: In this section you can acknowledge any support given which is not covered by the author contribution or funding sections. This may include administrative and technical support, or donations in kind (e.g., materials used for experiments).
Data Availability: Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request
Accepted Manuscript
References
1. Allolio B, Fassnacht M. Clinical review: Adrenocortical carcinoma: Clinical update. Journal of Clinical Endocrinology and Metabolism. 2006;91(6):2027-2037. doi:10.1210/jc.2005-2639
2. Kebebew E, Reiff E, Duh QY, Clark OH, McMillan A. Extent of disease at presentation and outcome for adrenocortical carcinoma: Have we made progress? World Journal of Surgery. 2006;30(5):872-878. doi:10.1007/s00268-005-0329-x
3. Else T, Rodriguez-Galindo C. 5th International ACC Symposium: Hereditary Predisposition to Childhood ACC and the Associated Molecular Phenotype: 5th International ACC Symposium Session: Not Just for Kids! Hormones and Cancer. 2016;7(1):36-39. doi:10.1007/s12672-015-0244-z
4. Courtney R, Ranganathan S. Simultaneous adrenocortical carcinoma and neuroblastoma in an infant with a novel germline p53 mutation. Journal of Pediatric Hematology/Oncology. 2015;37(3):215-218. doi:10.1097/MPH.0000000000000281
5. Herrmann LIM, Heinze B, Fassnacht M, et al. TP53 germline mutations in adult patients with adrenocortical carcinoma. Journal of Clinical Endocrinology and Metabolism. 2012;97(3):476-485. doi:10.1210/jc.2011-1982
6. Raymond VM, Else T, Everett JN, Long JM, Gruber SB, Hammer GD. Prevalence of Germline TP53 mutations in a prospective series of unselected patients with adrenocortical carcinoma. Journal of Clinical Endocrinology and Metabolism. 2013;98(1):119-125. doi:10.1210/jc.2012-2198
7. Gatta-Cherifi B, Chabre O, Murat A, et al. Adrenal involvement in MEN1. Analysis of 715 cases from the Groupe d’étude des Tumeurs Endocrines database. European Journal of Endocrinology. 2012;166(2):269-279. doi:10.1530/EJE-11-0679
8. Medina-Arana V, Delgado L, González L, et al. Adrenocortical carcinoma, an unusual extracolonic tumor associated with Lynch II syndrome. Familial Cancer. 2011;10(2):265-271. doi:10.1007/s10689-010-9416-8
9. Raymond VM, Everett JN, Furtado L v., et al. Adrenocortical carcinoma is a lynch syndrome-associated cancer. Journal of Clinical Oncology. 2013;31(24):3012-3018. doi:10.1200/JCO.2012.48.0988
10. Kaur RJ, Pichurin PN, Hines JM, Singh RJ, Grebe SK, Bancos I. Adrenal Cortical Carcinoma Associated With Lynch Syndrome: A Case Report and Review of Literature. Journal of the Endocrine Society. 2019;3(4):784-790. doi:10.1210/js.2019-00050
11. Challis BG, Kandasamy N, Powlson AS, et al. Familial adrenocortical carcinoma in association with lynch syndrome. Journal of Clinical Endocrinology and Metabolism. 2016;101(6):2269-2272. doi:10.1210/jc.2016- 1460
12. Petr EJ, Else T. Adrenocortical carcinoma (ACC): When and why should we consider germline testing? Presse Medicale. 2018;47(7-8P2):e119-e125. doi:10.1016/j.lpm.2018.07.004
13. Berends MJW, Cats A, Hollema H, et al. Adrenocortical adenocarcinoma in an MSH2 carrier: Coincidence or causal relation? Human Pathology. 2000;31(12):1522-1527. doi:10.1053/hupa.2000.20409
14. Wright JP, Montgomery KW, Tierney J, Gilbert J, Solórzano CC, Idrees K. Ectopic, retroperitoneal adrenocortical carcinoma in the setting of Lynch syndrome. Familial Cancer. 2018;17(3):381-385. doi:10.1007/s10689-017-0042-6
15. Broaddus RR, Lynch PM, Lu KH, Luthra R, Michelson SJ. Unusual tumors associated with the hereditary nonpolyposis colorectal cancer syndrome. Modern Pathology. 2004;17(8):981-989. doi:10.1038/modpathol.3800150
16. Giardiello FM, Allen JI, Axilbund JE, et al. Guidelines on genetic evaluation and management of lynch syndrome: A consensus statement by the US multi-society task force on colorectal cancer. American Journal of Gastroenterology. 2014;109(8):1159-1179. doi:10.1038/ajg.2014.186
17. Ryan NAJ, Morris J, Green K, et al. Association of mismatch repair mutation with age at cancer onset in lynch syndrome implications for stratified surveillance strategies. JAMA Oncology. 2017;3(12):E1-E5. doi:10.1001/jamaoncol.2017.0619
18. Møller P, Seppälä T, Bernstein I, et al. Incidence of and survival after subsequent cancers in carriers of pathogenic MMR variants with previous cancer: A report from the prospective Lynch syndrome database. Gut. 2017;66(9):1657-1664. doi:10.1136/gutjnl-2016-311403
19. Moreira L, Balaguer F, Lindor N, et al. Identification of Lynch syndrome among patients with colorectal cancer. JAMA - Journal of the American Medical Association. 2012;308(15):1555-1565. doi:10.1001/jama.2012.13088
20. Mills AM, Liou S, Ford JM, Berek JS, Pai RK, Longacre TA. Lynch syndrome screening should be considered for all patients with newly diagnosed endometrial cancer. American Journal of Surgical Pathology. 2014;38(11):1501-1509. doi:10.1097/PAS.0000000000000321
21. Hampel H, Frankel WL, Martin E, et al. Feasibility of screening for Lynch syndrome among patients with colorectal cancer. Journal of Clinical Oncology. 2008;26(35):5783-5788. doi:10.1200/JCO.2008.17.5950
22. Latham A, Srinivasan P, Kemel Y, et al. Microsatellite instability is associated with the presence of Lynch syndrome pan-cancer. Journal of Clinical Oncology. 2019;37(4):286-295. doi:10.1200/JCO.18.00283
23. Karamurzin Y, Zeng Z, Stadler ZK, et al. Unusual DNA mismatch repair-deficient tumors in Lynch syndrome: A report of new cases and review of the literature. Human Pathology. 2012;43(10):1677-1687. doi:10.1016/j.humpath.2011.12.012
24. Everett JN, Raymond VM, Dandapani M, et al. Screening for germline mismatch repair mutations following diagnosis of sebaceous neoplasm. JAMA Dermatology. 2014;150(12):1315-1321. doi:10.1001/jamadermatol.2014.1217
25. Ju JY, Mills AM, Mahadevan MS, et al. Universal Lynch Syndrome Screening Should be Performed in All Upper Tract Urothelial Carcinomas. American Journal of Surgical Pathology. 2018;42(11):1549-1555. doi:10.1097/PAS.0000000000001141
26. Thompson BA, Spurdle AB, Plazzer JP, et al. Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSIGHT locus-specific database. Nature Genetics. 2014;46(2):107-115. doi:10.1038/ng.2854
27. Møller P, Seppälä T, Bernstein I, et al. Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: First report from the prospective Lynch syndrome database. Gut. 2017;66(3):464-472. doi:10.1136/gutjnl-2015-309675
28. Stjepanovic N, Moreira L, Carneiro F, et al. Hereditary gastrointestinal cancers: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2019;30(10):1558-1571. doi:10.1093/annonc/mdz233
29. Broeke SWT, Klift HMV, Tops CMJ, et al. Cancer Risks for PMS2-associated lynch syndrom. Journal of Clinical Oncology. 2018;36(29):2961-2968. doi:10.1200/JCO.2018.78.4777
30. Dominguez-Valentin M, Sampson JR, Seppälä TT, et al. Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database. Genetics in Medicine. 2019;0(0). doi:10.1038/s41436-019-0596-9
31. Crosbie EJ, Ryan NAJ, Arends MJ, et al. The Manchester International Consensus Group recommendations for the management of gynecological cancers in Lynch syndrome. Genetics in Medicine. 2019;21(10):2390-2400. doi:10.1038/s41436-019-0489-y
32. Boyle P, Parkin DM. Cancer registration: principles and methods. Statistical methods for registries. IARC scientific publications. 1991;(95):126-158. http://europepmc.org/abstract/MED/1894318.
33. Pla Director d’Oncologia. 2019. Departament de Salut.
34. Win AK, Jenkins MA, Dowty JG, et al. Prevalence and penetrance of major genes and polygenes for colorectal cancer. Cancer Epidemiology Biomarkers and Prevention. 2017;26(3):404-412. doi:10.1158/1055- 9965.EPI-16-0693
35. Vasen HFA, Blanco I, Aktan-Collan K, et al. Revised guidelines for the clinical management of Lynch syndrome (HNPCC): Recommendations by a group of European experts. Gut. 2013;62(6):812-823. doi:10.1136/gutjnl-2012-304356
36. Dung T. Le,1,2,3 Jennifer N. Durham,1,2,3* Kellie N. Smith,1,3* Hao Wang 3, * Bjarne R. Bartlett, 2 4* Laveet, K. Aulakh, 2, 4 Steve Lu, 2, 4 Holly Kemberling, 3 Cara Wilt, 3 Brandon S. Luber, 3 Fay Wong, 2 4 Nilofer S., et al. Mismatch-repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;6733(June):409-413. doi:10.1126/science.aan6733
37. Marcus L, Lemery SJ, Keegan P, Pazdur R. FDA approval summary: Pembrolizumab for the treatment of microsatellite instability-high solid tumors. Clinical Cancer Research. 2019;25(13):3753-3758. doi:10.1158/1078-0432.CCR-18-4070
38. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. New England Journal of Medicine. 2015;372(26):2509-2520. doi:10.1056/NEJMoa1500596
39. Salman P, Panay S, Fernández R, Mahave M, Soza-Ried C. Evidence of response to pembrolizumab in a patient with lynch syndrome-related metastatic colon cancer. OncoTargets and Therapy. 2018;11:7295-7300. doi:10.2147/OTT.S167645
Figure Legends
Figure 1. Results of the genetic study performed in patient 1 at the germline and tumour level.
(A) Reference sequence for exon 12 of MSH2. (B) Result of the sequencing analysis in blood DNA showing the presence of the heterozygous germline mutation c.1980_1981delTA (C) Result of the sequencing analysis in tumour DNA showing loss of heterozygosity of the MSH2 mutation.
Figure 2. Result of the immunohistochemical study in the ACC from patient 2. An absence of nuclear staining is observed for MSH2 and MSH6 proteins and positive nuclear staining for proteins MLH1 and PMS2.
Accepted Manuscript
| Characteristic | Nº. patients | % |
|---|---|---|
| Sex | ||
| Female | 347 | 54.7 |
| Male | 287 | 45.3 |
| Age | ||
| Mean | 52 years | |
| Range | 18-96 years | |
| Gene | ||
| MLH1 | 286 | 45.1 |
| MSH2 | 180 | 28.4 |
| MSH6 | 112 | 17.7 |
| PMS2 | 41 | 6.4 |
| EPCAM | 15 Acepted Manus | 2.3 |
| Tumours diagnosed: | ||
| Colorectal cancer | ||
| 1 | 173 | 27.3 |
| 2 | 59 | 9.3 |
| >2 | 28 | 4.4 |
| Endometrial cancer | 92 | 26.5 |
| Ovarian cancer | 24 | 6.9 |
| Upper Urinary tract tumours | ||
| Ureter | 14 | 2.2 |
| Renal Pelvis | 10 | 1.6 |
| Both | 4 | 0.6 |
| Gastric cancer | 12 | 1.9 |
| Cerebral tumour | 8 | 1.3 |
| Pancreatic cancer | 5 | 0.8 |
| Sebaceous Tumours | ||
| 1 | 6 | 0.9 |
| 2 | 6 | 0.9 |
| >2 | 3 | 0.5 |
| Adrenocortical cancer | 3 | 0.5 |
| Breast cancer | 13 | 3.7 |
| Other tumours | 48 | 7.6 |
| Case | Sex | Age at | Stage | Treatment | Weiss score Manuscrip | Markers | Prior tumours | Tumor | Germline | Mutation | Molecular | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| number | MMR | studies | |||||||||||
| diagnosis | (Histological | ||||||||||||
| features) (1) | Testing | ||||||||||||
| 4 ( Necrosis, | Cromogranin- | No | Bethesda | c.1980_1981delTA | Loss | of | |||||||
| expression | |||||||||||||
| Atipical mitoses, | Synaptophysin + | in MSH2 | for | MSH2/ | |||||||||
| 1 | F | 34 | III | Adrenalectomy | >5 mitoses/50 HPF, | Vimentin+ | MSH6 | ||||||
| Venous invasion | CD56+ | LOH | |||||||||||
| MSS | |||||||||||||
| 7 (High nuclear | Epithelial and | Transverse | Bethesda | ||||||||||
| grade, | |||||||||||||
| Melanin markers - | colon cancer | c.[2635-3C>T; | 2635- | Loss | of | ||||||||
| > 5 mitoses/50HPF | 5T>C] in | MSH2 | expression | for | |||||||||
| 2 | M | 64 | II | Nephrectomy + | Inhibin- | at age 56 | |||||||
| MSH2/ | MSH6. | ||||||||||||
| Atypical mitoses, | |||||||||||||
| adrenalectomy | <25% clear cell | Synaptophysin + | MSI-H | ||||||||||
| component, | Vimentin+ | ||||||||||||
NNscrip
Diffuse architecture,
tumor necrosis,
Sinusoidal invasion
6
(Diffuse
Cromogranin-
Vulvar Cancer
Bethesda
architecture,
Inhibin +
at age 54,
c.754C>T in MSH2
of
< 25% of clear cell, tumor necrosis,
Loss expression MSH2/ MSH6
for
3
F
78
II
Adrenalectomy
Melanin
+
Colon cancer
Synaptophysin +
> 5 mitoses/50HPF,
at age 78,
MSS
Atypical mitoses,
Sebaceous
adenomas
Venous invasion
at age 78
Abbreviation: LOH: Loss of Heterozygosity, MSS: Microsatellite Stable, MSI-H: Microsatellite Unstable-High grade.
European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors. European J of Endocrinology 2018;179:G1-G46.
A
72590
72595
72600
72605
72610
72615
72620
72625
72630
72635
72645
000
72640
265
251.9 T
UUU
UND
(44
444
4
UU
3
4 4 4
UNU
UND.
000
-27.491
6
G
1
1
3.440
3.480
3.480
3.500
3.520
3.540
3.580
3.580
3.600
3.620
3.640
3.680
3.680
3.700
3.720
3.740
3.780
3.780
3.800
3.820
3.840
3.880
3.880
3.900
3.920
3.940
3.960
3.980
4.000
4.020
4.040
4.060
“251 gtk
850
855
E
860
605
-27. ab1
₱
₱
N
NI
D
0
F
F
—
G
0
V
A
K
!!
D
A
K
M
ca
M
-
M
- -
G
12
*
*
NM_000251_F_Synthesis_72531.scf→
Quality(0-200)-90
8.000
345
350
385
365
370
375
380
390
:
400
405
7.000
G_
3 AT
T
.T.A
A … T
A … A.
H
T 2
7
G
G.
A. C
T
G.
A.A
LA
A .. A
H
G
A
A. A
A.
6
A
W
T
C
CA
A
C
A.
A
G
T
6.000
5.000
4.000
.
3.00
2.000
KE
1.000
3.440
3.460
3.480
3.500
3.520
3.540
3.560
3.580
3.600
3.620
3.640
3.660
3.680
3.700
3.720
3.740
3.760
3.780
3.800
3.820
3.840
3.860
3.880
3.900
1 920
3540
3.960
3 980
4.000
4.040
4.060
4.020 crip
C
12881_E12_MSH2_F_G09_20 12-10-27.ab1→
Quality (0-100):19
1.800
200
205-
210
215
220
225
230
235
245
245
250
255
60
1.600 T I.
G.
A.
T I.T.
.T.
C
C
.. A
G
:
G
.T
L
A
a
…
L.A.AJA.A
… G .. A .. A
1.
C
.
:
2
C
-
I
C
1
IT.A.
G 1
A
1.400
1.200
1.000
800
600
400
200
O
3.440
3.460
3.480
3.500
3.520
3.540
3.560
3.580
3.600
3.620
3.640
3.660
3.680
3.700
3.720
3.740
3.760
3.780
3.000
3.820
3.840
3.860
3.880
3.900
3.920
3.940
3.960
3.980
4.000
4.020
4.040
4.060
14145_12_F_E10_2014-01-28.ab1→
Quality(0-100):23
2.000
215-
220
225
230
235
240
245
250
255.
260
265
270
275
1.800
..
G ..
6
A. T.
T
. C. T.
… G
A CIG
G … TIA. T.A . C
T.I.T.G
.. G.
A
L.L.A … C.
.A … G.
AG
A
C … A
C … A
A
.A.
TA
1
0
.A
AU
G … G.
T
1.600
1.400
1.200
1.000
800
600
400
200
7-
3.500 ACC
3.440
3.460
3.480
3.520
3.540
3.560
3.580
3.600
3.620
3.640
3.660
3.680
3.700
3.720
3.740
3.760
3.780
3.820
3.840
3.860
3.880
3.900
3.920
3.940
3.960
3.980
4.000
4.020
4.040
4.060
MLH1
PMS2
ipt
MSH2
MSH6
Accepted Ma