Familial Adrenocortical Carcinoma in Association With Lynch Syndrome
Benjamin G. Challis,* Narayanan Kandasamy,* Andrew S. Powlson, Olympia Koulouri, Anand Kumar Annamalai, Lisa Happerfield, Alison J. Marker, Mark J. Arends, Serena Nik-Zainal, and Mark Gurnell
Metabolic Research Laboratories (B.G.C., N.K., A.S.P., O.K., A.K.A., M.G.), Wellcome Trust-MRC Institute of Metabolic Science , and Departments of Histopathology (L.H., A.J.M.) and Medical Genetics (S.N .- Z.), University of Cambridge and National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke’s Hospital, Cambridge, UK CB2 OQQ; Division of Pathology (M.J.A.), University of Edinburgh, Edinburgh, UK
Context: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis. Although the majority of childhood ACC arises in the context of inherited cancer susceptibility syndromes, it remains less clear whether a hereditary tumor predisposition exists for the devel- opment of ACC in adults. Here, we report the first occurrence of familial ACC in a kindred with Lynch syndrome resulting from a pathogenic germline MSH2 mutation.
Case: A 54-year-old female with a history of ovarian and colorectal malignancy was found to have an ACC. A detailed family history revealed her mother had died of ACC and her sister had previously been diagnosed with endometrial and colorectal cancers. A unifying diagnosis of Lynch syndrome was considered, and immunohistochemical analyses demonstrated loss of MSH2 and MSH6 ex- pression in both AACs (proband and her mother) and in the endometrial carcinoma of her sister. Subsequent genetic screening confirmed the presence of a germline MSH2 mutation (resulting in deletions of exons 1-3) in the proband and her sister.
Conclusion: Our findings provide strong support for the recent proposal that ACC should be con- sidered a Lynch syndrome-associated tumor and included in the Amsterdam II clinical diagnostic criteria. We also suggest that screening for ACC should be considered in cancer surveillance strat- egies directed at individuals with germline mutations in DNA mismatch repair genes. (J Clin En- docrinol Metab 101: 2269-2272, 2016)
A drenocortical carcinoma (ACC) is a rare and aggres- sive endocrine cancer with an incidence of less than 1 case per million individuals per year (1). Most childhood ACC occurs in patients with familial cancer susceptibility syndromes such as Li-Fraumeni syndrome, but whether a hereditary tumor predisposition exists for the develop- ment of ACCin adults is less clear (1). Although most ACC in adulthood is sporadic, increasing evidence supports as- sociation between adult ACC and inherited cancer sus- ceptibility syndromes including Li-Fraumeni syndrome,
multiple endocrine neoplasia type 1, and Lynch syndrome (LS) (1). However, given the low prevalence of ACC, as- certaining whether this cancer is a bona fide syndrome- associated malignancy is challenging.
LS is an autosomal-dominant familial cancer syndrome caused by pathogenic germline mutations in one of several DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2), and associated with an estimated life- time colorectal cancer risk of 80% (2). LS is also associated with an increased risk of several extracolonic tumors (en-
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*B.G.C. and N.K. contributed equally to this work.
Abbreviations: ACC, adrenocortical carcinoma; IHC, immunohistochemical; LS, Lynch syn- drome; MMR, mismatch repair; MSI, microsatellite instability.
dometrial, stomach, small intestinal, hepatobiliary, uri- nary tract), which are therefore included as part of the Amsterdam II clinical diagnostic criteria for LS (2). In ad- dition to these recognized cancers, previous reports have described a number of rare, nonclassical cancers, including ACC, in patients with LS. Given the low prevalence of ACC, it remains uncertain whether it is a true LS-associated tumor or arises independent of the primary genetic defect, although a recent study involving 114 subjects with primary ACC and 135 probands from MMR gene-positive kindreds has pro- vided important evidence for the former (3).
Here, we provide additional evidence to implicate ACC as an LS-associated cancer with the first description of an intergenerational (mother-to-daughter) occurrence of ACC in a family with LS resulting from a germline MSH2 mutation. We therefore propose that ACC be included in clinical diagnostic criteria for LS and considered in cancer surveillance recommendations for individuals with germ- line mutations in DNA MMR genes.
Case History
In 2001, the proband (patient III:2), a 54-year old female presented to her local hospital with right loin pain, lethargy, and weight loss. She had previously undergone a hysterec- tomy and bilateral salpingo-oophorectomy for ovarian can- cer at age 44 years and endoscopic removal of a malignant colonic polyp at age 47 years. Clinical examination re- vealed right loin tenderness but was otherwise unre- markable, with no evidence of catecholamine, gluco- corticoid, mineralocorticoid, or androgen excess. Abdominal ultrasonography demonstrated a right su- prarenal lesion and subsequent computed tomography confirmed the presence of a 14-cm mass arising from the right adrenal gland. There was no evidence of extraa- drenal disease. Biochemical investigations excluded phaeochromocytoma and confirmed a nonsecretory ad- renal lesion.
I
1:1
1:2
II
II:1
11:2
II:3
III
Colorectal cancer
III:1 NM
III:2 NM
Adrenocortical cancer
Ovarian cancer
IV
Endometrial cancer
IV:1 NN
IV:2 NM
IV:3 NN
IV:4 NM
IV:5 NM
The patient underwent a laparoscopic right adrenalec- tomy and nephrectomy to remove a 14 × 10 cm adrenal mass. Pathological examination of the resected specimen showed an adrenocortical tumor with adrenal capsular in- vasion, areas of confluent necrosis, and possible vascular in- vasion (Figure 2A, a and b). The tumor was composed of lobules of oncocytic cells separated by fibrous septae. The tumor cells showed focal marked nuclear pleomorphism with bizarre nuclear forms. The mitotic index was 1/50 hpf. Immunohistochemically, tumor cells were positive for vi- mentin and Melan A and negative for calretinin, inhibin, S100, cytokeratin, carcinoembryonic antigen, chromo- granin A, neurofilament, and synaptophysin. Collectively, these features were in keeping with an oncocytic AAC based on Lin-Weiss-Bisceglia criteria (4, 5).
Adjunctive mitotane therapy (maximum tolerated dose, 500 mg three times daily) was commenced with concurrent hydrocortisone replacement (10 mg twice daily). To date, the patient has received regular clinical, biochemical, and radio- logical surveillance with no evidence of disease recurrence.
The proband’s sister (patient III:1) had no significant personal medical history until age 36 years when she was diagnosed with an adenocarcinoma of the descending co- lon, which required a left hemicolectomy. At age 47 years, she was diagnosed with endometrial carcinoma following investigations for intermenstrual bleeding, and treated by radical hysterectomy.
An underlying familial cancer syndrome was suspected and a more detailed family history revealed that the proband’s maternal aunt (patient II:3) and grandfather (patient I:1) had both been diagnosed with colorectal cancer (Figure 1). Impor- tantly, the certificate of death for the proband’s mother (patient II:2) stated metastatic ACC as the cause of death. Given the rarity and difficulty in establishing malignancy of adrenocorti- cal tumors, the histology of the resected adrenal tumor was reevaluated and confirmed the original diagnosis of primary AAC (Figure 2A, c).
In accordance with the Amster- dam II criteria and revised Bethesda criteria, the family fulfilled diagnos- tic requirements for LS and further immunohistochemistry was per- formed on both ACCs (patients III:2 and II:2) and the endometrial tumor (patient III:1) to determine MMR protein expression status (Figure 2B) (2). In all analyzed tumors, expres- sion of MLH1 and PMS2 was re- tained, whereas nuclear staining for MSH2 and MSH6 were absent, which is consistent with a LS pheno- type. Further germline genetic test-
A
B
MLH1
PMS2
MSH2
MSH6
.
ACC 11:2
a
a
b
C
d
ACC III:2
*
b
e
f
g
h
Endometrial tumour III:1
c
İ
j
k
I
ing was undertaken by multiplex ligation dependent probe amplification analysis in the proband and her sister and revealed a heterozygous deletion of exons 1, 2, and 3 of the MSH2 gene. Further genetic testing also identified the mu- tation in the proband’s son (patient IV:5), daughter (pa- tient IV:4), and niece (patient IV:2). In accordance with the Chompret testing criteria, TP53 germline mutations were excluded in the proband (6). The unavailability of genomic DNA from the proband’s mother (patient II:2) precluded further genetic study.
Discussion
ACC is not currently included in the diagnostic criteria for LS. However, our description of familial ACC arising in the context of a germline MSH2 mutation supports the recent proposal that ACC should be considered an LS- associated tumor (3). Currently, the diagnosis of LS re- quires patients/kindreds to fulfill the Amsterdam or re- vised Bethesda criteria, with demonstration of absent MMR protein expression on tumor immunohistochemis- try and/or microsatellite instability (MSI) genotyping sup- porting the diagnosis (2). Genetic testing for germline mu- tations in MMR genes is reserved for individuals with tumors that demonstrate MSI or absent MMR protein expression, or those deemed at risk based on computa- tional prediction models (2).
Isolated cases of ACC arising in single patients of fam- ilies with LS and germline mutations in DNA MMR genes (MLH1, MSH2, MSH6) have been previously reported, but given their rarity, determining whether these tumors
were coincidental or part of the LS tumor profile has re- mained controversial (3, 7, 8). Compelling evidence sup- porting ACC as an LS-associated cancer was recently pro- vided by Raymond and colleagues, who found that LS prevalence among patients with primary ACC was signif- icantly higher (3.2%) than in the background population (0.2%), and comparable to the prevalence of LS in colo- rectal (2-4%) and endometrial cancer (1-5%) (3). More- over, the prevalence of ACCin LS was increased compared with the general population. Given that ACC is typically an aggressive malignancy, with limited treatment options for advanced disease, recognizing association of this tu- mor with LS has important clinical implications. Specifi- cally, improved awareness and recognition of the syn- drome and entry into appropriate systematic cancer surveillance programs would be anticipated to lead to ear- lier diagnosis and timely intervention to reduce LS-related morbidity and mortality.
Immunohistochemical (IHC) analysis of tumor MMR proteins is often performed concomitantly with MSI to improve clinical sensitivity in the evaluation for LS. In our case, IHC analysis for LS-related tumors was informative and identified loss of MSH2 and MSH6 expression in the ACC and endometrial tumors analyzed from affected pa- tients with the germline MSH2 mutation. In contrast with colorectal tumors, which demonstrate high MSI, previous reports have consistently found that ACC tumors have low MSI in patients with LS; on this basis, MSI testing was not performed in our patient (3). Although a molecular basis for this discrepancy between tumor types remains unclear, it has been proposed that in some tumors, possi- bly from tissue-specific factors, the consequences of MMR
deficiency occur in the latter stages of carcinogenesis thereby preventing detectable accumulation of MSI. Fur- ther, currently used MSI tests have been optimized for colorectal cancers and are less sensitive for MSI detection in other tumor types. Therefore, low MSI does not nec- essarily exclude a diagnosis of LS and, for both sporadic and familial ACC, IHC analysis of MMR proteins should be considered the first-line molecular screening strategy, even in individuals without other LS-associated lesions, with germline genetic testing pursued in the absence of one or more MMR proteins. Currently, there are no estab- lished biochemical or radiological screening guidelines for those at risk of ACC. We have adopted an empirical ap- proach in the offspring of our proband, combining peri- odic surveillance magnetic resonance imaging with serum and urinary steroid profiling. It remains to be seen whether this is a clinically cost-effective approach.
In summary, we report the first description of familial ACC in conjunction with a germline MSH2 mutation and provide support for MMR genes as candidates in hered- itary ACC. We advocate ACC now be included in clinical diagnostic criteria for LS and considered in cancer sur- veillance strategies for individuals with germline muta- tions in DNA MMR genes. Moreover, in the absence of clinical management guidelines for ACC surveillance in patients with inherited cancer syndromes, including LS, we recommend individualized screening protocols cou- pled with ongoing clinical vigilance.
Acknowledgments
The authors thank Dr Joan Patterson for clinical advice and Drs Erik Schoenmakers and Louise Boyle for assistance with illustrations.
Address all correspondence and requests for reprints to: Mark Gurnell, PhD, FRCP, Metabolic Research Laboratories, Well- come Trust-MRC Institute of Metabolic Science, Box 289, level 4, Addenbrooke’s Hospital, Cambridge, CB2 0QQ, UK. E-mail: mg299@medschl.cam.ac.uk.
This work was supported by the National Institutes for Health Research Cambridge Biomedical Research Centre (to A.S.P., O.K., and M.G.). S.N.Z. is a Wellcome Trust Interme- diate Clinical Fellow (WT100183MA).
Disclosure Summary: The authors have nothing to disclose.
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