![ISSN: 2640-1037
Clinics of Oncology
Case Report
An Adrenal Mass in a Patient with Lynch Syndrome
Sarah B Fisher, Jeffrey E Lee, Paul H Graham
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
Volume 2 Issue 1- 2019
Received Date: 03 May 2019
Accepted Date: 26 May 2019
Published Date: 02 Jun 2019
1. Abstract
Adrenocortical cancer (ACC) is a rare malignancy (estimated annual incidence 0.7 to 2.0 cases
per million individuals worldwide) with a poor prognosis. In contrast, Lynch Syndrome (LS) is
a much more commonly encountered hereditary syndrome that predisposes individuals to colon
cancer and multiple other malignancies. Recently ACC has been described as a LS associated
malignancy. Identifying associations between LS and other malignancies such as ACC is
impor-tant as it promotes identification of individuals not already diagnosed with LS, may
influence decisions to screen families, and may impact screening or evaluation of otherwise
nonsuspicious findings (i.e. an adrenal nodule) in patients at risk.
2. Introduction
Lynch syndrome (LS) describes a subset of patients with germ-
line mutations in DNA mismatch repair (MMR) genes (most
commonly MLH1, MSH2, MSH6, and PMS2) that account for
2-4% of all colorectal cancers [1, 2] with varying phenotypes
de-pending on specific mutation. Patients with LS have an
estimated lifetime risk of 80% for developing colorectal cancer
and an in-creased risk for other extracolonic malignancies,
including endo-metrial, gastric, ovarian, pancreas, ureter and
renal pelvis, biliary tract, brain, and small intestinal cancers.2
Recently adrenocor-tical cancer (ACC), a rare and aggressive
malignancy, has been associated with LS [3-7], although the
low prevalence of ACC makes it difficult to attribute causality.
3. Case
A male in his 30s with a family history of colon cancer in mul-tiple
first degree relatives underwent colonoscopy for evaluation of
persistent diarrhea and was found to have a moderately dif-
ferentiated adenocarcinoma of the distal transverse colon. Pre-
operative staging did not demonstrate evidence of metastatic
disease. He underwent a laparoscopic-assisted partial colectomy,
with resection of a T2N1, stage IIIb moderately differentiated ad-
enocarcinoma with loss of expression of MSH2 and MSH6. Con-
firmatory genetic testing demonstrated a deletion of the MSH2
gene, consistent with Lynch Syndrome. Six weeks after surgery, a
staging PET-CT demonstrated a metabolically active left ad-
renal nodule (1.3 x 1.0 cm, SUV 8.6) without evidence of addi-
tional disease. High resolution CT imaging identified enhance-
ment and washout characteristics incompatible with a benign
adenoma (Figure 1A and B). Biochemical evaluation excluded a
hormonally functional adrenal tumor. Image-guided fine needle
aspiration biopsy of the nodule demonstrated adrenal tissue with
atypical cells, but failed to render a conclusive diagnosis. Immu-
nostaining on the biopsy specimen was positive for calretinin,
weakly positive for inhibin, and negative for CDX-2 and CK20;
estimates of the Ki-67 proliferation index were high (32%). The
patient was started on adjuvant FOLFOX therapy for treatment of
his colorectal cancer and later referred for surgical evaluation of
the adrenal mass. Following completion of therapy, repeat im-
aging demonstrated an increase in the size of the adrenal mass to
1.7 x 1.2 cm.
The patient underwent an uncomplicated open left adrenalec-
tomy for a clinical suspicion of a primary adrenal malignancy.
Pathologic examination showed adrenocortical carcinoma
(ACC) with oncocytic features, measuring 1.5 x 1.4 x 1.2 cm,
confined to the adrenal gland with surgical margins free of tu-
mor. The mitotic rate was 10 per 50 high power fields with
severe nuclear atypia and a ki-67 index of 32%, supporting the
malig-nant diagnosis. Immunostaining for MSH2 and MSH6
demon-strated loss of protein expression consistent with the
pattern ob-served in the patient’s initial colorectal cancer.
*Corresponding Author (s): Paul H Graham, Department of Surgical Oncology, The
University of Texas MD Anderson Cancer Center, 400 Pressler St. Unit 1484, Houston,
USA, Tel: 936-446-5246; Fax: 936-446-5266 E-mail: PHGraham@mdanderson.org
clinicsofoncology.com
Citation: Sarah B Fisher, Jeffrey E Lee, Paul H Graham, An Adrenal Mass in a Patient with Lynch Syn-
drome. Clinics of Oncology. 2019; 1(8): 1-3.](https://image.slidesharecdn.com/coo-v2-1032-220503105726/85/An-Adrenal-Mass-in-a-Patient-with-Lynch-Syndrome-1-320.jpg)
![Volume 2 Issue 1 -2019
Figure 1: A PET-avid left adrenal mass (arrow, A), measuring 1.3 x 1.0 cm
on contrasted CT (arrow, B).
4. Discussion
This case report describes a young man with colorectal cancer
and concomitant adrenocortical cancer. In both tumors immuno-
histochemistry demonstrated loss of protein expression of
MSH2 and MSH6, consistent with a diagnosis of LS and
suggestive of a relationship between ACC and LS.
To date, the largest study evaluating a link between LS and ACC
characterized 94 patients with ACC who underwent subsequent
genetic counseling – 3 were found to have LS, for a syndrome
prevalence of 3.2% amongst patients with ACC.7 This is signifi-
cantly higher than the prevalence of 0.72 per million individuals
amongst the general population [7,8]. The same group also ret-
rospectively evaluated 135 probands with LS and identified two
more patients with a personal history of ACC; both had MSH2
germline mutations. Of these five patients, ACC tumor tissue was
available for analysis in four, with two demonstrating loss of
MSH2/MSH6 protein expression (both with MSH2 germline
mutations), one demonstrating loss of MLH1/PMS2 expression
(MLH1 germline mutation in family), and one patient with a MSH6
germline mutation demonstrating intact protein expres-sion [7]. It is
possible the latter patient had a sporadic ACC. Oth-er case reports
in the literature identify MSH2 mutation as the common
denominator in LS associated ACC[4,6], as observed in this patient.
While difficult to assess due to the rarity of the disease, the
association between MSH2 germline mutation and ACC should be
further examined. The oncocytic classification of our patient’s
tumor makes this report unique amongst the other reports of LS-
associated ACC. Typically characterized by abun-dant eosinophilic
and granular cytoplasm due to the high number
Case Report
of mitochondria, the high mitotic rate and nuclear atypia in this
report meet the Lin-Weiss-Bisceglia criteria for oncocytic malig-
nancy[9]. Estimates of survival for patients with oncocytic ACC
are favorable, with a median survival of 58 months in one series of
13 patients [10]. To our knowledge this is the first report that
associates an oncocytic adrenocortical carcinoma with LS. Cur-
rently our patient is alive and well without evidence of either co-
lon or adrenal cancer after X months of follow-up
Although a PET-avid adrenal lesion in patients with known ma-
lignancy is concerning for metastasis, a primary adrenal tumor
should be excluded. Pheochromocytomas are characteristically
PET avid, and atypical adenomas can also demonstrate PET
avid-ity. However, in the setting of LS, a primary ACC should
be con-sidered with a higher index of suspicion, as highlighted
by this case, especially in the setting of normal plasma
metanephrines and relatively rapid enlargement. Although
infrequent, recogni-tion of an association between rare cancers
like ACC and LS may promote identification of families and
individuals at risk, influ-ence screening decisions, and may
heighten suspicion of new adrenal nodules in the patient with
LS. The current study lends support to the available data
supporting ACC as a LS associated malignancy.
Reference
1. Fassnacht M, Kroiss M, Allolio B. Update in adrenocortical
carcinoma. J Clin Endocrinol Metab. 2013; 98(12): 4551-64.
2. Provenzale D, Gupta S, Ahnen DJ. Genetic/Familial High-Risk Assess-
ment: Colorectal Version 1.2016, NCCN Clinical Practice Guidelines in
Oncology. J Natl Compr Canc Netw. 2016; 14(8): 1010-30.
3. Berends MJ, Cats A, Hollema H. Adrenocortical adenocarcinoma in
an MSH2 carrier: coincidence or causal relation? Human pathology.
2000;31(12):1522-1527.
4. Challis BG, Kandasamy N, Powlson AS. Familial Adrenocortical
Car-cinoma in Association with Lynch Syndrome. The Journal of
clinical en-docrinology and metabolism. 2016;101(6):2269-2272.
5. Karamurzin Y, Zeng Z, Stadler ZK. Unusual DNA mismatch repair-
deficient tumors in Lynch syndrome: a report of new cases and review
of the literature. Hum Pathol. 2012; 43(10): 1677-87.
6. Medina-Arana V, Delgado L, Gonzalez L. Adrenocortical
carcinoma, an unusual extracolonic tumor associated with Lynch II
syndrome. Fam Cancer. 2011; 10(2): 265-71.
7. Raymond VM, Everett JN, Furtado LV. Adrenocortical carcinoma is a
lynch syndrome-associated cancer. Journal of clinical oncology: official
journal of the American Society of Clinical Oncology. 2013;31(24):3012-
Copyright ©2019 Paul H Graham al This is an open access article distributed under the terms of the Creative Commons Attribution License,
2
which permits unrestricted use, distribution, and build upon your work non-commercially.](https://image.slidesharecdn.com/coo-v2-1032-220503105726/85/An-Adrenal-Mass-in-a-Patient-with-Lynch-Syndrome-2-320.jpg)
An Adrenal Mass in a Patient with Lynch Syndrome
- 1. ISSN: 2640-1037 Clinics of Oncology Case Report An Adrenal Mass in a Patient with Lynch Syndrome Sarah B Fisher, Jeffrey E Lee, Paul H Graham Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA Volume 2 Issue 1- 2019 Received Date: 03 May 2019 Accepted Date: 26 May 2019 Published Date: 02 Jun 2019 1. Abstract Adrenocortical cancer (ACC) is a rare malignancy (estimated annual incidence 0.7 to 2.0 cases per million individuals worldwide) with a poor prognosis. In contrast, Lynch Syndrome (LS) is a much more commonly encountered hereditary syndrome that predisposes individuals to colon cancer and multiple other malignancies. Recently ACC has been described as a LS associated malignancy. Identifying associations between LS and other malignancies such as ACC is impor-tant as it promotes identification of individuals not already diagnosed with LS, may influence decisions to screen families, and may impact screening or evaluation of otherwise nonsuspicious findings (i.e. an adrenal nodule) in patients at risk. 2. Introduction Lynch syndrome (LS) describes a subset of patients with germ- line mutations in DNA mismatch repair (MMR) genes (most commonly MLH1, MSH2, MSH6, and PMS2) that account for 2-4% of all colorectal cancers [1, 2] with varying phenotypes de-pending on specific mutation. Patients with LS have an estimated lifetime risk of 80% for developing colorectal cancer and an in-creased risk for other extracolonic malignancies, including endo-metrial, gastric, ovarian, pancreas, ureter and renal pelvis, biliary tract, brain, and small intestinal cancers.2 Recently adrenocor-tical cancer (ACC), a rare and aggressive malignancy, has been associated with LS [3-7], although the low prevalence of ACC makes it difficult to attribute causality. 3. Case A male in his 30s with a family history of colon cancer in mul-tiple first degree relatives underwent colonoscopy for evaluation of persistent diarrhea and was found to have a moderately dif- ferentiated adenocarcinoma of the distal transverse colon. Pre- operative staging did not demonstrate evidence of metastatic disease. He underwent a laparoscopic-assisted partial colectomy, with resection of a T2N1, stage IIIb moderately differentiated ad- enocarcinoma with loss of expression of MSH2 and MSH6. Con- firmatory genetic testing demonstrated a deletion of the MSH2 gene, consistent with Lynch Syndrome. Six weeks after surgery, a staging PET-CT demonstrated a metabolically active left ad- renal nodule (1.3 x 1.0 cm, SUV 8.6) without evidence of addi- tional disease. High resolution CT imaging identified enhance- ment and washout characteristics incompatible with a benign adenoma (Figure 1A and B). Biochemical evaluation excluded a hormonally functional adrenal tumor. Image-guided fine needle aspiration biopsy of the nodule demonstrated adrenal tissue with atypical cells, but failed to render a conclusive diagnosis. Immu- nostaining on the biopsy specimen was positive for calretinin, weakly positive for inhibin, and negative for CDX-2 and CK20; estimates of the Ki-67 proliferation index were high (32%). The patient was started on adjuvant FOLFOX therapy for treatment of his colorectal cancer and later referred for surgical evaluation of the adrenal mass. Following completion of therapy, repeat im- aging demonstrated an increase in the size of the adrenal mass to 1.7 x 1.2 cm. The patient underwent an uncomplicated open left adrenalec- tomy for a clinical suspicion of a primary adrenal malignancy. Pathologic examination showed adrenocortical carcinoma (ACC) with oncocytic features, measuring 1.5 x 1.4 x 1.2 cm, confined to the adrenal gland with surgical margins free of tu- mor. The mitotic rate was 10 per 50 high power fields with severe nuclear atypia and a ki-67 index of 32%, supporting the malig-nant diagnosis. Immunostaining for MSH2 and MSH6 demon-strated loss of protein expression consistent with the pattern ob-served in the patient’s initial colorectal cancer. *Corresponding Author (s): Paul H Graham, Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 400 Pressler St. Unit 1484, Houston, USA, Tel: 936-446-5246; Fax: 936-446-5266 E-mail: PHGraham@mdanderson.org clinicsofoncology.com Citation: Sarah B Fisher, Jeffrey E Lee, Paul H Graham, An Adrenal Mass in a Patient with Lynch Syn- drome. Clinics of Oncology. 2019; 1(8): 1-3.
- 2. Volume 2 Issue 1 -2019 Figure 1: A PET-avid left adrenal mass (arrow, A), measuring 1.3 x 1.0 cm on contrasted CT (arrow, B). 4. Discussion This case report describes a young man with colorectal cancer and concomitant adrenocortical cancer. In both tumors immuno- histochemistry demonstrated loss of protein expression of MSH2 and MSH6, consistent with a diagnosis of LS and suggestive of a relationship between ACC and LS. To date, the largest study evaluating a link between LS and ACC characterized 94 patients with ACC who underwent subsequent genetic counseling – 3 were found to have LS, for a syndrome prevalence of 3.2% amongst patients with ACC.7 This is signifi- cantly higher than the prevalence of 0.72 per million individuals amongst the general population [7,8]. The same group also ret- rospectively evaluated 135 probands with LS and identified two more patients with a personal history of ACC; both had MSH2 germline mutations. Of these five patients, ACC tumor tissue was available for analysis in four, with two demonstrating loss of MSH2/MSH6 protein expression (both with MSH2 germline mutations), one demonstrating loss of MLH1/PMS2 expression (MLH1 germline mutation in family), and one patient with a MSH6 germline mutation demonstrating intact protein expres-sion [7]. It is possible the latter patient had a sporadic ACC. Oth-er case reports in the literature identify MSH2 mutation as the common denominator in LS associated ACC[4,6], as observed in this patient. While difficult to assess due to the rarity of the disease, the association between MSH2 germline mutation and ACC should be further examined. The oncocytic classification of our patient’s tumor makes this report unique amongst the other reports of LS- associated ACC. Typically characterized by abun-dant eosinophilic and granular cytoplasm due to the high number Case Report of mitochondria, the high mitotic rate and nuclear atypia in this report meet the Lin-Weiss-Bisceglia criteria for oncocytic malig- nancy[9]. Estimates of survival for patients with oncocytic ACC are favorable, with a median survival of 58 months in one series of 13 patients [10]. To our knowledge this is the first report that associates an oncocytic adrenocortical carcinoma with LS. Cur- rently our patient is alive and well without evidence of either co- lon or adrenal cancer after X months of follow-up Although a PET-avid adrenal lesion in patients with known ma- lignancy is concerning for metastasis, a primary adrenal tumor should be excluded. Pheochromocytomas are characteristically PET avid, and atypical adenomas can also demonstrate PET avid-ity. However, in the setting of LS, a primary ACC should be con-sidered with a higher index of suspicion, as highlighted by this case, especially in the setting of normal plasma metanephrines and relatively rapid enlargement. Although infrequent, recogni-tion of an association between rare cancers like ACC and LS may promote identification of families and individuals at risk, influ-ence screening decisions, and may heighten suspicion of new adrenal nodules in the patient with LS. The current study lends support to the available data supporting ACC as a LS associated malignancy. Reference 1. Fassnacht M, Kroiss M, Allolio B. Update in adrenocortical carcinoma. J Clin Endocrinol Metab. 2013; 98(12): 4551-64. 2. Provenzale D, Gupta S, Ahnen DJ. Genetic/Familial High-Risk Assess- ment: Colorectal Version 1.2016, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2016; 14(8): 1010-30. 3. Berends MJ, Cats A, Hollema H. Adrenocortical adenocarcinoma in an MSH2 carrier: coincidence or causal relation? Human pathology. 2000;31(12):1522-1527. 4. Challis BG, Kandasamy N, Powlson AS. Familial Adrenocortical Car-cinoma in Association with Lynch Syndrome. The Journal of clinical en-docrinology and metabolism. 2016;101(6):2269-2272. 5. Karamurzin Y, Zeng Z, Stadler ZK. Unusual DNA mismatch repair- deficient tumors in Lynch syndrome: a report of new cases and review of the literature. Hum Pathol. 2012; 43(10): 1677-87. 6. Medina-Arana V, Delgado L, Gonzalez L. Adrenocortical carcinoma, an unusual extracolonic tumor associated with Lynch II syndrome. Fam Cancer. 2011; 10(2): 265-71. 7. Raymond VM, Everett JN, Furtado LV. Adrenocortical carcinoma is a lynch syndrome-associated cancer. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2013;31(24):3012- Copyright ©2019 Paul H Graham al This is an open access article distributed under the terms of the Creative Commons Attribution License, 2 which permits unrestricted use, distribution, and build upon your work non-commercially.
- 3. Volume 2 Issue 1 -2019 Case Report 3018. 8. Golden SH, Robinson KA, Saldanha I, Anton B, Ladenson PW. Clini-cal review: Prevalence and incidence of endocrine and metabolic dis-orders in the United States: a comprehensive review. J Clin Endocrinol Metab. 2009; 94(6): 1853-78. 9. Bisceglia M, Ludovico O, Di Mattia A. Adrenocortical oncocytic tu- mors: report of 10 cases and review of the literature. Int J Surg Pathol. 2004; 12(3):231-43. 10. Wong DD, Spagnolo DV, Bisceglia M, Havlat M, McCallum D, Plat-ten MA. Oncocytic adrenocortical neoplasms--a clinicopathologic study of 13 new cases emphasizing the importance of their recognition. Hum Pathol. 2011; 42(4):489-99. clinicsofoncology.com 3