AVARTMENT OF HEALTH & HUMAN
HHS Public Access Author manuscript Fam Cancer. Author manuscript; available in PMC 2023 May 13.
Published in final edited form as: Fam Cancer. 2018 July ; 17(3): 381-385. doi:10.1007/s10689-017-0042-6.
Ectopic, retroperitoneal adrenocortical carcinoma in the setting of Lynch syndrome
Jesse P. Wright1, Kathleen W. Montgomery2, Joshua Tierney3, Jill Gilbert4, Carmen C. Solórzano1, Kamran Idrees1
1Division of Surgical Oncology, Department of Surgery, Vanderbilt University Medical Center, 2220 Pierce Avenue, Nashville, TN 37232-2391, USA
2Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA
3Department of Surgery, University of Louisville, Louisville, KY, USA
4Division of Medical Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
Abstract
Adrenocortical carcinoma (ACC) is rare within the adult population. Ectopic ACC proves even rarer. This variant is formed by cortical fragments arrested during embryologic migration. ACC is also known to be associated with several genetic syndromes and has recently been linked to Lynch syndrome in 3% of cases. We present the case of a 68-year-old male with a confirmed diagnosis of Lynch syndrome secondary to a germline MSH2 mismatch-repair gene-mutation who presented with 2 months history of non-specific abdominal pain. After imaging work-up, the patient was found to have a right upper quadrant, retroperitoneal mass. Biochemical tests were without any evidence of a hormonally active process. Fine needle aspiration of the mass revealed a poorly differentiated carcinoma of unknown etiology. The lesion was resected and found to be consistent with ectopic ACC with an associated MSH2 mutation.
Keywords
Adrenocortical carcinoma; Lynch syndrome; Ectopic ACC; Adrenal rests
Introduction
Although tumors of the adrenal gland are common, adrenocortical carcinoma (ACC) is rare within the adult population with an estimated annual incidence of one to two patients per million [1]. ACC is often aggressive with an estimated 5-year survival of 25%. Approximately 50% of lesions are hormonally active [2]. Less common is the presentation of ectopic ACC lesions, which are believed to arise from adrenal rests formed by cortical fragments left behind during embryologic migration. Adrenal rests can be found along
the celiac axis, genitourinary system and broad ligament and often discovered incidentally during surgical exploration or autopsy [3, 4].
ACC has additionally been linked with several well-described genetic disease processes. Within the pediatric population, ACC can be present in Li-Fraumeni Syndrome, caused by a germline TP53 mutation, and Beckwith-Wiedemann syndrome caused by mutations within the 11p15 locus (including CDKN1C, IGF genes) [5]. Within the adult population, ACC is a known manifestation ofMEN-1 (multiple endocrine neoplasia) syndrome resulting from a mutation in the MEN1 tumor suppressor gene and more rarely in patients with familial adenomatous polyposis (FAP) syndrome caused by a germline mutation of the APC gene [5]. Recently, ACC has been associated with Lynch syndrome (LS) [6]. Here we describe a case of a 68-year-old male with LS and a symptomatic retroperitoneal abdominal mass. After resection, the lesion was found to be an ectopic, non-functional, poorly differentiated ACC.
Case report
A 68-year-old Caucasian male presented to his gastroenterologist with 2 months of dull, non-specific, mid-abdominal pain. The patient had a history of prostate cancer, treated 10 years prior with prostatectomy and cryotherapy, and Lynch syndrome, diagnosed after resection of several cutaneous sebaceous carcinomas in the preceding years. Mismatch repair (MMR) gene mutational analysis by immunohistochemistry staining of the skin lesions prompted genetic testing and confirmed an MSH2 germline mutation, one of the several DNA MMR gene mutations present in Lynch syndrome. The patient’s family history is suggestive of LS, notable for his mother having had both breast cancer, diagnosed at age 65, and colon cancer, diagnosed before age 50 (deceased, age 79), a maternal uncle diagnosed before age 50 with a brain tumor, likely glioblastoma, (deceased, age mid-50s), maternal grandmother having died of colon cancer in her 40s, a sister diagnosed with breast cancer at age 53 (living), one of his daughters having a “neoplasm of the brain”, likely glioblastoma, (deceased, age 20) and another daughter having uterine and colon cancers, diagnosed in her early 1920s (living). His father (deceased, age 68) had prostate cancer diagnosed at age 61.
Since his diagnosis with LS, the patient had undergone annual surveillance colonoscopies with complete removal of one tubular adenoma. He was enrolled in an established LS surveillance program. He had no other significant medical comorbidities or prior abdominal surgery. At the time of presentation, the patient denied any recent weight change, gastrointestinal symptomatology (nausea, vomiting, diarrhea, etc.), changes in blood pressure, or any significant deviation from his medical baseline.
A contrasted computed tomography (CT) scan of the abdomen and pelvis was obtained to further investigate his abdominal pain that revealed a 3.5 cm, heterogeneous, right-sided retroperitoneal mass located above the right kidney and separate from the right adrenal gland, adjacent to the diaphragm posterior to the right lobe of the liver (Fig. 1). There were no other radiographic findings. CT-guided fine needle aspiration (FNA) biopsy of the mass revealed a poorly differentiated carcinoma of unknown origin or etiology. The mass was
strongly avid on [18F]-fluorodeoxyglucose (FDG) positron emission computed tomography -(PET-CT) and there was no evidence of metastases.
Serum tests were as follows: alpha fetoprotein (AFP) 2.9 ng/ml (normal < 10.0 ng/ml), carcinoembryonic antigen (CEA) 1.1 ng/ml (normal ≤3.0 ng/ml), cancer antigen (CA) 125-21.1 units/mL (normal < 35.0 units/mL), CA 19-9-9.0 units/mL (normal <37.0 units/mL), and prostate-specific antigen (PSA) 1.4 ng/ml (normal < 4.0 ng/ml). Serum adrenocorticotropic hormone (ACTH) was 10 pg/mL (normal for morning draw 10.0-50.0 pg/mL), aldosterone was 7.7 ng/dL (normal supine 23.6 ng/dL), cortisol level was 11.6 ug/dL (normal morning draw 3.7-19.4 µg/dL), progesterone was 0.1 ng/ml (normal for male < 1.0 ng/ml), and dehydroepiandrosterone (DHEA) was 164.5 µg/dL (normal for male of his age 42.0-290.0 µg/dL). His complete metabolic panel and complete blood counts were also within normal limits.
Materials and methods
Based on the available information on this solitary lesion, a decision was made to proceed with surgical resection. With no evidence of peritoneal or metastatic disease on diagnostic laparoscopy, the surgical team proceeded with laparotomy and resection. Intraoperatively, the mass was found to be completely separate from the right adrenal gland but adherent to the adjacent right diaphragm which was resected, en bloc, with the specimen (Fig. 2a). The resected tissue was submitted for gross and histopathological examination and was fixed in 10% neutral buffered formalin and embedded in paraffin. Sections with 3-4 um thickness were obtained for routine hematoxylin and eosin (H&E) staining and immunohistochemical stains for diagnostic purposes were performed using antibodies against synaptophysin, MDM2, INI-1, TFE-3, EMA, WT-1, calretinin, chromogranin, SOX10, CD31, HMB45, PAX-8, desmin, myoD1, and myogenin.
Results
The surgically resected specimen consisted of a tan, round, well defined mass with nodular heterogenous borders measuring 4.1 × 4.0 × 3.8 cm and adherent diaphragmatic tissue measuring 8.3 × 6.0 × 1.6 cm. The mass extended through the diaphragmatic muscle but did not invade the parietal pleura. Surgical margins were negative. There were no surrounding renal, liver or adrenal tissue from which this tumor was arising.
H&E sections showed a tumor comprised of sheets and nodules of malignant cells with extensive (geographic) areas of necrosis (Fig. 2b). Morphologically, the tissue had features of carcinoma but in the setting entirely of soft tissue (Fig. 2c, d). Immunohistochemical staining showed strong, diffuse synaptophysin expression and an absence of chromogranin expression. Tumor cells were negative for pancytokerain (AE1/AE3) and PAX8, positive for cytokeratin 8/18, and showed retained expression of INI-1. Mitotic rate was 2 per 10 high-power fields and the Ki-67 index was 30%. These findings combined with the morphology were most consistent with ACC. With this diagnosis and the patient’s known history, further immunohistochemical staining for mismatch repair (MMR) genes were performed and demonstrated complete loss of nuclear expression of MSH2 (Fig. 2e) and
patchy loss of nuclear expression of MSH6 (Fig. 2f). This additional testing confirms that the lesion is a result of the patient’s germline mutation and Lynch syndrome rather than a sporadic mutation.
The patient tolerated the procedure well and was discharged on the second post-operative day. Since resection, the patient was referred to radiation oncology because of parietal pleural involvement. He completed a full adjuvant radiation (5000 cGy) regimen and remains well on adjuvant mitotane therapy. Recent surveillance imaging is without any evidence of recurrent disease at 24 months.
Discussion
ACC remains an uncommon cancer with a minority of cases occurring in the setting of LS. LS results from an autosomal dominant germline mutation of one of the DNA MMR genes MSH2, MSH6, PMS2, MLH1, and TACSD1/EPCAM. These mutations alter the function of the mismatch repair function, leading to an accumulation of mutations and increased risk of malignant transformation.
Traditionally referred to as hereditary non-polyposis colorectal cancer (HNPCC), LS is the most commonly inherited colorectal cancer (CRC) syndrome, associated with an estimated lifetime risk of developing CRC ranging from 30 to 75% [7, 8]. Patients with LS also have increased lifetime risk of developing malignancies of the endometrium, ovaries, gastrointestinal tract, urinary tract, central nervous system and skin. The proband in this report has a maternal family history consistent with known LS pathologies (colorectal and CNS cancers), while his paternal family history is significant for prostate cancer. This likely indicates that LS was inherited through his mother and that he could have inherited a separate susceptibility to prostate cancer via his father.
Likely as a result of increased surveillance and screening, additional malignancies, including ACC, have been increasingly reported within the LS population. In a prospective study of 114 patients with ACC, Else et al. report a prevalence of LS secondary to MMR genes mutations of 3.2% [6]. As a result of these data, it has been suggested that a history of ACC should be included in standardized clinical diagnostic questionnaires for LS such as the Amsterdam II Criteria [9]. It has also been proposed that MMR gene testing should be performed in all patients with ACC which may allow for increased patient and family screening and surveillance in patients with positive results [6]. Lastly, but more importantly, these ACC arising in patients with LS or those with somatic mismatch repair-deficient tumors may benefit from immunotherapy (anti-PD1 therapy) as opposed to cytotoxic, non- targeted chemotherapy (mitotane) used currently as standard of treatment in the metastatic setting [10].
This case is interesting in many regards. This is the first case of which the authors are aware of a patient with an extra-adrenal, non-functioning ACC with an associated MSH2 germline mutation. Additionally, this patient’s initial diagnosis of LS was made after resection of concerning skin lesions found to be sebaceous carcinomas with subsequent MMR gene testing identifying the causative MSH2 mutation. By convention, the presence
of sebaceous carcinomas in the setting of an MMR gene mutation, diagnoses this patient with Muir-Torre syndrome, a variant of LS, present in approximately 9% of patients with LS [11]. Furthermore, this patient’s remote history of prostate cancer, although present in his paternal history, may be a result of his MSH2 mutation as well. One recent study notes that approximately 6% of males with LS develop prostate cancer with a higher incidence specifically in those with an MSH2 mutation [12].
Ultimately, this patient may have developed three separate malignant processes as a result of his MSH2 mutation and thus reinforces the need for appropriate screening for the entire spectrum of known pathologies associated with LS. With recent advances in immunotherapy, there is now potential for immune checkpoint blockade in patients with MMR mutations, which may mitigate the need for non-targeted, cytotoxic systemic therapy though studies in ACC need to be performed [10]. Hypothetically, with increased screening, genetic testing and immunotherapy, ACC patients with LS may have the potential for superior outcomes and long-term survival over their non-LS counterparts. Further investigation is warranted.
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