ENDOCRINE SOCIETY
OXFORD
Metastatic Merkel Cell Carcinoma Within a Cortisol-producing Adrenal Adenoma
Lauren Cutrone,1 Jose Subauste,2 Celso Gomez-Sanchez,2 and Sarah Joiner20D
1Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA
2Department of Specialty Services, G.V. (Sonny) Montgomery Veteran Affairs Medical Center, Jackson, MS 39216, USA
Correspondence: Sarah Joiner, MD, G.V. (Sonny) Montgomery Veteran Affairs Medical Center, Specialty Service 111, 1500 E Woodrow Wilson Dr, Jackson, MS 39216, USA. Email: sarah.joiner@va.gov.
Abstract
A 54-year-old man with hypertension, type 2 diabetes mellitus, and a history of Merkel cell carcinoma (MCC) of the right thigh presented to the emergency department with a 4-day history of right lower-quadrant abdominal pain associated with constipation and decreased appetite. Workup showed a heterogenous 6-cm right adrenal mass with macroscopic fat. Imaging was suggestive of benign pathology. Hormonal workup for the adrenal nodule led to the diagnosis of Cushing syndrome. The patient underwent a right adrenalectomy for Cushing syndrome with pathology revealing a 6.5-cm adrenocortical adenoma harboring a 2-cm, well-circumscribed neuroendocrine tumor consistent with metastatic MCC. Adrenal collision tumors are exceedingly rare. This case describes a collision tumor that has not previously been identified-a cortisol- producing adrenal adenoma and metastatic MCC.
Key Words: adrenal collision tumor, Merkel cell carcinoma, Cushing syndrome
Abbreviations: CK, cytokeratin; CYP17A1, cytochrome P450, family 17, subfamily A, polypeptide 2; FDG, fluorodeoxyglucose; MCC, Merkel cell carcinoma; PET, positron emission tomography.
Introduction
Adrenal collision tumors are 2 histologically distinct neoplasms within a single adrenal mass, a tumor so rare that the preva- lence is unknown [1]. Merkel cell carcinoma (MCC) is a rare neuroendocrine carcinoma of the skin that is highly ag- gressive with locoregional metastatic spread in 30% of cases at the time of diagnosis. It is typically found in sun-exposed areas of older or immunosuppressed patients. Sites of metas- tases are not well studied due to the rarity of MC tumors, but case reports suggest regional lymph node metastases occur in addition to metastases to the liver and lungs. Few case reports have noted metastasis to the adrenal glands [2]. To our knowledge, there are no other case reports of an adrenal collision tumor with metastatic MCC and a hormonally active adrenal nodule.
Case Presentation
A 54-year-old man with class III obesity, essential hyperten- sion, type 2 diabetes mellitus, obstructive sleep apnea, and previously resected MCC of the right thigh presented to the clinic for an evaluation of an adrenal mass. The mass was dis- covered after a visit to the emergency department for a 4-day history of right lower-quadrant abdominal pain. The pain was associated with constipation and decreased appetite. He de- nied any other symptoms including vomiting or diarrhea. Contrasted computed tomography of the abdomen revealed
a large, 6-cm right adrenal mass as seen in Fig. 1. It was a well- circumscribed, heterogeneous mass with macroscopic fat but also areas of high attenuation. The Hounsfield units ranged from -70 in many areas to 74 in other areas. Magnetic reson- ance imaging was not obtained. In the clinic, his pain had re- solved without intervention. On review of systems, he admitted to hyperhidrosis, occasional palpitations, tremors, and fatigue. Family history was significant for colon cancer and prostate cancer in his paternal uncle. The patient smoked a half-pack of cigarettes per day. Physical examination was notable for central obesity with a body mass index of 44.1 and facial plethora. No other cushingoid features were present on physical examination.
Two years prior to his presentation, he was diagnosed with MCC and underwent a surgical resection of the tumor with clear margins and no evidence of invasion. He subse- quently had a sentinel lymph node evaluation that revealed microscopic focus of MCC in right inguinal lymph nodes. Positron emission tomography (PET) scan showed no abnormal uptake within the thorax, abdomen, or pelvis ex- cept for heterogeneous low-level fluorodeoxyglucose (FDG) avidity in the 6-cm right adrenal lesion that was interpreted as likely an adrenal myelolipoma and considered benign ap- pearing. Magnetic resonance imaging of the brain was negative for metastatic disease. He completed radiation therapy to the right thigh and groin, and repeat PET scan showed no abnormal uptake and unchanged right adrenal lesion.
Diagnostic Assessment
Hormonal workup for the adrenal nodule included renin and aldosterone levels, plasma metanephrines, and a dexametha- sone suppression test. Renin and aldosterone were not indicative of excessive aldosterone production. Plasma nor- metanephrine and metanephrine were normal as well. The dexamethasone suppression test was abnormal. The morn- ing cortisol level was 166 nmol/L (6 mcg/dL) after taking 1 mg of dexamethasone by mouth the previous night (normal = < 50 nmol/L [<1.8 mcg/dL] after 1 mg of dexa- methasone [3]). Due to the abnormal dexamethasone suppression test, 2 salivary free cortisol levels were measured at midnight that were normal at 0.66 nmol/L (0.024 mcg/dL) and 1.13 nmol/L (0.041 mcg/dL) (normal = 0.28-2.48 nmol/ L [0.010-0.090 mcg/dL]). Adrenocorticotropin and dehydroe- pian-drosterone-sulfate were suppressed at 0.95 pmol/L (4.3 pg/mL) (normal =1.58-13.93 pmol/L [7.2-63.3 pg/mL]) and 0.38 umol/L (14.1 mcg/dL) (normal = 1.93-10.14 µmol/L [71.6-375.4 mcg/dL]), respectively. There was concern for endogenous cortisol production despite the normal and ab- normal cortisol results. A 24-hour urine cortisol test was not obtained.
Treatment
Due to the size of the mass and concern for cortisol produc- tion, the patient underwent a surgical resection of the right ad- renal gland. He was started on hydrocortisone replacement therapy immediately after surgery. Pathology of the adrenal mass was consistent with a 6.5-cm adrenocortical adenoma harboring a 2-cm, well-circumscribed mass consistent with metastatic MCC with evidence of lymphovascular invasion. Fig. 2A and 2B show the hematoxylin and eosin stain of the border between the MC tumor and the adrenocortical ad- enoma at different magnifications. Fig. 3 shows 3 different stains of the entire tumor. The neuroendocrine tumor stained positive for cytokeratin 20 (CK20) and chromogranin A but negative for cytochrome P450, family 17, subfamily A, poly- peptide 2 (CYP17A1), while the adrenocortical adenoma stained positive for CYP17A1 and negative for CK20 and chromogranin A. Additional staining showed the neuroendo- crine tumor stained positive for pancytokeratin and negative for CK7, CD20, and CD3, which was consistent with the pathology from the patient’s previous MC tumor. At that time, the patient was started on systemic immunotherapy with pembrolizumab for metastatic MCC.
Outcome and Follow-up
The patient has been on pembrolizumab for treatment of metastatic MCC and has tolerated treatment well. He has completed 30 months of therapy with plans to continue treat- ment for at least 12 additional months. His most recent PET scan showed no FDG-avid residual, recurrent, or metastatic disease. He recently underwent a cosyntropin stimulation test that failed to stimulate adequate cortisol production. His cortisol level was 287 nmol/L (10.4 mcg/dL), 408 nmol/L (14.8 mcg/dL), and 444 nmol/L (16.1 mcg/dL) before, 30 mi- nutes after cosyntropin, and 60 minutes after cosyntropin, re- spectively (normal ⇒500 nmol/L [>18 mcg/dL]). He remains on steroid replacement therapy while awaiting recovery of his remaining left adrenal gland.
Discussion
Prior to surgical resection, the differential diagnosis for this mass included a hormonally active adrenal myelolipoma or a hormonally active adrenal adenoma. Metastatic disease from MCC was lower on the differential. The areas of in- creased density with only mild FDG activity on PET were con- sidered typical of an adrenal myelolipoma. It is also the second
A
B
*
*
CK20
Chromogranin A
CYP17A1
3
most common type of adrenal incidentaloma [4]. The size of the mass was concerning for a more aggressive pathology; however, several myelolipomas have been described as greater than 10 cm [5, 6]. Hormonally active adrenal myelolipomas are uncommon but they have been shown in the literature [7]. Due to the macroscopic fat and areas of low attenuation on imaging, pheochromocytoma and adrenocortical carcin- oma were thought to be unlikely.
After surgical resection, pathology revealed an adrenal collision tumor of an adrenal adenoma and MCC. MCC is a cutaneous neuroendocrine malignancy with aggressive features. Regional lymph node involvement is common, and approximately one-third of patients will eventually de- velop distant metastasis with the abdominal viscera being the most common site [2]. While MCC is uncommon, ad- renal collision tumors between hormonally active adrenal adenomas and metastatic cancer are exceedingly rare. One example includes a non-small cell lung cancer and cortisol- producing adrenal adenoma [8]. Another example is a meta- static breast tumor, adrenal adenoma, and myelolipoma all within the same adrenal gland [9]. It is uncertain if adrenal collision tumors are simply the result of 2 different tumors occurring together by coincidence or if 1 tumor modifies the surrounding environment so as to increase the likeli- hood of another tumor harboring in the same vicinity [1]. Moriya et al [10] studied this phenomenon in lung cancer. By studying the autopsy of 160 lung cancer cases and an ex- tensive literature review, they determined that the incidence of lung cancer metastasis to adrenocortical adenomas was higher than the theoretical probability. To the authors’ knowledge, this is the first case of an adrenal collision tumor between a cortisol-producing adrenal adenoma and meta- static MCC.
This case highlights the need to maintain a broad differential diagnosis for benign-appearing adrenal nodules in the setting of an underlying malignancy. This patient’s PET scan that showed a heterogeneous adrenal mass with mild FDG avidity and his contrasted computed tomography scan that showed a large, het- erogeneous adrenal mass were both characterized as likely be- nign due to the macroscopic fat and areas of low attenuation. Due to the lack of certainty presented by current imaging modal- ities, it is important to consider the possibility of metastatic dis- ease if there is a known underlying malignancy and to consider adrenal collision tumors in the setting of a heterogeneous mass.
Learning Points
· Adrenal collision tumors between an adrenal adenoma and metastatic disease can occur and should be considered in all patients with history of a malignancy.
· One possible collision tumor that has not previously been identified is a cortisol-producing adrenal adenoma and metastatic MCC.
· Imaging studies are limited in their ability to definitively diagnosis adrenal masses, and the entire mass should be carefully reviewed for heterogenicity.
Contributors
All authors were involved in the diagnosis and management of this patient. L.C. was responsible for drafting the manuscript. L.C. and J.S. were involved in the literature review of similar cases. C.G. helped prepare the histology slides for images. S.J. completed the manuscript review and editing. All authors were involved in manuscript submission. All authors reviewed and approved the final draft.
Funding
No public or commercial funding.
Disclosures
None of the authors have financial conflicts of interest to disclose.
Informed Patient Consent for Publication
Signed informed consent obtained directly from the patient.
Data Availability Statement
Data sharing is not applicable to this article as no data sets were generated or analyzed during the current study.
References
1. Katabathina VS, Flaherty E, Kaza R, et al. Adrenal collision tumors and their mimics: multimodality imaging findings. Cancer Imaging. 2013;13(4):602-610.
2. Song Y, Azari FS, Tang R, et al. Patterns of metastasis in Merkel cell carcinoma. Ann Surg Oncol. 2021;28(1):519-529.
3. Nieman LK, Biller BM, Findling JW, et al. The diagnosis of Cushing’s syndrome: an Endocrine Society clinical practice guide- line. J Clin Endocrinol Metab. 2008;93(5):1526-1540.
4. Calissendorff J, Juhlin CC, Sundin A, et al. Adrenal myelolipomas. Lancet Diabetes Endocrinol. 2021;9(11):767-775.
5. Rowe SP, Javadi MS, Solnes LB, et al. Appearance of adrenal mye- lolipomas on 2-deoxy-2-(18F) fluoro-D-glucose positron emission tomography-computed tomography. World J Nucl Med. 2017;16(4):271-274.
6. Blake MA, Slattery JM, Kalra MK, et al. Adrenal lesions: character- ization with fused PET/CT image in patients with proved or sus- pected malignancy-initial experience. Radiology. 2006;238(3): 970-977.
7. Corpas Jiménez MS, Ortega Salas R, Tenorio Jiménez C, Molina Puerta MJ. Myelolipoma associated with adrenocortical adenoma: an unusual cause of Cushing’s syndrome. Endocrinol Nutr. 2014;61(1):e7-e9.
8. Martin JT, Alkhoury F, Helton S, et al. Metastatic adenocarcinoma within a functioning adrenal adenoma: a case report. Cases J. 2009;2(1):7965.
9. Liu D, Kumar SA. An exceedingly rare adrenal collision tumor: ad- renal adenoma-metastatic breast cancer-myelolipoma. J Community Hosp Intern Med Perspect. 2017;7(4):241-244.
10. Moriya T, Manabe T, Yamashita K, Arita S. Lung cancer metastasis to adrenocortical adenomas. A chance occurrence or a predilected phenomenon ?. Arch Pathol Lab Med. 1988;112(3):286-289.