Cases 1 & 2 -

Early and Precursor Lesions of the Adrenal Gland Thomas J. Giordano Department of Pathology University of Michigan Health System Ann Arbor , MI , USA

Introduction Incipient neoplasia is one of the most challenging areas of surgical pathology. This is particularly true for lesions of the endocrine system, including those of the adrenal gland. Much controversy exists regarding the definitions of commonly used terms such as "within normal limits", "diffuse and nodular hyperplasia" and "neoplasm". This is a direct consequence of the rarity of these lesions and the lack of availability of specimens that represent the entire population spectrum. Many of these lesions are asymptomatic and thus usually go clinically undetected until they have developed well beyond the incipient category. For instance, it is especially difficult to derive the age and sex-appropriate cutoffs for how many C cells constitute C cell diffuse hyperplasia due to the lack of availability of truly normal thyroids from across the full spectrum of the population. Adrenal cortex Adrenal Incidentaloma One of the recent trends in medicine is the increasing incidence of the adrenal incidentaloma, i.e. a mass of the adrenal gland incidentally discovered during imaging studies for other medical conditions such as trauma [1]. The majority of these tumors are benign cortical adenomas, but occasionally they are either malignant (adrenal cortical carcinoma) or rarely evolve into carcinoma over time. Case #1. The patient is a 42 old female who was found to have a 2 cm adrenal mass by CT. She was otherwise in reasonably good general health and was lost to followup. About 4 years later, she developed excessive hair growth on her face, abdomen, and legs. She also complained of a 25 lb weight gain over the past 2 years. Ultrasound of the abdomen uncovered a left adrenal mass. Laboratory evaluation revealed an elevated testosterone. The patient underwent left adrenal resection. The resection specimen consisted of an adrenal yellow-tan encapsulated mass with up to 20% areas of necrosis and weighed 180 with a maximum diameter of 6 cm. A somewhat distinct appearing 1.5 cm area was also noted grossly. Case 1 - Clinical Summary: The patient is a 42 old female who was found to have a 2 cm adrenal mass by CT. She was otherwise in reasonably good general health and was lost to followup. About 4 years later, she developed excessive hair growth on her face, abdomen, and legs. She also complained of a 25 lb weight gain over the past 2 years. Ultrasound of the abdomen uncovered a left adrenal mass. Laboratory evaluation revealed an elevated testosterone. The patient underwent left adrenal resection. The resection specimen consisted of an adrenal yellow-tan encapsulated mass with up to 20% areas of necrosis and weighed 180 with a maximum diameter of 6 cm. A somewhat distinct appearing 1.5 cm area was also noted grossly. Case 1 - Figure 1 Click to view with ImageScope Click to view with a Web-Based Viewer Microscopically, the bulk of the tumor consisted of a cellular neoplasm with large cells separated by prominent yet delicate blood vessels. Tumor cells displayed abundant eosinophilic cytoplasm, round nuclei with prominent nucleoli, occasional mitotic figures, and patchy areas of tumor necrosis. Focally, areas of lipid-rich cells with clear cytoplasm were present. The tumor was surrounded by a fibrous capsule, but importantly there were numerous foci of both vascular and capsular invasion. The overall picture of the pathology of this tumor was a low-grade adrenal cortical carcinoma with capsular and vascular invasion. The distinct area noted grossly was an area of relatively pure lipid-rich cells without the associated features of carcinoma described above. Thus, this nodule displayed the typical pathologic features of an adrenal cortical adenoma. Despite treatment, the following year the patient developed a prominent skull-based metastasis that was proven to be metastatic adrenal cortical carcinoma by biopsy. The patient then followed a downhill course and expired with the year of metastatic disease. Case Discussion This case illustrates the rare instance in which a small adrenal cortical tumor eventually developed into a life-ending adrenal cortical carcinoma. As is often the case, finding small adrenal cortical carcinomas is exceedingly difficult, but given the increasing incidence of incidentaloma, cases like these are bound to become more frequent. Even rare is finding a carcinoma with areas that resemble adenoma, a finding that has led to the belief by some that adrenal adenomas are not precursor lesions of carcinomas. However, it is entirely possible that another explanation exists. It is possible that the risk of an adenoma acquiring the necessary molecular changes to evolve into a carcinoma is very low, similar to or lower than to the risk of a colonic adenoma evolving into an adenocarcinoma. Given the exceptionally low incidence of cortical tumors to begin with, it can then be argued that the scarcity of small adrenal cancers is a consequence of the above factors and not a function of its biology. Admittedly, there is controversy in this area and much research needs to done. One of the active areas of work in my research laboratory is the molecular biology of adrenal cortical tumors. In previously published work [2], we derived a gene expression signature of benign and malignant adrenal cortical tumors using DNA microarrays. While the tumor set was limited, there was one low-grade tumor (C13 in figure below) by mitotic activity that closely globally resembled the benign tumors in gene expression, but that clustered with the malignant tumors when using a selected gene set for the analysis. Clearly, this work needs to greatly expanded, but it suggests that early or low-grade adrenal carcinomas share gene expression patterns that are intermediate between benign adenomas and high-grade carcinoma, a finding that lends support to a model in which adenomas can rarely evolve into carcinomas. Other recent molecular work supports this model. Investigation of the wnt signaling pathway revealed mutations of beta-catenin in both adenomas and carcinoma [3], suggesting some commonality in their pathogeneses and leading the authors to suggest that there "may be a common pathophysiologic mechanism involving a multistep tumorigenesis process as speculated for other types of tumors." Adrenal medulla Case #2. The patient is a 38 year-old female who is in good overall health. A family member was recently discovered to have multiple endocrine neoplasia, type IIA. Genetic testing of the patient showed a RET mutation. The patient underwent serum calcitonin testing which revealed elevated levels. 24 hour urinary catecholamines were also elevated. A nuclear medicine scan with I131- iodine-131-meta-iodobenzylguanidine (MIBG) revealed bilateral adrenal uptake that was interpreted as abnormal. The patient underwent bilateral adrenalectomy. Subsequently, the patient underwent total thyroidectomy. Case 2 - Figure 2a Click to view with ImageScope Click to view with a Web-Based Viewer Case 2 - Figure 2b Click to view with ImageScope Click to view with a Web-Based Viewer The left adrenal gland was trimmed and weighed (8 gm) and was serially sectioned and found to contain a well circumscribed brown nodule that measured 0.8 cm in greatest dimension. The adrenal gland away from the nodule was grossly unremarkable. The right adrenal gland was trimmed and weighed (7 gm). It was grossly unremarkable. Microscopically, the left adrenal gland showed a circumscribed nodule consisting of large cells growing in nests surrounded by blood vessels. The tumor cells contained abundant granular cytoplasm. Mitotic figures were not identified. The adjacent medullary tissue appeared to be increased in volume, but morphometric studies were not performed. The right adrenal gland showed a similar nodule that was 0.2 cm and one area in which the medullary volume was increased relative to the cortex. Adrenal Medullary Hyperplasia The definition of adrenal medullary hyperplasia (AMH) is simply defined as an increased number of medullary cells. It can be divided into nodular and diffuse forms. As is the situation with case, it is usually associated with a genetic syndrome that predisposes to its development as well as pheochromocytoma, such as Multiple Endocrine Neoplasia, types IIa and IIb. Also illustrated by this case is the prominent role that genetic testing of the RET gene has assumed in the management of MEN-II patients (see [4, 5] for recent reviews). Differential Diagnosis with Pheochromocytoma The distinction between nodular medullary hyperplasia and pheochromocytoma is completely arbitrary. A 1 cm cutoff has been suggested [6] but is largely based on historical precedent than any biologic or pathologic parameter. As is the situation with other endocrine organs in MEN (such as parathyroid glands in MEN-1) many are beginning to believe that nodular hyperplasia actually represents confluent growth of neoplasms rather than true hyperplasia. This is supported by clonality work done on nodular hyperplasia that demonstrated that nodular AMH is clonal and thus likely to represent true neoplasms [7]. Thus, it can also be argued that all nodules of AMH should actually be regarded as pheochromocytoma. Regardless of the definitions used by pathologists, there will be an arbitrary nature until molecular profiling or other studies can definitely differentiate hyperplasia from neoplasia, if it is even possible. Diffuse AMH and Morphometric Analysis The diagnosis of the diffuse type of AMH is quite difficult and requires careful sectioning of the gland with particular attention to where in the adrenal gland the sections are taken. This is true because the adrenal:medullary ratio varies in the different regions of the gland (body, hear and tail). References and Additional Reading Bertherat J, Mosnier-Pudar H, Bertagna X. Adrenal incidentalomas. Curr Opin Oncol 2002;14(1):58-63. Giordano TJ, Thomas DG, Kuick R, et al. Distinct transcriptional profiles of adrenocortical tumors uncovered by DNA microarray analysis. Am J Pathol 2003;162(2):521-31. Tissier F, Cavard C, Groussin L, et al. Mutations of beta-catenin in adrenocortical tumors: activation of the Wnt signaling pathway is a frequent event in both benign and malignant adrenocortical tumors. Cancer Res 2005;65(17):7622-7. de Groot JW, Links TP, Plukker JT, Lips CJ, Hofstra RM. RET as a Diagnostic and Therapeutic Target in Sporadic and Hereditary Endocrine Tumors. Endocr Rev 2006. Pawlu C, Bausch B, Reisch N, Neumann HP. Genetic testing for pheochromocytoma-associated syndromes. Ann Endocrinol (Paris) 2005;66(3):178-85. Carney JA, Sizemore GW, Sheps SG. Adrenal medullary disease in multiple endocrine neoplasia, type 2: pheochromocytoma and its precursors. Am J Clin Pathol 1976;66(2):279-90. Diaz-Cano SJ, de Miguel M, Blanes A, Tashjian R, Galera H, Wolfe HJ. Clonal patterns in phaeochromocytomas and MEN-2A adrenal medullary hyperplasias: histological and kinetic correlates. J Pathol 2000;192(2):221-8. de Fraipont F, El Atifi M, Cherradi N, et al. Gene expression profiling of human adrenocortical tumors using complementary deoxyribonucleic Acid microarrays identifies several candidate genes as markers of malignancy. J Clin Endocrinol Metab 2005;90(3):1819-29. DeLellis RA, Wolfe HJ, Gagel RF, et al. Adrenal medullary hyperplasia. A morphometric analysis in patients with familial medullary thyroid carcinoma. Am J Pathol 1976;83(1):177-96. Kurihara K, Mizuseki K, Kondo T, Ohoka H, Mannami M, Kawai K. Adrenal medullary hyperplasia. Hyperplasia-pheochromocytoma sequence. Acta Pathol Jpn 1990;40(9):683-6. Machens A, Dralle H. Multiple endocrine neoplasia type 2 and the RET protooncogene: from bedside to bench to bedside. Mol Cell Endocrinol 2006;247(1-2):34-40. McNichol AM. Differential diagnosis of pheochromocytomas and paragangliomas. Endocr Pathol 2001;12(4):407-15. Rudy FR, Bates RD, Cimorelli AJ, Hill GS, Engelman K. Adrenal medullary hyperplasia: a clinicopathologic study of four cases. Hum Pathol 1980;11(6):650-7. Schteingart DE, Doherty GM, Gauger PG, et al. Management of patients with adrenal cancer: recommendations of an international consensus conference. Endocr Relat Cancer 2005;12(3):667-80. Tissier F, Louvel A, Grabar S, et al. Cyclin E correlates with malignancy and adverse prognosis in adrenocortical tumors. Eur J Endocrinol 2004;150(6):809-17. Visser JW, Axt R. Bilateral adrenal medullary hyperplasia: a clinicopathological entity. J Clin Pathol 1975;28(4):298-304.