The Adrenal Gland and Paraganglia
Louis P. Dehner
I. NORMAL ANATOMY AND HISTOLOGY. The definitive or adult adrenal glands are located anterior to the upper poles of the kidneys. The glands are pyramidal on the right and crescentic on the left. In adults the normal combined weight should not exceed 6 g. Each adrenal gland is divided into head (most medial), body (middle), and tail (most lateral).
The adrenal gland is composed of an outer cortex and an inner medulla, and as a compound gland is unique to mammals (Pharmacol Rev. 1971;23:1971). The gland is derived from two embryologic progenitors: the coelomic epithelium between the urogenital ridge and dorsal root mesentery as the primordial cortex, and migratory neural crest cells as the future medulla as well as the ganglia and paraganglia. Migratory neural crest cells are identified as small dark cells as they pass through the cortex into the center of the gland as individual cells or small aggregates of neuroblasts (Endocr Pathol. 2009;20:92; Folia Histochem Cytochem. 2010;48:491); however, a definitive medulla does not become apparent until 1 to 1½ years of age.
Microscopically, the cortex consists of three zones: the outer zona glomerulosa (secreting aldosterone), middle zona fasciculata (secreting mainly cortisol and minor amounts of sex steroids), and inner zona reticularis (secreting mainly sex steroids) (e-Fig. 26.1).* The zona glomerulosa is composed of a thin, usually discontinuous layer of cells with ball-like formations; these cells have less cytoplasm than those in other two cortical zones. The zona fasciculata consists of radial cords or columns of cells with abundant lipid-rich cytoplasm. The cells of the zona reticularis have compact, finely eosinophilic cytoplasm with or without lipofuscin pigment. Normally the medulla accounts for 10% of the adrenal volume and grossly has a gray-white color. The predominant cells in the medulla are the mature chromaffin cells, the pheochromocytes, organized in nests and cords (e-Fig. 26.2). The cytoplasm of the chromaffin cells is usually basophilic but may be amphophilic or even eosinophilic. These cells have indistinct cell borders and usually a single nucleus which may show variation in size and hyperchromasia. The chromaffin cells are peripherally surrounded by the sustentacular cells; rare ganglion cells may be identified in the adrenal unlike their prominence in ganglia (e-Fig. 26.3). The major function of adrenal medulla is the synthesis and secretion of catecholamines (epinephrine and norepinephrine).
II. GROSS EXAMINATION OF ADRENAL GLAND SPECIMEN. The adrenal gland is removed either as part of a radical nephrectomy or for excision of an adrenal tumor. Biopsies of the adrenal are generally fine needle aspirations or thin needle biopsies to evaluate for the presence of metastatic tumor.
A. Needle biopsy. The entire tissue should be submitted for histologic examination.
B. Adrenal gland removed as part of radical nephrectomy. After gross examination of the kidney, the gland should be measured and weighed. Then the gland should be serially sectioned at 2- to 3-mm intervals perpendicular to its long axis; the thickness of the cortex and medulla should be noted. Infrequently,
the adrenal may be invaded directly by renal cell carcinoma or be the site of discontinuous metastases.
C. Adrenectomy for a primary pathologic process. The first step is to orient the specimen and examine the contour of the adrenal gland. If it is apparent that the gland has been largely replaced by a mass, the periphery should be inked since the margins may be important (assuming that the mass has not already invaded surrounding structures like the liver). If the cortex and medulla maintain their normal relationship to each other, the thickness of each should be recorded. Serial sectioning should be done at intervals appropriate for the pathology. If the disease process is apparently diffuse hyperplasia, the periadrenal soft tissue should be removed and the gland should be measured and weighed. If the adrenal contains a solitary mass or multiple nodules, three dimensional measurements should be obtained. The cut surface of the lesion and its relationship to any identifiable normal tissue should be described, including color, consistency, presence of hemorrhage or necrosis, degree of circumscription, and degree of encapsulation. If any portions of adjacent organs such as liver, kidney, spleen, or abdominal wall are attached (usually for tumors), their appearance and relationship to the gland should be noted. A large, en bloc resection will require numerous sections from the peripheral margins. For diffuse and/or nodular hyperplasia, representative sections are sufficient.
For a neoplasm, the following sections should be taken: tumor, (including sections demonstrating the relationship of the tumor to the associated soft tissues and adjacent organs, and relationship of the tumor to uninvolved adrenal gland); the tumor capsule, if present; margins; periadrenal fatty tissue overlying a bulging mass; a representative section from uninvolved adrenal, if any; and regional lymph nodes. The gross description should clearly document the site of the sections. For large specimens, a gross photograph is extremely helpful in that it depicts the specimen at a time when landmarks are still maintained with some anatomic orientation.
D. Neuroblastoma specimens. Neuroblastic tumors present some special issues regarding acquisition of neoplastic tissue for a variety of special studies to biologically profile the tumor for children enrolled in a Children’s Oncology Group (COG) protocol. If the specimen is an adrenal-based neuroblastoma (NB), then generally the amount of available tumor is sufficient for pathologic diagnosis as well as for all other ancillary studies. The difficulties arise in those cases of NB when only biopsies are obtained prior to chemotherapy in cases of nonresectable tumors. Accuracy of tumor grading is based upon a thorough microscopic examination which may be limited by the amount of well-preserved tumor in the specimen.
A resected primary NB of the adrenal, or extraadrenal retroperitoneal mass, should be examined fresh if at all possible as discussed in section C above. The COG reference laboratory requests at least 1 g of snap frozen tumor tissue but will accept any frozen sample of tumor; the snap freezing should occur as soon as the specimen becomes available following resection. Tumor samples should be labeled “primary” or “metastatic”; involved bone marrow is required as well. Storage at −70°C is preferable to −20°C.
Fresh tissue should also be collected for local institutional studies including conventional cytogenetic studies. Snap-frozen fresh tissue should be saved for possible molecular studies. Tumor for fluorescent in situ hybridization can be recovered from formalin-fixed, paraffin-embedded tissue without compromising the quality of results.
III. ADRENAL CORTICAL LESIONS
A. Congenital abnormalities. The most common congenital anomaly of the adrenal is an incidental finding of heterotopia consisting of microscopic foci of cortical tissue or nodule(s) along the path of descent of the gonads, although rare cases
of heterotopia at a wide variety of other anatomic sites have been reported. Heterotopias are identified in 1.5% to 2.7% of groin procedures in males (BJE Int. 2005;95:407); the spermatic cord, inguinal hernia sac, or paraepididymal soft tissues are the three most common sites (Int Surg. 2006;91:125). Only cortical tissue is identified as a rule (e-Fig. 26.4), but cortex and medulla have been seen in heterotopias in the celiac axis. Other congenital abnormalities include adrenal union/fusion, adrenal cytomegaly, intraadrenal heterotopic tissue, and congenital adrenal hyperplasia. Adrenal cytomegaly is characterized by the presence of foci of bizarre cells with eosinophilic granular cytoplasm and large hyperchromatic nuclei with pseudoinclusions; this finding is detected in Beckwith-Wiedemann syndrome. Heterotopic tissues within the adrenal gland include liver, thyroid, and ovarian stroma.
B. Incidental adrenal cortical nodules. Nonfunctional cortical nodules are found in 1% to 10% of autopsies, are usually multiple and bilateral, and can protrude into adjacent fat. These variably sized nodules have a yellow appearance on cut surface. Circumscribed but nonencapsulated nodules consist of fasciculata-type cells with various patterns. Myelolipomatous metaplasia, osseous metaplasia, and secondary changes (hyalinization, calcification, or hemorrhage) may be present. Pigmented nodules are composed of zona reticularis-type cells with lipofuscin or neuromelanin.
C. Adrenal cortical hypofunction (insufficiency) is divided into primary and secondary types.
1. Primary adrenal cortical insufficiency (Addison disease) is due to destruction of the adrenal cortex. In developed countries, over 80% of cases are due to autoimmune adrenalitis as an isolated manifestation of autoimmune polyendocrinopathy (Lancet. 2003;361:1881). This T-cell mediated immunologic destructive process of the cortex results in small glands which have a mixed inflammatory infiltrate of lymphocytes, plasma cells, and histiocytes. Lymphoid follicles with germinal centers may be present in a pattern similar to that in Hashimoto thyroiditis (Endocr Dev. 2011;20:161). Cortical cells may be difficult to identify, but the medulla remains intact. Various inborn errors of metabolism, hemorrhage, and neoplastic infiltrates or replacement are other etiologies.
Adrenal cortical insufficiency may occur on the basis of infectious etiologies including tuberculosis, other bacterial infections (including Meningococcus, Pseudomonas, Streptococcus pneumoniae, and Haemophilus influenzae), fungal infections, cytomegalovirus, herpes simplex virus, and toxoplasmosis (in HIV-infected individuals). These infections lead to destruction of the entire gland. Acute adrenal insufficiency with bilateral cortical hemorrhage and necrosis are features of the Waterhouse-Friderichsen syndrome, more commonly seen at autopsy. Adrenoleukodystrophy (X-linked peroxisomal disorder) is also manifested by adrenal insufficiency with cortical nodules composed of enlarged ballooned cells (J Clin Endocrinol Metab. 2011;96:E925).
Other causes of primary insufficiency include amyloidosis and drugs. Treatment with mitotane may cause adrenal atrophy with fibrosis.
Congenital adrenal hypoplasia (CAHP) is an uncommon condition that is more likely to be encountered in a fetopsy or perinatal autopsy. Its estimated incidence is 1:12,500 live births, compared to the incidence of anencephaly of 2.23:10,000 live births in the United States. It should be anticipated that 1% to 2% of fetopsies have CAHP as defined as combined adrenal weights of <2 g at term, or more accurately an adrenal weight over body weight of <1:1000. There are three distinct morphologic patterns: cytomegaly type (most common with X-linked inheritance with inactivating deletion mutations at Xp 21.2 in the gene that encodes DAX-1);
anencephalic type (without CNS or pituitary defects but the cortex is attenuated and the fetal cortex is inconspicuous); and a miniature type with a definitive cortex and an attenuated fetal cortex.
2. Secondary and tertiary adrenal cortical insufficiencies. These are due to the failure of the pituitary gland to secrete ACTH (secondary) or of the hypothalamus to secrete CRH (tertiary). The gland size is decreased. Histologically, the zona fasciculata is atrophic whereas the zona glomerulosa and medulla are usually relatively normal.
D. Adrenal cortical hyperplasia can be divided into congenital and acquired types.
1. Congenital adrenal hyperplasia is an autosomal recessive disorder caused by one of five enzymatic defects that result in a failure in cortisol synthesis; 21-hydroxylase deficiency accounts for 90% to 95% of cases (Lancet. 2005;365:2125; Endocr Dev. 2011;20:80). Marked diffuse hyperplasia of the zona fasciculata results from ACTH stimulation, whereas cells of the zona fasciculata are lipid-depleted due to their conversion into zona reticularis-type cells with compact eosinophilic cytoplasm. Persistent ACTH stimulation may also give rise to adrenal cortical neoplasms. Nodules resembling hyperplastic adrenal cortical tissue in testis can develop into the so-called testicular tumors of the adrenogenital syndrome (Am J Surg Pathol. 1988;12:503).
2. Acquired adrenal cortical hyperplasia is a nonneoplastic bilateral process characterized by a gland weighing in excess of 6 g. The gland has either a diffuse, nodular, or combined appearance.
a. Diffuse hyperplasia is usually ACTH dependent and caused by a hyperfunctional pituitary (most often pituitary adenoma, less often corticotropin-releasing hormone (CRH) from the hypothalamus) or an ectopic ACTH/CRH-producing tumor. The latter neoplasms include small cell carcinoma (usually from the lung), low grade neuroendocrine carcinoma or carcinoid (usually from the lung or thymus), medullary thyroid carcinoma, pancreatic endocrine neoplasms, and pheochromocytoma (PHEO). Both glands are symmetrically enlarged. The zonae fasciculata and reticularis are expanded with their relative proportions varying from case to case. The zona fasciculata is lipid depleted but markedly expanded by a population of cortical cells with abundant eosinophilic cytoplasm (e-Fig. 26.5).
b. Nodular cortical hyperplasia is ACTH-independent in most cases. The glands are markedly enlarged, in excess of 15 to 20 g in some cases. The cortical nodules may constitute a transformation from diffuse hyperplasia in its late stage; these nodules are yellowish and vary from 0.2 to over 4.0 cm. Fasciculata-type clear cells, reticularis-type cells, or a mixture of these two cell types characterize the nodules. Nodular adrenal cortical disease with discrete nodules of hyperplastic zona glomerulosa with intervening cortical atrophy is seen in children with McCune-Albright syndrome (Am J Surg Pathol. 2011;35:1311).
c. Primary pigmented nodular adrenocortical disease (PPNAD), an uncommon but specific form of ACTH-independent nodular hyperplasia, is generally diagnosed in the second decade of life with or without the other stigmata of Carney complex (Orphanet J Rare Dis. 2006;1:21; Best Pract Res Clin Endocrinol Metab. 2010;24:389). A germline heterozygous inactivating mutation of PRKR1A is found in the Carney complex (65% to 70% of cases) and may also have a role in primary PPNAD (Pituitary. 2006;9:211). The glands are of normal size, but the cut surface has scattered pigmented micronodules, or less often macronodules measuring 1 to 4 mm in size. Uniform compact cells with eosinophilic cytoplasm and some balloon cells are histologic features of the nodules. Pigmentation is
due to intracytoplasmic lipofuscin. The same cells are strongly positive for synaptophysin but nonreactive for chromogranin. The nodules may abut the cortical medullary junction, extend into the periadrenal fat, or involve the entire thickness of the cortex.
TABLE 26.1 World Health Organization Histologic Classification of Tumors of Adrenal Gland and with Additional Entities
Adrenal cortical tumors
Adrenal cortical adenoma
Adrenal cortical carcinoma
Adrenal medullary tumors
Benign pheochromocytoma
Malignant pheochromocytoma
Composite pheochromocytoma
Other adrenal tumors
Adenomatoid tumor
Sex cord-stroma tumor
Soft tissue and germ cell tumors
Myelolipoma
Teratoma
Schwannoma
Ganglioneuroma
Angiosarcoma
Leiomyoma
Wilms tumor (extrarenal)
Secondary or metastatic tumors
Extraadrenal paraganglioma
Jugulotympanic
Vagal
Laryngeal
Orbital nasopharyngeal
Carotid body
Aorticopulmonary
Gangliocytic
Cauda equine
Cervical paravertebral
Intrathoracic
Intra-abdominal
Superior paraaortic
Inferior paraaortic
Urinary bladder
Modified from: DeLellis RA, Lloyd RV, Heitz P, et al., eds. World Health Organization Classification of Tumours. Pathology and Genetics. Tumours of Endocrine Organs. Lyon, France: IARC Press; 2004. Used with permission.
d. Adrenal cortical hyperplasia with hyperaldosteronism (Conn syndrome) occurs in the absence of an adenoma in 30% of cases as bilateral cortical hyperplasia. The size, weight, and appearance of the glands are variable and the size may be within the normal range. The zona glomerulosa has tongue-like projections toward the underlying zona fasciculata. Micronodules may be present with fasciculata-type cells.
E. Adrenal cortical neoplasms are traditionally divided into adenomas and carcinomas (Table 26.1). In terms of functioning adrenal cortical neoplasms, these tumors present with the following: Cushing syndrome (60% to 65% of cases), mineralocorticoids-androgens (20%), combined Cushing-androgens (4%), estrogen (12%), and aldosterone (4%).
1. Adrenal cortical adenoma is typically unilateral, solitary, rarely larger than 50 g or 5 cm in size, and heterogeneous with or without clinical manifestations due to hyperfunction (e-Fig. 26.6). The hormone-associated syndromes are hyperaldosteronism, Cushing syndrome, and adrenogenital syndrome in descending order of frequency. Most cortical adenomas are nonfunctioning and detected as incidentalomas.
a. Hyperaldosteronism (Conn syndrome) is associated with an adenoma in 70% of cases; the adenoma is <2 cm in size in most cases (e-Fig. 26.7) (Orphanet J Rare Dis. 2010;19(5):9). Histologically, a yellowish, circumscribed, but encapsulated nodule is composed of zona fasciculata-type cells, zona reticularis-type cells, zona glomerulosa-type cells, or cells showing hybrid features (e-Fig. 26.8). Occasionally, the adjacent cortex may show hyperplasia of the zona glomerulosa (paradoxical hyperplasia). If there has been treatment with spirolactone (an aldosterone
antagonist), characteristic spirolactone bodies are usually present, consisting of small, intracytoplasmic, 2 to 6 µm round to oval inclusions with a slightly eosinophilic appearance and two to six concentric rings within the tumor cells and the adjacent zona glomerulosa (Am J Clin Pathol. 1970;54:22). A halo separates the spirolactone bodies from the surrounding cytoplasm.
b. Cushing syndrome is characterized by an adenoma which is sharply demarcated or even capsulated and has a homogeneous yellow to golden-yellow appearance or irregular foci of dark discoloration on cut surface. Solid nests or alveolar-like profiles are present, composed of cells which are usually larger than the normal cortical cells. The cells of the adenoma have features of zona fasciculata-type cells with the occasional presence of foci of smaller zona reticularis-type cells (e-Fig. 26.9); both types of tumor cells usually have single, round to oval nuclei with a small nucleolus. In some cases, there are scattered cells with larger, hyperchromatic nuclei with pseudoinclusions; they have no prognostic importance. Mitotic figures are rare. Fibrosis, organizing thrombi within sinusoids, and lipomatous and myelolipomatous metaplasia are other features. The compressed residual cortex is invariably atrophic.
c. Adrenogenital syndrome with sex hormone production is infrequently caused by an adenoma, but is more often associated with cortical carcinomas that produce estrogen. Androgen-producing adenomas are generally larger than those in Cushing syndrome and are also sharply demarcated from the adjacent cortex. The tumor cells have the features of zona reticularis cells with compact, eosinophilic cytoplasm.
2. Other adrenocortical neoplasms with special microscopic features beyond the usual appearance of adenoma and carcinoma include oncocytic tumor, myxoid adrenal cortical neoplasm, sarcomatoid carcinoma, and the so-called adrenal blastoma.
a. Black (pigmented) adenoma is associated with Cushing syndrome, and rarely with Conn syndrome (Int J Surg Pathol. 2004;12:57). In most cases the tumor is composed predominantly or entirely of cells resembling zona reticularis cells with a variable amount of intracytoplasmic brown or golden-brown pigment (lipofuscin) (Endocr Pathol. 1999;10:353).
b. Oncocytic neoplasms include both benign and malignant tumors as in other organs. A cytoplasm rich in mitochondria accounts for the oncocytic appearance of the tumor cells in common with extraadrenal oncocytoma. These tumors are often characterized by large, bizarre cells; despite the presence of these very atypical cells, the histologic criteria to differentiate an adenoma from a carcinoma are applicable (Int J Surg Pathol. 2004;12:231; Ann Diagn Pathol. 2010;14:204). These tumors may have cytoplasmic globules and inclusions like those seen in pheochromocytoma (Virchow Arch. 2008;453:301), which can be problematic since the latter tumor may also have oncocytic features in rare cases (Am J Surg Pathol. 2000;24:1552).
c. Myxoid neoplasms are rare morphologic variants of a cortical adenoma or carcinoma with a focal or near diffuse background that has a myxoidmucoid appearance consisting of hyaluronidase digestible Alcian blue positive stromal mucin. The myxoid stroma separates the tumor cells into cords, nests, pseudoglands (e-Fig. 26.10), and trabecula (Ann Diagn Pathol. 2008;12:344; Am J Surg Pathol. 2010;34:973). The individual tumor cells are spindled to epithelioid. The various microscopic features for differentiation of a benign from malignant tumor are applicable to the myxoid variant.
d. Ectopic adrenal cortical adenoma has been reported in the kidney and within the spinal canal (Mod Pathol. 2009;22:175; Brain Tumor Pathol.
2010;27:121). Ectopic adrenal rest or “tumor” has been described in congenital adrenal hyperplasia in the testis (Eur J Endocrinol. 2008;159:489).
e. Sarcomatoid carcinoma, like similar high-grade neoplasms in the lung and kidney, has a pleomorphic spindle cell pattern in addition to focal areas of recognizable but poorly differentiated ACC (Pathol Res Pract. 2010;206;59).
f. Adrenal blastoma has been reported in a single case (Hum Pathol. 1992;23:1187). This tumor had a biphasic epithelial and mesenchymal pattern.
3. Adrenal cortical carcinoma (ACC) is a rare neoplasm with an incidence of about one per million in the United States. This tumor can occur in any age, but it appears to have a bimodal age distribution with one peak in children <5 years old and another peak in adults in the fourth or fifth decade of life. However, many of the cases of putative ACC in children, especially those diagnosed early in the first decade of life, do not behave clinically as their adult counterparts although the microscopic features associated with ACC in adults are present (discussed later). ACC is a manifestation of several hereditary syndromes including Li-Fraumeni syndrome (TP53), Beckwith-Wiedemann syndrome (CDKN1C/NSD1), MEN1 (MEN1), and Gardner’s syndrome (APC) (J Clin Pathol. 2008;61:787; Adv Anat Pathol. 2011;18:206); together hereditary cases represent 5% or less of all ACCs. ACC presents as a functioning neoplasm in 50% to 60% of cases, with Cushing syndrome as the most common presentation (Nat Rev Endocrinol. 2011;7:323). Approximately 40% to 45% of ACCs are confined to the adrenal and are completely resectable; only 5% to 10% of tumors are ≤5 cm (T1) whereas 35% to 40% are >5 cm (T2); over 50% of cases have infiltrated beyond the adrenal (T3) or have already metastasized at presentation in 30% to 35% of cases (T4) (Best Pract Res Clin Endocrinol Metab. 2009;23:273). The AJCC Staging scheme for adrenal neoplasms is presented in Table 26.2.
Grossly, hemorrhage and necrosis often provide the background for a soft yellowish to tan neoplasm with or without cystic areas (e-Fig. 26.11). However, ACC can have a variety of gross features in terms of coloration and presence or absence of apparent necrosis. Those ACCs <5 cm tend to have a more uniform gross appearance as do adenomas; these are the cases which may prove to be problematic in the differential diagnosis between an ACC and adenoma, a point that is especially pertinent as it relates to adrenocortical neoplasms in children (Pediatr Dev Pathol. 2009;12:284). Any number of individual microscopic features have been evaluated in primary adrenocortical neoplasms in adults for discrimination between an adenoma and carcinoma. The modified Weiss system requires a score of 3 or more to predict malignant behavior (of the following five microscopic features): mitotic rate (>5 per 50 hpf), cytoplasm (dense eosinophilic cytoplasm in 75% or more of tumor cells since a predominant clear cell pattern is a feature of adenomas); atypical or bizarre mitotic figures; necrosis; and capsular invasion (e-Fig. 26.12A-D) (Hum Pathol. 2009;40:757). Once an adrenal cortical neoplasm has invaded into adjacent soft tissues or organs, invaded a major vessel, or metastasized to regional lymph nodes or remote site(s), the diagnosis of ACC is beyond dispute.
Immunohistochemistry to corroborate that a primary neoplasm is cortical in nature is infrequently necessary, with the uncommon exception of a dilemma between a cortical and medullary neoplasm (which is generally obvious in most cases). Another example is metastatic renal cell carcinoma to the adrenal which can mimic a primary cortical neoplasm. A more
frequent diagnostic challenge is presented by a needle biopsy of a retroperitoneal mass in which the microscopic features consist of dense cords and nests of eosinophilic, epithelioid appearing cells that raise the differential diagnosis of a hepatic, adrenal, or renal neoplasm, as well as perivascular epithelioid cell tumor (PEComa), angiomyolipoma (AML), epithelioid smooth muscle neoplasm, epithelioid mesothelioma, and epithelioid gastrointestinal stromal tumor (Table 26.3). Most adrenal cortical neoplasms are vimentin (70% to 80% of cases), inhibin (85% to 90%), melan-A (85% to 90%), adrenal cortical antigen SF-1 (85% to 90%), and calretinin (85% to 90%) immunopositive (Am J Surg Pathol. 2011;35:678). There is an overlap of the immunophenotype with ovarian and testicular sex-cord stromal neoplasms, which should come as no surprise since these tumors have similar developmental and functional attributes (Semin Diagn Pathol. 2005;22:3; Semin Diagn Pathol. 2005;22:33).
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